WO2011008202A1 - Piégeurs disokétal et réduction des troubles impliquant une lésion oxydative - Google Patents
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- WO2011008202A1 WO2011008202A1 PCT/US2009/050644 US2009050644W WO2011008202A1 WO 2011008202 A1 WO2011008202 A1 WO 2011008202A1 US 2009050644 W US2009050644 W US 2009050644W WO 2011008202 A1 WO2011008202 A1 WO 2011008202A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
Definitions
- the present invention relates generally to the field of treating neurodegenerative and cardiovascular diseases, and more specifically to the field of controlling isoketals and neuroketals.
- the present inventors have discovered a substantial body of evidence for the occurrence of overproduction of free radicals, i.e. oxidative injury or oxidative stress, has been implicated is an increasing number and variety of human diseases. These include neurodegenerative diseases, e.g.
- IsoPs and NeuroPs are prostaglandin-like compounds produced by free radical induced peroxidation of arachidonic acid (AA) and docosahexaenoic acid (DHA), respectively.
- Isoketals (IsoKs) and neuroketals (NeuroKs) are highly reactive ⁇ -ketoaldehydes produced by the IsoP and NeuroP pathways, respectively. IsoKs and NeuroKs rapidly adduct to lysyl residues of proteins and also Exhibit A unique and remarkable proclivity to crosslink proteins.
- the present invention encompasses discoveries from studies both in brains from patients with Alzheimer's disease (AD) and an animal model of age-related dementia relevant to AD, ApoE null mice overexpressing human ApoE4.
- an aspect of the present invention is identification of proteins adducted by IsoKs and NeuroKs in brains from patients with AD and the mouse model of AD dementia. Furthermore, the present invention demonstrates the relationship between onset of behavioral abnormalities and the occurrence of oxidative stress and IsoK/NeuroK adduct formation in the mouse model. Thus, the ability of selected antioxidants to suppress oxidative injury and IsoK/NeuroK adduct formation and improve behavioral abnormalities in these mice is determined.
- Another aspect of the present invention is a novel pharmacologic intervention with IsoK scavengers such as pyridoxamine (PM) and salicylamine (SA), for example, that
- Oxidative stress plays a fundamental role in the pathogenesis of such diseases, which leads to the formation of IsoKs and NeuroKs that adduct to and alter the function of critical cellular proteins. This in turn also impairs proteasomal degradation of adducted proteins and inhibits proteasome function, causing neuronal dysfunction and death resulting in dementia.
- F 2 -isoprostane F 2 -IS0P
- F/t-neuroprostane F 4 - NeuroP
- isoketal IsoK
- neuroketal NeuroK
- 4-hydroxynonenal HNE
- AD Alzheimer's disease
- AA arachidonic acid
- DHA docosahexaenoic acid
- APP amyloid precursor protein
- a ⁇ paired helical filament
- PHF neurofibrillary tangles
- PM pyridoxamine
- SA salicylamine
- ApoE apo lipoprotein E
- VaD dementia with Lewy bodies
- DLB multisystem atrophy
- MSA transgenic
- Tg homocysteine
- HCys liquid chromatography
- ESI electrospray ionization
- MS collisional induced dissociation
- Isoketals are the most reactive products of lipid peroxidation heretofore identified. IsoKs adduct almost instantaneously to protein lysine residues and readily induce protein-protein cross-links. In spite of the remarkable reactivity of IsoKs, the present inventors have identified compounds that effectively intercept (scavenge) IsoKs from adducting to proteins.
- the IsoK scavengers of the present invention are compounds of the present invention, such as salicylamine (SA), for example, and analogs thereof. The compounds of the present invention prevent cell death in cells exposed to a lethal concentration of a general oxidant - hydrogen peroxide.
- SA salicylamine
- IsoKs are a major mediator of oxidant induced cell injury/death.
- IsoK scavengers of the present invention have beneficial effects in a wide variety of diseases associated with oxidative injury.
- Age-related dementias are a major and costly public health problem.
- the most prominent cause of dementia in the elderly is Alzheimer's disease (AD), but others include vascular dementia (VaD), dementia with Lewy bodies (DLB), and multisystem atrophy (MSA).
- AD Alzheimer's disease
- VaD vascular dementia
- DLB dementia with Lewy bodies
- MSA multisystem atrophy
- AD Alzheimer's disease
- a considerable body of evidence has been obtained that supports a potential role for oxidative injury in the pathogenesis of AD.
- levels of biomarkers of oxidant injury are increased in the brain and CSF from patients with AD.
- risk factors for AD induce an oxidant stress.
- elevated levels of homocysteine has been identified as an important risk factor for AD and inheritance of the ⁇ 4 allele of ApoE has been identified as a risk factor for both sporadic AD and DLB. Both of these risk factors, as well as well as elevated levels of A ⁇ i_ 42 , have been implicated in promoting oxidative stress.
- Lipids are a major target of free radical attack, which leads to lipid peroxidation. A variety of products of lipid peroxidation are formed.
- the present inventors have focused on the characterization of isoprostanes (IsoPs).
- IsoPs are prostaglandin-like compounds that are formed non-enzymatically in vivo by free radical-induced peroxidation of arachidonic acid (AA) (C20:4 ⁇ 6).
- AA arachidonic acid
- the first class of IsoPs discovered had a prostaglandin F-type cyclopentane ring structure (F2-IsoPs).
- IsoPs Intermediate in the formation of IsoPs are labile bicyclic PGtt-like endoperoxides (H 2 -ISoPs), which are reduced to form F 2 -IsoPs.
- H 2 -ISoPs labile bicyclic PGtt-like endoperoxides
- the present inventors have found that thiols catalyze this reduction both in vitro and in vivo. However, this reduction is not entirely efficient, allowing rearrangement of H 2 -ISoPs in vivo to form firing and D-ring IsoPs and also isothromboxanes.
- IsoP-like compounds are formed from oxidation of docosahexaenoic acid (DHA) (C22:6 ⁇ 3).
- DHA docosahexaenoic acid
- NeuroPs neuroprostanes
- the present inventors have also found that levels of F 4 -NeuroPs are increased approximately two-fold in the hippocampus, superior and medial temporal gyri, and inferior parietal lobe of AD brain compared to aged-matched controls. Importantly, however, no significant differences were found in the cerebellum, an area of the brain that is unaffected by AD pathology.
- Lipid peroxidation also generates a number of reactive aldehydes, including 4-hydroxy-2- nonenal (FTNE), malondialdehyde (MDA), and acrolein.
- FTNE 4-hydroxy-2- nonenal
- MDA malondialdehyde
- acrolein 2-hydroxy-2- nonenal
- Interest in these aldehydes derives from the fact that they are reactive molecules that adduct and covalently modify proteins and DNA. Levels of these aldehydes have also been found to be increased in AD.
- the present inventors discovered a series of ⁇ -ketoaldehydes that are orders of magnitude more reactive than any other known product of lipid peroxidation. Moreover, these compounds exhibit a unique proclivity to crosslink proteins to an extent that is not shared by these other aldehydes.
- Reversible Schiff base adducts were also identified. Schiff base adducts are formed rapidly and then decline over time, whereas lactam adducts accumulate slowly over time. Lysyl protein adducts of IsoKs and NeuroKs are analyzed by LC/MS/MS following enzymatic digestion of proteins to individual amino acids. Enzymatic digestion of proteins is necessary because the adducts degrade during acid hydrolysis. However, this analysis is further complicated by the proclivity of IsoKs and NKs to induce protein crosslinking, which is resistant to hydrolysis. This is demonstrated following incubation of ovalbumin (OVA) with 10 molar equivalents of IsoK for about 4 hours.
- OVA ovalbumin
- IsoKs/NeuroKs are the most attractive products of lipid peroxidation heretofore identified as candidates that may be responsible for neuronal injury and protein aggregation in AD and other dementias associated with oxidative stress.
- the extent to which H2-IS0PS undergo rearrangement depends on cellular efficiency to reduce them. Therefore, the amounts of IsoKs and NeuroKs formed depends not only on the amount of H 2 -IsoPs formed but also cellular reduction conditions. This is an important consideration when choosing therapeutic interventions to suppress the formation of IsoKs and NeuroKs.
- thiol antioxidants would not only suppress the amount of H 2 -IsoPs/H 2 -NeuroPs formed but also effectively reduce them to F2-IsoPs/F4-NeuroPs, thereby preventing their rearrangement to IsoKs/NeuroKs. Therefore, thiol antioxidants would likely be more effective than non-thiol containing antioxidants in reducing the formation of IsoKs/NeuroKs.
- an aspect of the present invention is a method of suppressing the formation of
- IsoKs/NeuroKs by administering an effective amount of thiol antioxidants.
