US20100291233A1 - Treatment of neurological disorders - Google Patents

Treatment of neurological disorders Download PDF

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US20100291233A1
US20100291233A1 US12/681,569 US68156908A US2010291233A1 US 20100291233 A1 US20100291233 A1 US 20100291233A1 US 68156908 A US68156908 A US 68156908A US 2010291233 A1 US2010291233 A1 US 2010291233A1
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selenate
pharmaceutically acceptable
acceptable salt
neurological disorder
amount
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Grant Morley
Christopher Hovens
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Velacor Therapeutics Pty Ltd
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Velacor Therapeutics Pty Ltd
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Definitions

  • This invention relates to the use of selenate or a pharmaceutically acceptable salt thereof in methods and compositions of treating or preventing non-tauopathy neurological disorders.
  • the invention relates to the use of selenate or a pharmaceutically acceptable salt thereof in combination with other therapies for use in methods of treating or preventing non-tauopathy neurological disorders.
  • Neurological disorders are disorders that affect the central nervous system, the peripheral nervous system or the autonomic nervous system.
  • tau protein is not only implicated in neurodegenerative disorders such as Alzheimer's disease, but also in other neurological disorders, [Satch et al., 2006; Wen et al., 2004; Roberson et al., 2007; Deutsch et al., 2006; Bartosik-Psujek, 2006, Ost et al., 2006].
  • tau protein is known to be phosphorylated at a number of phosphorylation sites by glycogen synthase kinase 3 ⁇ (GSK3 ⁇ ) in vivo, including the Alzheimer's disease specific Ser 396 residue [Li and Paudel, 2006].
  • GSK3 ⁇ is known to be phosphorylated by the protein kinase Akt and the activity of Akt is known to be attenuated by the protein phosphatase PP2A.
  • PP2A accounts for approximately 71% of the total tau phosphatase activity of human brain [Liu et al., 2005].
  • the total phosphatase activity and the activities of PP2A toward tau are significantly decreased in brains of Alzheimer's disease patients whereas that of other phosphatases such as PP2B are actually increased in the Alzheimer's disease brain [Liu et al., 2005].
  • PP2A activity negatively correlates to the level of tau phosphorylation at most phosphorylation sites in human brains. This indicates that PP2A is the major tau phosphatase that regulates its phosphorylation at multiple sites in human brain.
  • the present invention is based, at least in part, on the implication of tau protein, such as hyperphosphorylated tau protein, in a number of non-tauopathy neurological diseases and that the activity of the protein phosphatase PP2A may be enhanced by exposure to selenate or a pharmaceutically acceptable salt thereof.
  • the enhancement of the activity of PP2A may reduce or inhibit phosphorylation of tau protein, especially hyperphosphorylation, with a two pronged approach: i) dephosphorylation and inactivation of Akt, thereby reducing phosphorylation of GSK3 ⁇ and consequently reducing phosphorylation of tau protein, and ii) direct dephosphorylation of tau protein.
  • a reduction in the phosphorylation, including hyperphosphorylation of tau protein reduces or prevents the accumulation or deposition of abnormal tau protein in neurons and glial cells and therefore is useful in the treatment or prevention of neurological disorders.
  • the present invention provides a method for the treatment or prevention of a non-tauopathy neurological disorder in a subject comprising administering to the subject an effective amount of selenate or a pharmaceutically acceptable salt thereof and wherein the non-tauopathy neurological disorder is not an ⁇ -synucleopathy.
  • the non-tauopathy neurological disorder is selected from the group consisting of Creutzfeldt-Jakob disease, Huntington's disease, stroke, cerebral ischaemia, dementia associated with stroke or cerebral ischaemia, dementia associated with HIV, disorders associated with excitotoxicity, epilepsy, seizures, schizophrenia, multiple sclerosis, acute brain trauma (severe traumatic brain injury) and oxygen glucose deprivation.
  • the selenate or a pharmaceutically acceptable salt thereof is administered in combination with other therapies suitable for treatment or prevention of non-tauopathy neurological disorders or therapies suitable for relieving the symptoms of non-tauopathy neurological disorders.
  • a method of reducing the amount of tau protein in a cell comprising exposing the cell to an effective amount of selenate or a pharmaceutically acceptable salt thereof.
  • an element means one element or more than one element.
  • the term “about” refers to a quantity, level, value, dimension, size or amount that varies by as much as 30%, 20% or 10% to a reference quantity, level, value, dimension, size or amount.