- IsoKs and NeuroKs are believed to participate in the oxidative neuronal injury that occurs in these and other neurodegenerative diseases.
- Risk factors for AD include increasing age, inheritance of genetic mutations that increase levels of A ⁇ 1-42, inheritance of the ApoE4 allele, vitamin deficiencies that increase levels of
- a ⁇ i_ 42 is toxic to cultured neuronal cells, but the mechanism for this toxicity is still somewhat controversial.
- One potential mechanism is the production of free radicals, since incubating amyloid peptide with neuronal membranes has been shown to induce lipid peroxidation.
- soluble A ⁇ i_42 rather than A ⁇ i_42 in deposits is probably more capable of inducing lipid oxidation.
- Folate, vitamin B6, and vitamin B 12 are important cofactors in the homocysteine/methionine conversion cycle. Therefore, deficiencies in these vitamins increase homocysteine levels.
- Folate, vitamin B 6 , vitamin Bi 2 deficiencies and hyperhomocysteinemia have been reported to be risk factors for AD. In certain at risk populations, from 10 to 30% of elderly persons may be folate or vitamin Bi 2 deficient.
- a number of studies link hyperhomocysteinemia to increased lipid peroxidation. The present inventors have recently shown that even small increases in homocysteine levels in normal humans are positively and significantly correlated with plasma concentrations of F 2 -IsoPs. This finding has since been confirmed independently by Davi et al.
- vitamin B6 deficiency itself has been found to be an independent risk factor for AD. This suggests that vitamin B6 may play an additional role in limiting oxidative damage.
- Inheritance of the ⁇ 4 allele of ApoE is associated with poorer cognitive performance with age and is currently the only known genetic risk factor for sporadic AD. Inheritance of ApoE4 may also be a genetic risk factor for (DLB). Homozygosity for ⁇ 4 is associated with increased oxidative damage in hippocampal pyramidal cells. In the brain, ApoE protein is produced by astrocytes and microglial cells and then secreted as part of lipoprotein particles. ApoE lipoprotein is recognized and internalized by the LDL receptor-related protein (LRP), which in brain is primarily expressed on neuronal cells, including hippocampal pyramidal neurons. ApoE has been identified
- ApoE3 lipoproteins induce neurite outgrowth in primary neuronal cultures, whereas ApoE4 lipoproteins do not, a process that requires recognition by LRP. For this reason, ApoE3 appears to enhance the ability of neurons to recover from injury. In keeping with this hypothesis, inheritance of ApoE4 increases risk of neurological deficits following head injury.
- ApoE4 mice have been generated by placing the transgene under the control of different promoters, including human glial fibrillary acidic protein (gfap- ApoE4), human apoE (apoe-ApoE4), neuron-specific enolase (nse-ApoE4), mouse Thyl (thy-ApoE4), or the human PDGF- ⁇ gene (pdgf-ApoE4).
- gfap- ApoE4 human glial fibrillary acidic protein
- apoe apoE
- nse-ApoE4 neuron-specific enolase
- mouse Thyl thy-ApoE4
- pdgf-ApoE4 human PDGF- ⁇ gene
- ApoE4 mice have some forms of neurological deficit with individual variations in their effects on neurodegeneration and protein aggregation. Because gfap-ApoE4 mice produce ApoE4 in astrocytes, the major source of ApoE production, the present inventors have chosen these mice to study the effects of ApoE4 on lipid peroxidation, protease function, and neurodegeneration.
- Aggregated ubiquinated proteins is a prevailing feature of many neurodegenerative diseases and dementias. In AD, these take the form of senile plaques and neurofibrillary tangles. In DLB, these aggregates primarily consist of ⁇ -synuclein. The cause of protein aggregation is not well understood, but the presence of ubiquitinated proteins suggests a defect in the ubiquitin/proteasome pathway.
- Proteins can be degraded by the proteasome via 2 independent pathways, both of which are relevant to oxidized proteins and proteins modified by products of lipid peroxidation.
- the most common pathway is tagging proteins with ubiquitin by specific E2 and E3 ubiquitinating enzymes.
- the criteria for recognition and tagging of proteins by E2/E3 is a matter of intense investigation, but remains unknown for many proteins.
- Only multi-ubiquinated proteins are recognized and degraded by the 26S proteasome.
- the 26S proteasome consists of two major complexes, the 2OS proteasome and either 1 IS or 19S regulatory subunits. The regulatory subunits recognize and unfold ubiquinated proteins, allowing them to enter into the catalytic core of the 2OS proteasome.
- the 2OS proteasome is composed of 7 alpha and 7 beta subunits and has three major protease activities: chymotrypsin-like activity, trypsin-like activity, and post-glutamyl peptidase activity. While the 26S proteasome degrades the majority of proteins, the 2OS proteasome can function independently to degrade oxidized and denatured proteins. Proteasome inhibitors such as lactacystin and various peptide-aldehydes act by reacting with the catalytic subunits of the 2OS proteasome, and thereby inhibit both 2OS and 26S proteasome activity.
- IDE insulin degrading enzyme
- NFT Neurofibrillary tangles
- PHF -tau is phosphorylated at several well-characterized sites.
- tau promotes microtubule assembly, stabilizes cellular microtubules, affects their dynamic behavior, and may play an important role in regulating microtubule interactions with membranes.
- microtubules include axonal and dendritic growth and support of sympatic activity.
- Ultrastructural analysis of cortical neurons suggest abnormalities of the cytoskeleton in AD. The underlying cause of this disruption is unknown, but products of lipid peroxidation, e.g. HNE, have been hypothesized to play a role.
- Incubation of mouse neuroblastoma Neuro2A cells with HNE results in disruption of microtubule organization and inhibition of neurite outgrowth.
- HNE adducts were found on both tubulin and tau protein. Since one of the major functions of tau protein is to organize tubulin filaments, these experiments suggest that adduction of these proteins is responsible for microtubule disruption.
- Impairments in cholinergic neurotransmitter systems of the basal forebrain are a hallmark of Alzheimer's disease pathophysiology.
- the deficit in acetylcholine synthesis results from reduction in choline acetyltransferase activity.
- Reduction of acetyltranferase activity is greater than the loss of cholinergic neurons. Therefore, neuronal death may be a result of, not the cause of, the reduction in acetytransferase activity.
- exposure of neuronal cells in culture to HNE or subjecting them to an oxidative stress has been shown to decrease choline acetyltransferase activity.
- NGF Nerve Growth Factor
- trkA mRNAs are decreased in AD, loss of NGF binding appears to precede the loss of TrkA immunoreactivity and neuronal loss, suggesting that at least some of the loss of receptor function is due to receptor modification. Exposure of neuronal cultures to hydrogen peroxide or A ⁇ i-42 reduces the level of trkA protein, suggesting that oxidative injury may play a role in receptor loss.
- aspects of the present invention include the determination that these proteins in AD brain and brain from an animal model of a risk factor for AD are adducted by IsoKs and/or NeuroKs.
- a first aspect of the present invention is to provide a method for assessing the formation of
- IsoK and NeuroK adducts quantitatively and qualitatively in AD brain are quantitatively and qualitatively in AD brain.
- a second aspect of the present invention is a method to assess potential causative factors involved in age-related dementia. This may include the use of ApoE null mice transgenically expressing human ApoE4 by evaluating the brain levels of F 2 -IsoPs, F 4 -NeuroPs, and levels and distribution of
- a third embodiment of the present invention is a method to determine the role of oxidative stress/injury in general and specifically the role of IsoK/NeuroK adduct formation by using
- pharmacologic interventions that include effective amounts of at least one of antioxidants, Tempol, and lipoic acid.
- a fourth aspect of the present invention is a method of identifying the proteins adducted by
- IsoKs and NeuroKs in the hippocampus of brains from patients with AD and in ApoE4 Tg mice fed a normal or folate deficient/homocysteine enriched diet may include determining whether there is enhanced adduction of the following proteins by IsoKs and NeuroKs: tau, tubulin, proteasome subunits, insulin degrading enzyme, acetylcholine acyltransferase, ApoE, and neuronal growth factor receptors.
- One embodiment of the present invention is a method of treating and/or preventing oxidative damage that comprises administering an effective IsoK/NeuroK adduct formation suppressing amount of a phenolic amine compound and/or a pyridoxamine compound.
- Another embodiment of the present invention is a method of preventing myocardial damage that comprises administering a damage preventing effective amount of phenolic amine compound or a pyridoxamine analog or salicylamine analog.
- Another embodiment of the present is a method of preventing cardiac sodium channel dysfunction, inactivation, and/or blocking that comprises administering an effective amount of a phenolic amine compound and/or a pyridoxamine analog or salicylamine analog.
- Another embodiment of the present invention is a method of preventing or treating ventricular fibrillation and/or arrhythmias that comprises administering an effective amount of a phenolic amine compound and/or a pyridoxamine analog or salicylamine analog.
- Yet another embodiment of the present invention is a method of preventing or retarding the progression of neurodegenerative disease that comprises administering an effective oxidative stress preventing or decreasing amount of a phenolic amine compound and/or a pyridoxamine or salicylamine compound.
- the neurodegenerative disease of this or other embodiments may include, but is not limited to, Parkinson's disease, Alzheimer's disease, Huntington's disease and/or dementia.
- Another embodiment of the present invention is a method of preventing or retarding the progression of oxidative stress associated with vascular dementia or stroke, comprising administering an effective oxidative stress preventing or decreasing amount of a phenolic amine compound and/or a pyridoxamine or salicylamine compound.
- Any of these embodiments may include the use of a pyridoxamine, salicylamine, tyrosine compound or an analog thereof.
- Examples of these compounds or analogs include, but are not limited to, compounds selected from the formula:
- R is N or C
- R2 is independently H, substituted or unsubstituted alkyl
- R3 is H, halogen, alkoxy, hydroxy 1, nitro;
- R4 is H, substituted or unsubstituted alkyl, carboxyl; or analogs thereof.
- Figure 1 is a scheme showing compounds formed as rearrangement products of H 2 -IsoP and
- Figure 2 is a graph showing the time course of disappearance of free IsoK and FINE.
- Figure 3 is a scheme showing that IsoKs adduct to lysines.
- Figure 4 is a Western blot showing the proclivity of IsoKs and NKs to induce protein crosslinking.
- Figures 5-11 are graphs showing data in connection with the present invention.
- Figure 12 is a series of color photographs showing staining of hippocample pyramidal neurons.
- Figures 13-15 are graphs showing data in connection with the present invention.
- Figure 16 is a color photograph showing immunohistochemistry of IsoK adducts in the cerebral cortex of tested mice.
- Figures 17-27 are graphs showing data in connection with the present invention.
- Figure 28 is a scheme showing formation of IsoK and F 2 -IS0P.
- Figures 29-32 are graphs showing data in connection with the present invention.
- Figure 33 shows Alz50 immunoactivity.
- Figure 34 shows mass spectrometry results.
- Figure 36 is a color photograph showing precipitated HRP.
- Figures 37-40 are graphs showing data in connection with the present invention.
- Figure 41 is a series of color photographs showing F2-IS0PS esterified in heart samples.
- Figure 42 is a graph showing that IskK adducts are increased in infarcted area of dogs.
- Figure 43 is a graph showing improved systolic function with treatment with SA, and shoes
- SA treatment reduced infarct size of hearts harvested after coronary ligation.
- Figure 44 shows location of IsoK adducts in AD brains.
- Figure 45 is a pair of graphs showing development and memory in transgenic animals treated with an embodiment of the present invention.
- Figure 46 shows characterization of the potency and selectivity of pyridoxamine derivatives for scavenging gamma ketoaldehydes.
- Figure 47 is a graph that shows benefits of SA pretreatment.
- Figure 48 shows a 6-arm water radial maze.
- Figure 49 is a graph showing combined diets and Z score latency.
- an embodiment of the present invention is to provide a method of treating and/or preventing oxidative damage, comprising administering an effective IsoK/NeuroK adduct formation suppressing amount of a phenolic amine compound of the present invention.
- that compounds is a salicylamine compound or an analog thereof.
- Another embodiment of the present invention is a method of preventing myocardial damage, comprising administering a damage preventing effective amount of phenolic amine compound of the present invention.
- Another embodiment of the present invention is a method of preventing cardiac sodium channel dysfunction, inactivation, and/or blocking , comprising administering an effective amount of a compound of the present invention.
- Another embodiment of the present invention is a method of preventing or treating ventricular fibrillation and/or arrhythmias, comprising a compound of the present invention.
- Another embodiment of the present invention is a method of preventing or retarding the progression of neurodegenerative disease, comprising administering an effective oxidative damage preventing or decreasing amount of a compound of the present invention.
- the neurodegenerative may be chosen from, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, dementia.
- Another embodiment of the present invention is a method of preventing or retarding the progression of oxidative damage associated with vascular dementia or stroke, comprising administering an effective oxidative damage preventing or decreasing amount of a compounds of the present invention.
- Another embodiment is to provide a method for accessing the formation of IsoK and NeuroK adducts quantitatively and qualitatively in AD brain.
- This embodiment can comprise determining whether levels of IsoK and NeuroK protein adducts are increased in CSF from patients with AD compared to age-matched controls. This method may be used to obtain a single chain antibody against
- NeuroK lysyl adducts and/or determine the localization of IsoK and NeuroK adducts in AD brain and other age-related dementias.
- therapeutically effective amount refers to that amount of a compound of the present invention that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment.
- the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
- treatment means any treatment of a disease in a mammal, including:
- FIG. 5 shows CSF F 2 -IsoP concentrations in 41 living patients with probable AD and 35 aged matched controls. The average time since diagnosis for the AD patients was less than two years. CSF F 2 -IsoP concentrations were approximately 38% higher in probable AD patients compared to aged-matched controls (p ⁇ 0.001).
- the present inventors examined AD brain by region, and found that F 4 -NeuroPs were elevated about two-fold in the hippocampus (Hippo), superior and medial temporal gyrus (SMTG), and inferior parietal lobe (IPL) of AD brain (solid bars) compared to the same regions of brain from aged-matched controls (hatched bars). Importantly, however, no significant differences were found in the cerebellum (CBL), an area of brain unaffected by AD pathology (Figure 7). When F 2 -IsoPs were measured in these regions, all three affected regions were increased, although only IPL reached statistical significance (not shown). Measurement of F 4 -NeuroPs provides a more sensitive indicator of oxidative injury in the brain than measurement of F 2 -IsoPs.
- Figure 8 shows that levels of NeuroK- lysyl-lactam protein adducts in the hippocampus from six AD patients were significantly increased compared to six aged- matched controls (p ⁇ 0.02). Again, and importantly, as was found with NeuroPs, no significant difference was found in the level of NeuroK adducts between AD brain and controls in an area of brain unaffected by AD pathology, the cerebellum.
- Antibodies are required to determine the location of adducts in AD brain.
- the present inventors obtained an antibody against IsoK lysyl adducts by pursuing a single chain antibody (ScFv) strategy, rather than the standard polyclonal antibody approach.
- ScFv single chain antibody
- extensive adduction of the immunizing protein which would also induce substantial cross-linking of the protein.
- Crosslinking would alter the protein's conformation and probably expose buried epitopes on the immunizing protein unrelated to the actual adducts. Therefore, antibodies generated by this method would not be specific to the IsoK adduct.
- screening of phage-displayed antibodies can be done with extremely short peptides, eliminating conformational changes.
- the present inventors examined the location of IsoK adducts in the hippocampus of AD brain by immunohistochemistry using DI l ScFv. Paraffin embedded sections were stained using DI l ScFv ( Figure 12). There is staining of hippocampal pyramidal neurons that are localized to the neuron soma and neuropil. The staining was specific for neurons in that staining of glial cells was not observed. The present inventors then examined hippocampal sections in aged-matched controls. Remarkably, we found no neuronal staining in the controls. We also examined cerebellum sections from AD brain and no staining was observed.
- Another aspect of the present invention is a method to assess potential causative factors involved in age-related dementia.
- This may include the use of ApoE null mice trans genically expressing human ApoE4 fed either a normal diet or a folate deficient/homocysteine enriched diet by evaluating at least one of performance on memory tests, brain levels of F 2 -IsoPs, F 4 -NeuroPs, and levels and distribution of IsoK and NeuroK adducts, activities of brain proteasome, calpain, and insulin degrading enzyme, brain levels of amyloid ⁇ i-40 and A ⁇ i_42, and the extent and localization of neurodegeneration.
- mice with the risk factor for AD are genetically altered mice with the risk factor for AD, ApoE4. These mice lack the mouse gene for ApoE and are hemizygous for the ⁇ 4 allele of human ApoE. Human ApoE is expressed in astrocytes in these mice under the control of the GFAP promoter. These ⁇ ApoE-/-, ApoE4+ ⁇ mice display significantly increased cerebral levels of F 2 -IsoPs at 12-16 months compared ⁇ ApoE-/-, ApoE3+ ⁇ mice, whose levels were not statistically different from wild type mice (Figure 13).
- mice with 2 risk factors for sporadic AD, advancing age and inheritance of ApoE4 have both increased oxidative damage and increased A ⁇ production.
- hyperhomocysteinemia is a strong risk factor for AD
- APPswe mice fed a folate deficient diet supplemented with homocysteine exhibited neurodegeneration in the hippocampus, which was not observed in APPswe mice fed a normal diet, and that homocysteine can promote oxidative stress.