  • dephosphorylation refers to the chemical removal of a phosphate group (PO 4 2- ) from a biochemical entity such as a protein. Under cellular conditions, dephosphorylation is achieved enzymatically by an enzyme such as a phosphatase.
  • hyperphosphorylation refers to the circumstance where phosphorylation sites on a biochemical entity such as a protein, are phosphorylated at a level higher than normal.
  • inhibiting or reducing hyperphosphorylation includes preventing all sites or some sites on a biochemical entity from being phosphorylated and decreasing the number of biochemical entities that have all or some of their phosphorylation sites phosphorylated.
  • the term “in combination with” refers to the treatment of a subject with at least two agents such that their effects on the neurological disorder occur, at least in part, over the same time period. Administration of at least two agents may occur simultaneously in a single composition, or each agent may be simultaneously or sequentially administered in separate compositions.
  • non-tauopathy neurological disorder refers to a neurological disorder which does not display the pathology of classical tauopathies.
  • tauopathies are considered to be a group of diverse dementias and movement disorders which have as a common pathological feature, the presence of intracellular aggregations of abnormal filaments of tau protein.
  • the tau protein in the aggregations may be hyperphosphorylated tau.
  • These aggregations of tau protein filaments in tauopathies can be identified by standard diagnostic techniques such as staining and light microscopy.
  • non-tauopathy neurological disorders some of which while associated with aberrant tau protein, such as hyperphosphorylated tau protein, or to an abnormal amount of tau protein, do not display intracellular aggregations of abnormal tau.
  • non-tauopathy neurological disorders include Creutzfeldt-Jakob disease, Huntington's disease, stroke, cerebral ischaemia, dementia associated with stroke or cerebral ischaemia, dementia associated with HIV, disorders associated with excitotoxicity, epilepsy, seizures, schizophrenia, multiple sclerosis, acute brain trauma (severe traumatic brain injury) and oxygen glucose deprivation.
  • ⁇ -synucleopathy refers to a neurodegenerative disorder or disorder that involves aggregation of ⁇ -synuclein or abnormal ⁇ -synuclein in nerve cells in the brain.
  • the non-tauopathy neurological disorders of the present invention are not ⁇ -synucleopathies.
  • disorders associated with excitotoxicity are disorders that involve excessive activation of glutamate receptors in the brain.
  • disorders associated with excitotoxicity include, ischaemia during stroke, trauma, hypoxia, hypoglycaemia and hepatic encephalopathy; disorders related to long term plastic changes in the central nervous system such as chronic pain, drug tolerance, drug dependence, drug addiction and tardive dyskinesia, epilepsy, schizophrenia, anxiety, depression, acute pain and tinnitis.
  • the term “nutritional amount” includes an amount of selenium that is less than the maximum FDA restricted dietary supplement dose. In the United States, the maximum daily dose for a dietary supplement is 400 ⁇ g per day.
  • salts which are toxicologically safe for human and animal administration.
  • suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascor
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, iron, nickel, zinc, ammonium and alkylammonium.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower alkyl halide such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • Suitable metal ion salts of selenate include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, iron, nickel, zinc, ammonium and alkylammonium salts.
  • a preferred salt of selenate is the sodium salt, Na 2 SeO 4 .
  • phosphorylation refers to the chemical addition of a phosphate group (PO 4 2- ) to a biochemical entity such as a protein. Under cellular conditions phosphorylation is achieved enzymatically by an enzyme such as a kinase.
  • inhibiting or reducing phosphorylation includes preventing phosphorylation of one or more phosphorylation sites on a biochemical entity, including preventing phosphorylation of all phosphorylation sites as in hyperphosphorylation. This phrase also includes decreasing the extent of phosphorylation of a biochemical entity by preventing phosphorylation occurring at one or more phosphorylation sites or as a result of dephosphorylation occurring at one or more phosphorylated sites on the biochemical entity.
  • subject or “individual” or “patient”, used interchangeably herein, refer to any subject, particularly a vertebrate subject and more particularly a mammalian subject, for whom prophylaxis or treatment is desired.
  • Suitable vertebrate animals that fall within the scope of the invention include, but are not limited to, primates, avians, livestock animals (e.g. pigs, sheep, cows, horses, donkeys), laboratory test animals (e.g. rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g. cats and dogs) and captive wild animals (e.g. foxes, deer, dingoes).
  • a preferred subject is a human in need of treatment or prophylaxis of a neurological disorder. However, it will be understood that the aforementioned terms do not imply that symptoms are present.
  • sodium sulpranutritional refers to an amount which is greater than the amount considered as a nutritional requirement.