- Pertinent to this is observations that plasma concentrations of F 2 -IsoPs are positively correlated with plasma concentrations of homocysteine over the quintile of homocysteine levels measured in normal adult human males (Figure 15). The coefficient for association was 0.40 (p ⁇ 0.001).
- An independent study by Davi et. al. also found a linear increase in urinary F 2 -IS0P levels with increasing plasma homocysteine levels in patients with hyperhomocysteinemia.
- antioxidants to suppress oxidative injury: An important aspect of antioxidant clinical trials that has not received sufficient attention until recently, is the scientific rational for the choice of a particular antioxidant to test, the dose to test, and the duration of treatment. Often times, when a clinical trial fails to show significant efficacy for an antioxidant, no effort has been made to ensure that the dose of the antioxidant tested effectively suppressed oxidant injury. The importance of having such information is highlighted by our studies defining the clinical pharmacology of vitamin E. First, the present inventors found that sixteen weeks of vitamin E supplementation was required to reach the plateau in maximum suppression of plasma concentrations of F 2 -IS0PS in subjects with hyperocholesterolemia (Figure 23).
- the present inventors chose antioxidants to test in the models of AD that we have found effective in suppressing oxidative stress in other animal models of oxidative injury.
- One model of oxidative injury is the porcine model of global ischemia/reperfusion resulting from induction of cardiac arrest for 3 mins followed by cardiopulmonary resuscitation (CPR). Shown in Figure 25 are results using this model. As shown, cardiac arrest followed by CPR induced a dramatic increase in plasma concentrations of F 2 -IsoPs. Intravenous injection of 30 mg/kg of Tempol, a superoxide dismutase mimetic, during CPR prior to defibrillation and reperfusion completely ablated this increase in plasma levels Of F 2 -ISoPs.
- Another antioxidant of the present invention is lipoic acid.
- This antioxidant has been shown to be effective in improving cognitive impairment in aged SAMP mice that have been found to have increased levels of A ⁇ .
- the inventors have found it to be highly effective in suppressing the increase in formation of F 2 -IsoPs in the kidney of a model of human hepatorenal syndrome, galactosamine treated rats (Figure 27).
- Treatment of rats with galactosamine was associated with a significant increase in levels of F 2 -IsoPs esterified in the kidney which was completely suppressed to below control levels in rats treated with lipoic acid (1 g/L drinking water).
- Dihydrolipoic acid is a dithiol. As mentioned previously, thiols reduce the endoperoxide intermediates in the IsoP pathway in vivo to F 2 -IsoPs.
- mechanistically lipoic acid is an antioxidant to test in animal models of AD. It is also an antioxidant to test because it is available over the counter for human use.
- Another embodiment of the present invention is the use of pyridoxamine and/or pyridoxamine analogs to prevent IsoK/NeuroK from adducting to proteins. This is a novel approach to mitigate the deleterious effects of adduction of IsoKs/NeuroKs to proteins.
- pyridoxamine and/or an analog thereof prevents the adduction of these reactive products of lipid peroxidation selectively by acting as a surrogate amine for adduction rather than acting as an antioxidant to suppress the formation of IsoKs/NeuroKs.
- Pyridoxamine has been shown to prevent the formation of advanced glycation endproducts (AGE) in diabetes by trapping reactive carbonyl intermediates in the formation of AGEs. It is in Phase II trials in patients with diabetes where high plasma concentrations are achieved with this drug and no toxicity has been observed.
- AGE advanced glycation endproducts
- the rate constants are as follows: N ⁇ acetyllysine (70 x 10 6 IVrV 1 ), 2-aminoethanol (310 x 10 6 IVrV 1 ), 4-picolinylamine (1,100 x 10 6 IVr 1 S “ l ), and pyridoxamine (53,200 x 10 6 M 1 S 1 ).
- 4-Picolinylamine has the structure of pyridoxamine without the CH2OH, OH, and CH3 phenyl ring substituents.
- Embodiments of the IsoK scavengers/compounds of the present invention have excellent oral pharmacokinetics, are non-toxic, and passes the blood-brain barrier.
- any of these embodiments may include the use of a pyridoxamine, salicylamine, tyrosine compound or an analog thereof.
- examples of these compounds or analogs include, but are not limited to, compounds selected from the formula:
- R is N or C
- R2 is independently H, substituted or unsubstituted alkyl
- R3 is H, halogen, alkoxy, hydroxyl, nitro;
- R 4 is H, substituted or unsubstituted alkyl, carboxyl; or analogs thereof.
- alkyl group includes a straight or branched saturated aliphatic hydrocarbon chain having from 1 to 8 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl (1 -methyl ethyl), butyl, tert-butyl (1,1-dimethylethyl), and the like.
- the alkyl groups may optionally be interrupted in the chain by a heteroatom, such as, for example, a nitrogen or oxygen atom, forming an alkylaminoalkyl or alkoxyalkyl group, for example, methylaminoethyl or methoxymethyl, and the like.
- alkoxy group includes an alkyl group as defined above joined to an oxygen atom having preferably from 1 to 4 carbon atoms in a straight or branched chain, such as, for example, methoxy, ethoxy, propoxy, isopropoxy (1-methylethoxy), butoxy, tert-butoxy (1,1-dimethylethoxy), and the like.
- the compounds may also be chosen from:
- pyridoxamine for the purposes of the present invention, the terms pyridoxamine, pyridoxamine compounds, and pyridoxamine analogs can be considered to have alike meaning in terms of, for example, their presence in compositions, dosages, etc.
- the compounds of the present invention can be administered as the sole active pharmaceutical agent, or can be used in combination with one or more other agents useful for treating or preventing various complications, such as, for example, AD and other neurodegenerative diseases.
- the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
- the compounds of the present invention may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions). They may be applied in a variety of solutions and may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
- the compounds of the present invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration.
- adjuvants appropriate for the indicated route of administration.
- they may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
- the carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
- the compounds of the present invention may be administered to a mammalian patient in an amount sufficient to reduce or inhibit the desired indication. Amounts effective for this use depend on factors including, but not limited to, the route of administration, the stage and severity of the indication, the general state of health of the mammal, and the judgment of the prescribing physician.
- the compounds of the present invention are safe and effective over a wide dosage range. However, it will be understood that the amounts of pyridoxamine actually administered will be determined by a physician, in the light of the above relevant circumstances.
- Pyridoxamine may be administered by any suitable route, including orally, parentally, by inhalation or rectally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles, including liposomes.
- parenteral as used herein includes, subcutaneous, intravenous, intraarterial, intramuscular, intrastemal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques, intracavity, or intraperitoneally.
- pyridoxamine is administered orally or parentally.
- Pharmaceutically acceptable acid addition salts of the compounds suitable for use in methods of the invention include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
- nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like
- nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,
- Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
- salts of amino acids such as arginate and the like and gluconate, galacturonate, n-methyl glutamine, etc. (see, e.g., Berge et al., J. Pharmaceutical Science, 66: 1-19 (1977).
- the acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
- the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
- the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
- An embodiment of the present invention is a method of selecting proteins that are thought to be important in modulating the progression of AD are adducted by IsoKs and NeuroKs.
- One method of the present invention to examine specific proteins to use as anti-IsoK and anti- NeuroK lysyl adduct antibodies to perform sandwich ELISA In an example of this method, an antibody to a target protein is used to coat the plate, the sample is then added, and presence of IsoK adduct is detected with DI l ScFv (or anti-NeuroK ScFv) and anti-E HRP. To test the feasibility of this approach, the present inventors adducted commercially available recombinant tau (Sigma) with synthetic IsoK. Sandwich ELISA using a commercially available anti-tau antibody (Zymed) is them performed.
- ESI electrospray ionization
- CID collisionally- induced disassociation
- the m/z 497 ion is formed by the additional loss of the ⁇ -amino group (17 a.m.u.) from 514. Fragmentation at both peptide bonds A and B yields m/z 443. Fragmentation of the lysyl-lactam bond yields m/z 358, 332 and 84.
- Dosage unit forms of the pharmaceutical compositions of the present invention comprise, for example, between 25 mg and 1000 mg of pyridoxamine or salicylamine, or a pharmaceutically acceptable salt thereof.
- Such dosage unit forms can comprise, for example, 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of pyridoxamine or salicylamine, or a pharmaceutically acceptable salt thereof, or any range of such dosage unit forms.
- the dosage unit forms of the pharmaceutical compositions comprise between 50 mg and 500 mg of pyridoxamine or salicylamine, or a
- Such dosage unit forms can comprise, for example, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, or 500 mg of pyridoxamine or salicylamine, or a pharmaceutically acceptable salt thereof.
- the dosage unit form can be selected to accommodate the desired frequency of administration used to achieve a specified daily dosage of pyridoxamine or salicylamine, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
- the unit dosage form is prepared for once daily or twice daily administration to achieve a daily dosage of between 50 and 2000 mg, more preferably between 100 and 1000 milligrams.
- one aspect of the present invention is to assess the formation of IsoK and NeuroK adducts quantitatively and qualitatively in AD.
- [140] Part of this aspect is determining whether levels of IsoK/NeuroK protein adducts are increased in CSF from patients with probable AD compared to age-matched controls. Levels of NeuroK adducts are increased, as measured by LC/MS/MS, and that IsoK adducts detected by IHC are clearly increased and localize to neurons and neuropil in the brains of patients who died of AD.
- the present inventors have determined that IsoK and NeuroK adducts are increased late in the disease, but whether they are present early on in the course of the disease cannot be determined using post-mortem brain specimens. However, analysis of CSF from living patients may provide an opportunity to do that.
- the present inventors determine whether we can detect IsoK and/or NeuroK adducts by LC/MS/MS in postmortem ventricular CSF from patients who died from AD. This may be done first because we can obtain up to approximately 30 mis of postmortem ventricular CSF whereas only approximately 1 ml of CSF is available from living patients with AD. Ventricular and lumbar CSF samples are provided.
- CSF may also contain IsoK/NeuroK adducted peptides, which will not precipitate with ethanol. Therefore, one may analyze also for adducts in CSF eliminating the protein precipitation step.
- the proteolytic enzymes therefore may be added directly to CSF. There maybe endogenous inhibitors of proteolytic enzymes present in CSF in which case this approach would not be successful. This may be initially determined this by comparing the amount of lysyl IsoK adducts measured by LC/MS/MS from 1 mg of IsoK adducted OVA (ratio 5: 1 IsoK:OVA) digested in PBS with adducted OVA digested in CSF.
- protease inhibitors are present, first precipitate CSF with ethanol (to denature and inactivate any protease inhibitors) and analyzed for protein adducts. The supernatant may then be diluted in PBS and subjected to digestion and then analyzed for lysyl lactam adducts present on peptides.
- Another embodiment of the present invention is an antibody that may be used against NeuroK adducts.
- Another aspect of the present invention is the determination of the localization of IsoK and NeuroK Adducts in brain in AD and other age-related dementias. Neuronal degeneration also occurs in other areas of the temporal and parietal lobes, in particular the amygdala, locus caeruleus, and nucleus basalis of Maynert. These regions are examined and for comparison, other regions unaffected by the disease. For this analysis, IHC with the DI l ScFv is performed. Brain slices obtained from the various regions of brain are examined. There should be neuronal staining in all affected regions of the brain, and less or no staining in unaffected regions.
- An anti-NeuroK adduct antibody of the present invention can be used in these same analyses for NeuroK adducts.
- levels of F/t-NeuroPs are consistently increased in AD brain to a much greater extent than levels of F 2 -IS0PS, which is likely attributed to the fact that DHA is more easily oxidized than AA. Therefore, AD brain should exhibit even greater immunoreactivity for NeuroK adducts compared to that for IsoK adducts.
- IsoK and NeuroK adducts To compare the distribution of IsoK and NeuroK adducts in various age-related dementias, and with unrelated neurodegenerative diseases, post-mortem sections from the hippocampus, entorhinal cortex, temporal cortex, and frontal cortex of patients with DLB, VaD, MSA, ALS, and PD are analyzed by IHC for IsoK and NeuroK adducts as above. Samples are coded and analyzed.
- Another aspect of the present invention is the determination of the role of oxidative injury in ApoE4 transgenic mice fed either a normal diet or a folate deficient/homocysteine enriched diet.
- one aspect of the present invention is to determine the extent and localization of IsoK/NeuroK adduct formation in AD brain.
- these studies in humans do not easily allow determination of the time course of adduct formation in relationship to proteasome activity, behavioral abnormalities, and neurodegeneration during disease progression. Such studies can be best performed using transgenic mouse models.
- a mouse model may be used that combines established risk factors for dementia and AD, namely aging, presence of the ⁇ 4 allele of ApoE, overproduction of A ⁇ i_ 42 , and folate deficiency/hyperhomocysteinemia.
- risk factors interact synergistically to increase levels of F 2 -ISoPs, F/t-NeuroPs, and IsoK/NeuroK protein adducts.
- the ApoE4 Tg mice exhibit severe memory deficits, they do not show gross neuronal degeneration when fed a normal diet. Therefore, the effect of feeding these animals a folate deficient homocysteine enriched diet is studied to determine if this diet worsens cognitive defects and leads to neuronal degeneration.
- mice are fed standard chow diet until they reach 7 months of age. The diet is then changed to a defined amino acid diet supplemented with folate (normal) or the defined amino acid diet supplemented with 4.5 mg/kg D,L-homocysteine without added folate (homocysteine). These diets can be purchased from Dyets, Inc. The table below summarizes the study design and number of animals studied. At each of the time points listed, animals undergo behavioral testing and also are be sacrificed for measurements of IsoK/NeuroK adducts, F2-IS0PS, and F/t-NeuroPs.
- Biochemical measurements on animals in each group are performed. The times that mice are studied and sacrificed for biochemical determinations are chosen based the relationship between age and the occurrence of elevated levels of F 2 -IsoPs and memory deficit.
- mice are euthanized using carbon dioxide. For each set of mice, the brain is removed immediately, the hemispheres divided, and for four mice one of the hemispheres will be placed in formalin solution, while the remaining hemisphere is placed in liquid nitrogen. All of the remaining mice in the set have both hemispheres placed in liquid nitrogen and stored at -70° C until analysis.
- mice may be run individually on a commercially-available 8-arm radial maze (MED Associates, Georgia, VT) to assess short-term working memory. The maze is fully automated so that opening and closing of doors and food reinforcer delivery are controlled by a Windows-based computer running MED-PC software. Mice are introduced gradually to a food-restriction regimen that allows 2 hours free access to food per day, immediately following the daily session on the radial maze. Mice are not allowed to fall below 80% of their free-feeding weights. Typically on this restriction regimen mice lose weight initially, reach their free-feeding weights within a month, and then gradually gain weight over time.
- MED Associates 8-arm radial maze
- mice are required to retrieve one 20-mg food pellet from each of the eight arms before acquisition will begin.
- one food pellet will be available at the end of each arm of the maze.
- Mice are required to retrieve the pellet from each arm during each daily session, which will end with the retrieval of the eighth pellet or after 5 min., whichever comes first.
- Working memory errors are classified as re-visits to arms from which the reinforcer had already been retrieved.
- a criterion of one or zero errors per session for three consecutive sessions will be used to determine successful acquisition of maze-running behavior. Errors per session and sessions to criterion will be the primary dependent measures of interest.
- the Y-maze spontaneous alternation task is a test of spatial memory that is sensitive to other manipulations that are known to impair memory, such as blockade of NMDA or Ml muscarinic receptors, hippocampal lesions, or elevated AB levels. Mice are placed individually in the maze, and exploratory behavior will be recorded for five min. The number and pattern of arm choices are the dependent variables of interest.
- the radial maze and spontaneous alternation task are both choice tasks, in which sensorimotor requirements for correct and incorrect responses are identical.
- mice hemibrains are sufficient to detect a 30% difference in levels lipid peroxidation products. Therefore, in aspects of the present invention, 8 mice are randomly chosen, and 1 frozen hemibrain from these 8 mice is weighed, placed in 2.5 ml Folch solution containing butylated hydroxytoluene (BHT) and triphenylphosphine (TPP) and homgenized. The homogenate then has saline solution added to initiate separation of esterified IsoPs and NeuroPs (lower phase). The lower phase is analyzed for esterified F2-IsoPs and F/t-NeuroPs by GC/MS as described previously. The protein pellet at the interface of the Folch extraction is removed, further washed with EtOH and MeOH, and resuspended in PBS and subjected to complete enzymatic digestion using pronase and
- Assay of proteasome activity is performed as described previously. In one aspect, eight mice are randomly chosen and 1 frozen hemibrain from each mouse will by homogenized in 5 ml of buffer containing ATP and DTT and a 1 ml aliquot removed. The homogenate is then be centrifuged to remove cellular debris and proteasome activity is measured in the supernatant by hydrolysis of three fluorogenic substrates, z-LLVY-amc, boc-LRR-amc, and z-LLE- NA (Affiniti Research Products), which measure the chymotrypsin-like, trypsin-like, and peptidyl-glutamyl-hydrolyzing activities of the proteasome, respectively.