  • the FDA defined maximum daily dose for selenium dietary supplementation is 400 ⁇ g per day.
  • a supranutritional amount of selenium provides selenium to a subject above the maximum daily dose for dietary supplementation.
  • a supranutritional amount of selenium per day may be 5 ⁇ g/kg to 1.0 mg/kg, 5 ⁇ g/kg to 0.5 mg/kg per day, 5 ⁇ g/kg to 0.3 mg/kg, 0.01 mg/kg to 1.0 mg/kg, 0.01 mg/kg to 0.5 mg/kg, 0.025 mg/kg to 1.0 mg/kg, 0.025 mg/kg to 0.5 mg/kg, 0.05 mg/kg to 1.0 mg/kg, 0.05 mg/kg to 0.5 mg/kg, 0.05 mg/kg to 0.3 mg/kg, 0.1 mg/kg to 1.0 mg/kg, 0.1 mg/kg to 0.5 mg/kg or 0.1 mg/kg to 0.3 mg/kg, especially 0.025 mg/kg to 0.3 mg/kg or 0.01 mg/kg to 0.3 mg/kg per day.
  • an effective amount in the context of treating or preventing a neurodegenerative disease or inhibiting or reducing phosphorylation of tau protein or inhibiting the activity of GSK3 ⁇ is meant the administration or addition of an amount of selenate or a pharmaceutically acceptable salt thereof, either in a single dose or as part of a series of doses, that is effective in enhancing the activity of PP2A and especially that is effective for the prevention of incurring a symptom, holding in check such symptoms, and/or treating existing symptoms, associated with the neurological disorder.
  • the effective amount will vary depending on the health and physical condition of the individual to be treated, the taxonomic group of the individual to be treated, the formulation of the composition, the assessment of the medical situations and other relevant factors. It is expected that the amount will fall within a relatively broad range. In specific embodiments, an effective amount is a nutritional or supranutritional amount.
  • the present invention is predicated in part on the determination that selenate or a pharmaceutically acceptable salt thereof, is effective in enhancing the activity of PP2A which in turn may result in a reduction in phosphorylation of tau protein by GSK3 ⁇ and/or an increase in the rate of dephosphorylation of tau protein. It has also been observed that selenate or a pharmaceutically acceptable salt thereof is effective in decreasing the level or amount of tau protein present in cells.
  • the present invention can be used effectively to treat or prevent non-tauopathy neurological disorders.
  • the effective amount of selenate or a pharmaceutically acceptable salt thereof is a nutritional or supranutritional amount of selenate.
  • the amount of selenate or a pharmaceutically acceptable salt thereof delivers a supranutritional dose of selenium in an amount of from about 5 ⁇ g/kg to about 1.0 mg/kg, usually from about 0.01 mg/kg to 1.0 mg/kg or 0.01 mg/kg to 0.5 mg/kg per day or 0.01 mg/kg to 0.3 mg/kg per day.
  • the selenate or a pharmaceutically acceptable salt thereof is sodium selenate (Na 2 SeO 4 ).
  • the selenate or a pharmaceutically acceptable salt thereof is administered to a subject in combination with another therapy for treating or preventing a non-tauopathy neurological disorder.
  • therapies for treating or preventing a non-tauopathy neurological disorder include, but are not limited to, antiplatelet agents such as aspirin (e.g., 50-325 mg/day), clopidogrel (e.g., 75 mg/day), aspirin and dipyridamole (e.g., 25/200 mg twice daily) and ticlopidine, antihypertensive agents, antidepressants, anti-convulsant drugs such as carbamazepine (TegretolTM), clobazam (FrisiumTM), clonazepam (KlonopinTM), ethosuximide (ZarontinTM), felbamate (FelbatolTM), fosphenytoin (cere
  • antiplatelet agents such as aspirin (e.g., 50-325 mg/day), clopid
  • Combination therapies could include effective amounts of selenate or a pharmaceutically acceptable salt thereof together with an agent used for treating or preventing a non-tauopathy neurological disorder in an amount normally used in the absence of selenate.
  • the amount of agent used in the treatment of non-tauopathy neurological disorders may be decreased upon co-administration with selenate or a pharmaceutically acceptable salt thereof.
  • the combination may display a synergistic effect.
  • Certain embodiments of the present invention are directed to methods for treating or preventing non-tauopathy neurological disorders in a subject, which methods generally comprise administering to the subject an effective amount of selenate or a pharmaceutically acceptable salt thereof.
  • the person managing the subject can determine the effective dosage form of selenate or a pharmaceutically acceptable salt thereof for the particular condition and circumstances of the subject.