- Calpain can also hydrolyze LLVY-amc, therefore, a portion of each supernatant is treated with lactacystin or a calpastatin-derived peptide (American Peptide Company), which are selective proteasome and calpain inhibitors, respectively. Proteasome and calpain activities are calculated as difference between total LLVY-amc hydrolysis with and without their inhibitor. All activity will be normalized to amount of protein in the supernatant. [156] IDE activity is measured from homogenates as previously described by Qiu et al. Briefly, 125 I- amyloid beta (Amersham Pharmacia) is added to homogenate and after appropriate time precipitated with TCA and run on SDS-PAGE. Changes in the 4kD band are measured by densitometry.
- levels of synaptophysin in hemibrain homogenate by ELISA may be initially measured using a commercially available antibody (Accurate). If levels are
- the total number of neurons in the hippocampus are estimated using stereological techniques.
- an aspect of the present invention is methods of determining whether pharmacologic interventions suppress IsoK/NeuroK adduct levels and improve cognitive defects in ApoE4 tg mice.
- animals are fed a standard chow diet until they are 7 months old, after which they are either continued on a normal diet or switched to the folate
- mice undergo behavioral testing and sacrificed for analysis of F 2 -IS0PS, F/t-NeuroPs, IsoK and NeuroK adducts, protease activity, and neurodegeneration. Measurement of products of the IsoP and NeuroP pathways allows a determination of the ability of the different antioxidants to suppress oxidative injury in these animals. Doses and/or routes of administration, e.g. daily i.p. injections, may vary. This aspect of the invention suggests oxidative injury plays playing a pivotal role in causing the neurodegeneration.
- pyridoxamine is administered in the same dose that has been found effective in preventing and retinopathy and early renal disease in diabetic rats, 1 g/L of drinking water.
- the same parameters are evaluated as described above for the antioxidant studies. The outline of both studies is shown in the table below. The results from treating animals with antioxidants allows a determination of the role of oxidant injury in general in these processes and treatment with
- pyridoxamine will allow a determination of the specific role of reactive products of lipid peroxidation.
- PM to a more hydrophobic molecule enhances its ability to intercept IsoKs/NeuroKs in certain environments, including lipid environments.
- the amount of IsoK adduction to protein may be determined by the amount of radiolabel present in TCA precipitates of the adducted protein in the presence of the various PM analogs. If a PM analog has highly superior IsoK/NeuroK scavenging ability compared to PM, aspects of the present invention include examining the toxicity and effectiveness of these analogs in the ApoE4 Tg mice.
- Another aspect of the present invention is a method of identifying proteins adducted by IsoKs and NeuroKs in hippocampus of brains from patients with AD and in ApoE Tg mice fed either a normal or folate deficient/homocysteine enriched diet.
- IsoKs and NeuroKs tau, tubulin, proteasome subunits, insulin degrading enzyme, ApoE, choline acetyltransferase, and neuronal growth factor receptors.
- Antibodies may include: tau (Zymed), 2OS proteasome alpha and beta subunits (Affiniti Research Products), 19S regulator ATPase subunits rpt 1-6 (Affiniti), 19S regulator Non- ATPase subunits (Affiniti), ApoE (Biodesign Intenational), choline acetyltranferase (Abeam), p75NGFR (Abeam), trkA (Advanced Targeting Systems), and tubulin (Chemicon
- Proteins may include: tau protein (Sigma), proteasome subunits (Affinit), ApoE (Panvera, Madison, WI), and tubulin (Cytoskeleton).
- Target proteins are adducted using synthetic IsoK or NeuroK and the conditions for the sandwich ELISA optimized. Antibodies to the target protein are coated onto the 384-well plate, the plate blocked, and the adducted protein added. After washing, the Dl 1/AntiE-HRP is added and then after further washing detected with peroxidase substrate. To ensure that the sandwich ELISA conditions will detect small differences in adducted protein levels, a known amount of adducted protein may be spiked into some control brain samples.
- the ELISA can be initially performed on tissue samples without optimization, using the manufacturer's recommended dilutions to coat the plates. If necessary, synthetic peptides representing the immunogen for the appropriate antibody may be used for optimization of adducted immunogen binding. Adduct levels in these proteins are compared and analyzed from a minimum of 6 brains each from patients with AD and age-matched controls, 6 brains from wild type mice fed a normal diet and 6 brains from ApoE4 Tg mice fed a folate
- Proteins that are identified in the screening using ELISA that contain increased adducts may be further analyzed by LC/MS/MS.
- the protein may be immunoprecipitated using the appropriate antibody.
- a portion of the precipitate is digested with pronase and aminopeptidase and analyzed for IsoK or NeuroK lysyl lactam adducts by LC/MS/MS. Presence of lysyl IsoK and/or Neurok lactam adducts in the precipitate is partial confirmation. However, a more definitive confirmation may include identification of adducted peptides from a tryptic digest of isolated proteins.
- adducted protein To establish a potential profile of the adducted protein, take purified protein and adduct it with synthetic IsoK or NeuroK. The protein is then be subjected to digestion with trypsin and the fragments separated by HPLC. The fragments are then be analyzed by MS using the new highly sensitive LCQ instrument in the Vanderbilt Mass Spectrometry Core. The instrument is be set to MS/MS mode. In this mode, the instrument picks the five most abundant ions in each scan for fragmentation and analysis of product ions. The various scans are then analyzed using a SALSA algorithm program that scores each scan based on the primary and secondary characteristics of adducted peptides that we have established using the IsoK-adducted peptides in our preliminary studies.
- the information gained from this analysis may be used to analyze tryptic digests of immunoprecipitates from AD brain.
- One may look initially for the exact precursor ions that we found with purified proteins.
- the adduction in vitro may not fully mimic adduction that occurs in vivo because different lysine residues may be adducted. Therefore, one may also analyze trypsinized peptides by LC/MS/MS using the SALSA software to analyze LCQ scans as before.
- the high scoring scans may be manually examined to determine if they matched expected peptide sequences from the target protein. If these scans match predicted adduct sequence, the peptides may be synthesized.
- the peptide may be adducted with [ 13 Cs] IsoK, for use as an internal standard. Then, the levels in 6 AD brains and 6 aged-matched controls may be quantified and compared. Increased levels of these adducted peptides would be complete confirmation of increased adducted target protein in AD brain. Since the site of protein modification is known, this information allows prediction of the potential consequences of this adduct formation and would be the basis for studies to determine the effect of adduction on protein function.
- Cardiovascular Diseases As stated above, another aspect of the present invention relates to treating and preventing cardiac diseases. This aspect includes, but is not limited to, treating and preventing ventricular fibrillation and/or arrhythmias as well as preventing or retarding the progression of oxidative stress associated with vascular dementia or stroke.
- the methods of this embodiment may include the use of the above-described compounds and pharmaceutical formulations.
- VF ventricular fibrillation
- conventional antagonist "antiarrhythmic" drugs selectively targeting the molecular species driving cardiac excitability, the ion channel have not yielded convincing benefits in survival, and in many cases elicit a paradoxical increase in arrhythmia risk. While the seminal mechanistic features of ischemic VF remain obscure, growing evidence implicates an interaction between cardiac Na + channels and the recently injured or acutely ischemic myocardium.
- CAST Cardiac Arrhythmia Suppression Trial
- the Brugada Syndrome a rare autosomal dominant disorder of idiopathic ventricular fibrillation, has been attributed to alterations in Na + channel function arising from mutations in the gene encoding the human cardiac Na channel (hHl, or SCN5A).
- Functional analysis of recombinant Na + channels that carry these mutations often reveal familiar changes in gating function that resemble the effects of Na + channel blocking agents: enhanced sodium channel behavior.
- the phenotypic similarity between the genetic and pharmacologic arrhythmia models cast suspicion on enhanced Na + channel inactivation as a general proarrhythmic mechanism. A molecular mechanism whereby cardiac ischemia could alter Na + channel function in this proarrhythmic manner has not been identified.
- Acute hypoxia depletes the myocardial cells of intracellular defenses against reactive oxygen species, such as superoxide dismutase and glutathione. Unabated, reactive oxygen species are free to react with key cellular components, and can attack unsaturated fatty acids and form lipid peroxides that are known to affect membrane proteins. This process is potentiated by an ischemia-induced shift in anaerobic metabolism, forming xanthine oxidase, which generates superoxide anion upon reperfusion and reintroduction of oxygen. The products of free radical- induced lipid peroxidation can covalently adduct and modify membrane proteins. Recently E2-isoketals (IsoKs) were identified as an Isoketals (IsoKs) were identified as an Isoketals (IsoKs) as an Isoketals (IsoKs) were identified as an Isoketals (IsoKs) as an Isoketals (IsoKs
- IsoK's are generated via the isoprostane lipid peroxidation pathway, a non-enzymatic free radical-induced peroxidation of arachidonic acid. IsoKs rapidly adduct to amines and especially to the lysine residues on proteins.
- the present inventors have discovered a link consistent changes in Na + channel inactivation gating function, similar to those associated with Brugada syndrome, to the byproducts of a particular oxidative pathway.
- the present inventors show synergy between the pharmacological effects of flecainide, a proarrhythmic Na + channel blocker, and oxidative stress.
- the present inventors find that these reactive byproducts accumulate in cultured (HEK) cells upon exposure to oxidative stress, as well as in the specific canine infarct zones where Na + channels have been shown to exhibit enhanced inactivation.
- HEK cultured
- FIG. 37 shows voltage-dependent properties of sodium channel.
- A Voltage-dependence of inactivation of sodium channels transfected in HEK-293 cells in the presence of the general oxidant, t- BHP (1 mM).
- Figure 38 shows the effect of Iso-K on voltage and time-dependent inactivation in the presence of flecainide.
- A Voltage-dependence of inactivation in the presence of flecainide (1 ⁇ M) and/or Iso-K (10 ⁇ M) is obtained. While IsoK shifted the curve in the hyperpolarizing potential, flecainide had no additional effect on inactivation.
- B Recovery from inactivation was evaluated using the protocol shown in the inset.
- Figure 39 shows effects of oxidative stress on use-dependent flecainide block.
- Figure 40 shows the effect of oxidative stress in immortalized atrial myocytes. Voltage- dependence of inactivation is evaluated. Preincubation of t-BHP and IsoK reduced Na channel availability in HL-I cells, an effect that was similar to those seen on sodium channels expressed in HEK-293 cells.
- Figure 41 shows DI l ScFv immunohistochemistry - adduct formation in the epicardial border zone of infarct.
- A, C, and E represent remote sections of heart taken far away from the area of the infarct.
- B, D, and F represent sections of heart taken from the border zone of the infarct.
- a and B are low power (5X) sections where the Dl 1 ScFv primary antibody was not included in the protocol and demonstrate specificity of staining in other sections.
- C and D are high power (40X) sections stained with H&E and show that there are not fundamental morphological differences between the remote and border zones.
- E and F are sections stained with DI l ScFv primary antibody and anti-E tag HRP conjugated secondary antibody.
- cDNAs were transiently transfected into HEK-293 cells using lipofectamine (GIBCO-BRL, Gaithersburg, MD), and were cultured in MEM medium supplemented with 10% fetal bovine serum and 1% pen-strep in a 5% CO2 incubator at 37°C for 1 to 4 days. Cells exhibiting green fluorescence were chosen for electrophysiology analysis.
- Electrophysiology Whole-cell sodium currents were recorded at room temperature (Axopatch 200B, Axon Instruments, Foster City, CA) using electrodes of 1-2 M ⁇ when filled with a pipette solution containing (in mM): NaF 10, CsF 110, CsCl 20, EGTA 10, Hepes 10 (pH 7.35 with CsOH).
- the bath solution contained (in mM): NaCl 145, KCl 4.5, CaCl 2 1.5, MgCl 2 1, Hepes 10 (titrated to pH 7.35 with CsOH).
- the bath solution contained (in mM): NaCl 20, Choline Chloride 115, KCl 4.5, CaC12 1, CoC12 2, MgC12 1, BaC12 1, hepes 10, and niflumic acid 10 ⁇ M. In all recordings, 75% of the series resistance was compensated, yielding a maximum voltage error of ⁇ 1 mV.
- the disulfide reducing agents dithiothreitol (DTT) and glutathione were dissolved directly in the extracellular and pipette solutions at a concentration of 2 mM.
- the oxidative agents tert-butyl hydroperoxide (t-BHP), hydrogen peroxide(H 2 O 2 ), and lipid peroxidation products were dissolved directly in the extracellular solution..
- E 2 -isoketal was synthesized as previously described.
- the present inventors used mass spectrometry to analyze F 2 -isoprostanes formed following treatment of HEK 293 cells with t-BHP.
- HEK-293 cells (1 x 10 6 ) were treated for 30 minutes at room temperature with buffer containing 100 ⁇ M t-BHP, or 100 ⁇ M t-BHP and 200 ⁇ M FeCl 2 .
- IsoK shifted the steady-state availability curve to hyperpolarized potentials, similar to t-BHP ( Figure 37B, Y 112 : from -89.0 ⁇ 1.3 mV to -96.4 ⁇ 1.1 mV; PO.01).
- Iso-K speeded the rate of INa decay during a depolarizing pulse from -100 mV to -20 mV (inset, panel B).
- t-BHP and IsoK did not affect the voltage-dependence OfNa + channel activation as seen in figure 37C (Vy 2 control: -43.1 ⁇ 1.3 mV, t- BHP: 42.4 ⁇ 1.5 mV and Iso-K: -41.6 ⁇ 1.5 mV). While previous studies observed a persistent inward current due to oxidation (similar to the effects of long QT 3 mutations), the present inventors did not observe any sustained non-inactivating component OfNa + current during exposure to t-BHP or Iso-K. In summary, the gating effects of t-BHP and IsoK were similar, causing a hyperpolarizing effect on voltage-dependent availability, consistent with a selective stabilization of the "inactivated"
- Figure 38B plots the magnitude of W in the P2 pulse relative to Pl pulse.
- y yo + Ai(l-e "t/ ⁇ fast )+A 2 (l-e "t/ ⁇ slow ), where ⁇ fast and ⁇ s i ow represent rapid and slow kinetic components of recovery from inactivation.
- the fitted parameters are shown in Table 1.
- Flecainide alone had no effect as shown previously. IsoK delayed both kinetic components ( ⁇ fast ; from 12.5 ⁇ 1.1 to 17.4 ⁇ 2.2, P ⁇ 0.05: ⁇ s i ow ; from 48.7 ⁇ 3.2 to 155.1 ⁇ 32.9, PO.001, respectively).
- t-BHP 2 mM
- t-BHP 2 mM
- hyperpolarizing potentials W in- - 73.6 ⁇ 1.4 mV in control, -82.8 ⁇ 1.7 mV in t-BHP, p ⁇ .01
- Iso-K 10 ⁇ M
- hyperpolarizing potentials Vy 2 : -82.0 ⁇ 1.7 mV, p ⁇ 0.01.
- Severe ventricular arrhythmias can occur during ischemia-reperfusion.
- Reactive nitrogen and oxygen species including superoxide anion, hydrogen peroxide, and hydroxyl radicals, react with proteins, fatty acids, and DNA to provoke multiple functional changes.
- Intracellular defenses in the myocardium against reactive species include a variety of enzymatic pathways and small molecule oxidants (such as superoxide dismutase and glutathione), many of which are depleted by hypoxia.
- ischemia-induced shift in anaerobic metabolism forms xanthine oxidase, which generates superoxide anion upon reperfusion and reintroduction of oxygen.
- Free-radical scavengers or agents that prevent free radical production, reduce the incidence of ventricular fibrillation and myocardial damage due to ischemia. While functional changes have been described in multiple ion channels and transporters, Na channel dysfunction appears to play a key role under these conditions: ischemic arrhythmias often evolve from sites of slow conduction near the ischemic border zone, which displays rate dependent slowing and facilitated reentry due to sodium channel blockade.
- the present inventors show that the general oxidant, t-BHP, and IsoK, a product of lipid peroxidation, act to potentiate Na + channel inactivation, suggesting that free radical-induced lipd peroxidation might play a major role in the modulation OfNa + channel function during ischemia.
- Excess t-BHP can initiate any number of oxidative processes, including formation of reactive oxygen species and lipid peroxidation.
- the reactive oxygen species and lipid peroxidation products that ensue during oxidative stress tend to form irreversible adducts with membrane proteins and irreversibly alter function.
- a key role for lipid peroxidation in cardiac Na + channel dysfunction is supported by our findings that exposure of HEK cells to t-BHP, and rendering canine hearts ischemic, both induce the formation of abundant quantities of F 2 -IsoPs and IsoK.
- our functional data indicate that E 2 - IsoK altered Na + channel inactivation in a manner identical to the nonspecific oxidant, t-BHP.
- Example 1 IsoKs, IsoK Scavengers and the Heart
- IsoK adducts are increased in infarcted area of dog hearts (Fig. 42A) and in hearts from patients with coronary artery disease (ischemic cardiomyopathy ICM) (Fig. 42B)
- Example 2 IsoKs in Alzheimer's Disease (AD).
- This Example further demonstrates the role of IsoKs in Alzheimer's Disease (AD). IsoK adducts are significantly increased in disease affected areas of brain from patients with AD, which is not present in brains from normal age-matched controls.