  • An effective amount of selenate is one that is effective for the treatment or prevention of a non-tauopathy neurological disorder, including prevention of incurring a symptom, holding in check a symptom and treating a symptom.
  • the effective amount is a nutritional amount.
  • the effective amount is a supranutritional amount.
  • the selenate or a pharmaceutically acceptable salt thereof is sodium selenate.
  • the non-tauopathy neurological disorder to be treated may be determined by measuring one or more diagnostic parameters indicative of the course of the disease, compared to a suitable control.
  • a “suitable control” may be the individual before treatment, or may be a human (e.g., an age-matched or similar control) treated with a placebo.
  • the treatment of non-tauopathy neurological disorders includes and encompasses without limitation: (i) preventing a non-tauopathy neurological disorder in a subject who may be predisposed to the disease but has not yet been diagnosed with the disease and, accordingly, the treatment constitutes prophylactic treatment for the non-tauopathy neurological disorder; (ii) inhibiting a non-tauopathy neurological disorder, i.e., arresting the development of the non-tauopathy neurological disorder; or (iii) relieving symptoms resulting from the non-tauopathy neurological disorder.
  • the methods of the present invention are suitable for treating an individual who has been diagnosed with a non-tauopathy neurological disorder, who is suspected of having a non-tauopathy neurological disorder, or who is known to be susceptible and who is considered likely to develop a non-tauopathy neurological disorder.
  • the selenate is sodium selenate.
  • Exemplary subjects for treatment with the methods of the invention are vertebrates, especially mammals.
  • the subject is selected from the group consisting of humans, sheep, cattle, horses, bovine, pigs, dogs and cats.
  • a preferred subject is a human.
  • the selenate or a pharmaceutically acceptable salt thereof may be formulated by following any number of techniques known in the art of drug delivery. Selenate or a pharmaceutically acceptable salt thereof may of course be administered by a number of means keeping in mind that all formulations are not suitable for every route of administration. Selenate or a pharmaceutically acceptable salt thereof can be administered in solid or liquid form. The application may be oral, rectal, nasal, topical (including buccal and sublingual), or by inhalation. Selenate or a pharmaceutically acceptable salt thereof may be administered together with conventional pharmaceutical acceptable adjuvant, carriers and/or diluents.
  • the solid forms of application comprise tablets, capsules, powders, pills, pastilles, suppositories and granular forms of administration. They may also include carriers or additives, such as flavors, dyes, diluents, softeners, binders, preservatives, lasting agents and/or enclosing materials. Liquid forms of administration include solutions, suspensions and emulsions. These may also be offered together with the above-mentioned additives.
  • Solutions and suspensions of selenate or a pharmaceutically acceptable salt thereof may be injected. Suspensions too viscous for injection may be implanted using devices designed for such purposes, if necessary. Sustained release forms are., generally administered via parenteral or enteric means. Parenteral administration is another route of administration of the selenate or a pharmaceutically acceptable salt thereof used to practice the invention.
  • Parenteral administration is another route of administration of the selenate or a pharmaceutically acceptable salt thereof used to practice the invention.
  • Parenteral administration includes formulations suitable for injection and for nasal, vaginal, rectal, and buccal administration.
  • the administration of selenate or a pharmaceutically acceptable salt thereof may involve an oral dose formulation.
  • Oral dose formulations are preferably administered once daily to three times daily in the form of a capsule or tablet, or alternatively as an aqueous based solution.
  • Selenate or a pharmaceutically acceptable salt thereof may be administered intravenously either daily, continuously, once a week or three times a week.
  • the administration of selenate or a pharmaceutically acceptable salt thereof may include daily administration, preferably once daily in the form of a sustained release capsule or tablet, or once daily as an aqueous solution.
  • Combinations of selenate or a pharmaceutically acceptable salt thereof and at least one agent that is suitable for treating a neurological disorder may be administered in solid or liquid form in a single formulation or composition or in separate formulations or compositions.
  • the selenate or a pharmaceutically acceptable salt thereof and the agent for treating a neurological disorder are administered orally as a single tablet or capsule or separate tablets or capsules.
  • the selenate or a pharmaceutically acceptable salt thereof and the agent for treating a neurological disorder are administered intravenously in a single composition or separate compositions.
  • the present invention also provides pharmaceutical compositions for treating or preventing a neurological disorder, comprising a nutritional or supranutritional amount of selenate or a pharmaceutically acceptable salt thereof.