- the present inventors have determined that IsoK adducts increase in the brain of mice during aging. Additionally, in a transgenic mouse model of AD (hApoE4) animals develop memory and learning deficits as they age. The inventors have determined that the development of memory and learning deficits does not occur in transgenic animals treated with the compounds of the present invention. See Fig. 45.
- Example 3 This Example demonstrates the potency and selectivity of examples of scavengers of the present invention.
- 4- salicylamine 4-SA
- the inactive regioisomer of SA can be used as a negative control.
- PM, SA, and PPM were clearly very good at scavenging ⁇ KAs
- PM is known to also scavenge methylglyoxal and other ⁇ -ketoaldehydes derived from lipid peroxidation.
- any primary amine including PM should be able to react to some extent with any aldehyde, there is variation in their reaction rates, and the individual species of aldehyde that will be scavenged in vivo is determined by both reaction rate and local concentration of the various aldehydes.
- the present inventors found that PM reacted with the model ⁇ KA, 4-oxopentanal (OPA) 187 times faster than it reacted with the model ⁇ -ketoaldehyde, methylglyoxal and that PM only trivially reacted with HNE.
- PM, SA, and PPM scavenge ⁇ KAs relatively selectively compared to other lipid peroxidation products.
- PM is highly effective in intercepting ⁇ KAs from adduction to lysine in aqueous environments such as oxidation of arachidonic acid in buffer, it is quite hydrophilic. Therefore, PM poorly penetrates into nonpolar environments such as cellular membranes or organic solvents.
- both SA and PPM readily dissolve into ethyl acetate. Because ⁇ KAs form in situ on phospholipids during lipid peroxidation in cells, lipophilic ⁇ KA scavengers would be expected to be more effective than a hydrophilic scavenger like PM.
- PPM which is slightly less lipophilic than SA, provided slightly less protection, while the hydrophilic scavenger PM provided no significant protection.
- SA was tested to determine whether it could be used in vivo. 1 g/L or 5 g/L salicylamine was added to the drinking water of C57BL6 mice for 5 days and then harvested plasma and liver from the animals. SA was measured by monitoring absorption at 259 nm after derivatization with 1,1'- thiocarbonyldiimidazole. In part from this study, the present inventors concluded that SA is orally bioavailable and that the concentrations in plasma and in tissue are likely to be sufficient to provide protection.
- Example 4 Further demonstration of examples of scavengers of the present invention reducing lys-lactam protein adducts in mice after myocardial infarction
- the present inventors examined the effect of SA treatment on Lys-lactam protein adduct formation.
- Mouse hearts were harvested 7 days after coronary ligation and the atria and the right ventricular free wall were removed. The remainder of each heart (LV free wall and septum) was then cut into two, roughly equal tissue specimens of -50 mg wet weight: The anterior-apical part contained the infarct and the peri-infarct border zone (MI + borderzone), and the posterior-basal part was unaffected (Remote).
- the tissue content of Lys-lactam protein adducts was quantified using our LC MS 2 based analytical technique.
- Lys-lactam protein adducts were dramatically increased in the infarct and peri-infarct borderzone (Fig. 47) and did not changed in the remote, normal myocardium. Importantly, SA pretreatment appears to prevent the adduct formation (Fig. 47).
- the water radial arm maze test requires a mouse to find a hidden platform placed in one of six maze arms. The test takes place on 9 consecutive days, and the arm location of the hidden platform changes each of the 9 test days. On each test day, a mouse undergoes 4 consecutive training trials, with a different start arm for each trial. At the beginning of the trial, the mouse is placed at the opening of the start arm facing the center, the mouse released to swim, and the timer started. If the mouse enters an arm without the platform, an error is scored and the mouse is dragged by the tail back to the start arm and released. The latency timer does not stop during this time.
- a mouse swims in the central area for 12 sec without picking an arm an error is also scored and the animal is dragged back to the start arm and released.
- the latency timer ends when the mouse finds and mounts the hidden platform. If the latency timer reaches 60 sec before the mouse has found the platform, the mouse is gently guided to the platform. The mouse remains on the platform for 30 sees before being moved. After the fourth training trial, the mouse then rests for 30 min in a warming box before undergoing the final test trial, which starts from the last unused starting arm for that day. (The arm with the hidden platform is never used as a start arm.)
- the testing trials of the final 3 days are used for determining the memory performance and either latency time or errors in the testing trial can be used to measure this performance. A lower latency or error score is indicative of better working memory.
- the two cohorts were normalized to a Z-score and combined.
- the Z-score statistic preserves the mean and deviation of the cohort during normalization and is calculated as (raw score - cohort average)/ (cohort deviation).
- Z-score 0.0 for a group would mean that the group on average performed exactly as well as the cohort on average.
- a Z-score of -1.0 indicates a group performed one standard deviation better (lower latency time or errors) than the cohort average, while a Z-score of 1.0 indicates a group performed one standard deviation worse than the cohort average.
- the Z-scores for all individuals in both cohorts for each group were then added together for statistical comparisons.
- IsoKs appear to be a major mediator of oxidative induced cell injury and death.
- Embodiments of the present invention are compounds, compositions, and methods related to selective efficient scavengers of IsoKs.
- the present inventors have discovered that the IsoK scavenger compounds of the present invention have salutary effects in animal models of two major human diseases, i.e. myocardial infarction and Alzheimer's disease.
- the compounds of the present invention further are effective in the treatment of a wide variety of diseases associated with oxidative injury.
- IsoK scavengers represent a targeted novel mechanistic based pharmacologic approach to mitigate pathology in disorders involving oxidative injury.
- Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer's disease. Ann.Neurol. 44, 410-413
- Homocysteine induces iron-catalyzed lipid peroxidation of low-density lipoprotein that is prevented by alpha-tocopherol. Free Radic Res 2 ⁇ , 267-276.
- Homocysteine potentiates copper- and amyloid beta peptide- mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer's-type neurodegenerative pathways. J Neurochem 76, 1509-1520.
- Apolipoprotein E from atherosclerosis to
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- Apolipoprotein E is present in hippocampal neurons without neurofibrillary tangles in Alzheimer's disease and in age-matched controls.
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- Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc Natl Acad Sci USA 100, 6221-6226.
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- Amyloid beta-protein inhibits ubiquitin-dependent protein degradation in vitro. J Biol Chem 270, 19702-19708.
- the lipid peroxidation product 4- hydroxynonenal facilitates opening of voltage-dependent Ca2+ channels in neurons by increasing protein tyrosine phosphorylation. J Biol Chem 277:24368-24375.
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- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biochemistry (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Toxicology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
La présente invention concerne un procédé de traitement et/ou de prévention du dommage oxydatif, consistant à administrer une quantité efficace dun composé aminé phénolique et/ou de pyridoxamine ou dun analogue de la pyridoxamine supprimant la formation de ladduit IsoK/NeuroK. Dans certains modes de réalisation, le composé phénolique est au moins un composé parmi la pyridoxamine, la salicylamine, un composé de tyrosine ou leurs analogues.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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EP09847430A EP2477594A4 (fr) | 2009-07-15 | 2009-07-15 | Piégeurs d isokétal et réduction des troubles impliquant une lésion oxydative |
PCT/US2009/050644 WO2011008202A1 (fr) | 2009-07-15 | 2009-07-15 | Piégeurs disokétal et réduction des troubles impliquant une lésion oxydative |
Applications Claiming Priority (1)
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PCT/US2009/050644 WO2011008202A1 (fr) | 2009-07-15 | 2009-07-15 | Piégeurs disokétal et réduction des troubles impliquant une lésion oxydative |
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WO2011008202A1 true WO2011008202A1 (fr) | 2011-01-20 |
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PCT/US2009/050644 WO2011008202A1 (fr) | 2009-07-15 | 2009-07-15 | Piégeurs disokétal et réduction des troubles impliquant une lésion oxydative |
Country Status (2)
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EP (1) | EP2477594A4 (fr) |
WO (1) | WO2011008202A1 (fr) |
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WO2014116836A2 (fr) | 2013-01-23 | 2014-07-31 | Aldexa Therapeutics, Inc. | Maladies liées à un aldéhyde toxique et traitement |
US9604997B2 (en) | 2012-12-20 | 2017-03-28 | Aldeyra Therapeutics, Inc. | Peri-carbinols |
US9650342B2 (en) | 2005-05-26 | 2017-05-16 | Aldeyra Therapeutics, Inc. | Compositions and methods of treating retinal disease |
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JP2020517721A (ja) * | 2017-04-27 | 2020-06-18 | ヴァンダービルト ユニバーシティーVanderbilt University | γ−ケトアルデヒドスカベンジャーによるアテローム性動脈硬化症の治療方法 |
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Also Published As
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EP2477594A1 (fr) | 2012-07-25 |
EP2477594A4 (fr) | 2013-03-13 |
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