  • the compositions contain an amount of selenate that delivers selenium in an amount of from about 40 ⁇ g to about 80 mg, for example, 400 ⁇ g to 80 mg, of selenium as part of selenate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the selenate or its pharmaceutically acceptable salt delivers selenium in an amount of about 40 ⁇ g to about 80 mg or 400 ⁇ g to 80 mg.
  • the selenate or a pharmaceutically acceptable salt thereof delivers selenium in an amount of about 400 ⁇ g to 80 mg, 401 ⁇ g to 80 mg, 500 ⁇ g to 40 mg, especially 800 ⁇ g to 40 mg, for a single or divided daily dose.
  • compositions comprising selenate or a pharmaceutically acceptable salt thereof may further comprise another agent for treating or preventing a neurological disorder.
  • the composition may contain selenate or a pharmaceutically acceptable salt thereof and at least one antiplatelet agent such as aspirin (e.g., 50-325 mg/day), clopidogrel (e.g., 75 mg/day), aspirin and dipyridamole (e.g., 25/200 mg twice daily) and ticlopidine, antihypertensive agents, antidepressants, anti-convulsant drugs such as carbamazepine (TegretolTM), clobazam (FrisiumTM), clonazepam (KlonopinTM), ethosuximide (ZarontinTM), felbamate (FelbatolTM), fosphenytoin (cerebyxTM), flurazepam (DalmaneTM), gabapentin (NeurontinTM), lamotrigine (LanictalTM
  • the pharmaceutical composition of the present invention may include any additional components that are non-immunogenic and biocompatible with selenate, as well as capable of bioabsorption, biodegradation, elimination as an intact molecule.
  • the formulation may be supplied in a ready-to-use form or may be supplied as a sterile powder or liquid requiring vehicle addition prior to administration. If sterility is desired, the formulation may be made under sterile conditions, the individual components of the mixture may be sterile, or the formulation may be sterile filtered prior to use.
  • Such a solution can also contain appropriate pharmaceutically acceptable carriers, such as but not limited to buffers, salts, excipients, preservatives, etc.
  • oral formulations are used for administering selenate or a pharmaceutically acceptable salt thereof in the methods of the invention.
  • These formulations generally comprise selenate or a pharmaceutically acceptable salt thereof having decreased solubility in order to delay absorption into the bloodstream.
  • these formulations may include other components, agents, carriers, etc., which may also serve to delay absorption of the selenate or a pharmaceutically acceptable salt thereof.
  • Microencapsulation, polymeric entrapment systems, and osmotic pumps, which may or may not be bioerodible, may also be used to allow delayed or controlled diffusion of the selenate or a pharmaceutically acceptable salt thereof from a capsule or matrix.
  • the selenate or a pharmaceutically acceptable salt thereof can be used solus or as part of another agent. Accordingly, the present invention also contemplates an agent that comprises selenate or a pharmaceutically acceptable salt thereof for the treatment of a neurological disorder.
  • a method of reducing the amount of tau protein in a cell comprising exposing the cell to an effective amount of selenate or a pharmaceutically acceptable salt thereof.
  • the tau protein is abnormally phosphorylated such as hyperphosphorylated.
  • the tau protein has a normal amount of phosphorylation.
  • tau protein appears to be implicated in neurological disease and appears to be a mediator of neurotoxic insults. Reduction of the amount of tau protein, with normal levels of phosphorylation or hyperphosphorylation, may be neuroprotective.
  • FIG. 1 is a graphical representation showing the tissue culture toxicity of sodium selenate, sodium selenite and selenomethionine in serum free media at 5 ⁇ M, 25 ⁇ M and 100 ⁇ M after 24 hours exposure.
  • FIG. 2 is a graphical representation showing the tissue culture toxicity of sodium selenate, sodium selenite and selenomethionine in serum free media at 5 ⁇ M, 25 ⁇ M and 100 ⁇ M after 48 hours exposure.
  • FIG. 3 is a bar chart graphical representation illustrating the effects of sodium selenate, sodium selenite and selenomethionine on hypoxia induced neurodegeneration compared with the neuroprotectant MnTBAP.
  • FIG. 4 is a bar chart graphical representation illustrating the toxicity of sodium selenate in tissue culture at 100 ⁇ M, 250 ⁇ M and 500 ⁇ M.
  • FIG. 5 is a bar chart representation showing the effects of sodium selenate, sodium selenite and selenomethionine on ischaemia induced neurodegeneration.
  • FIG. 6 is a graphical representation illustrating the number of PTZ induced seizures in rats exposed to 120 ⁇ g and 1.2 mg of sodium selenate (mean ⁇ SEM).
  • FIG. 7 is a graphical representation illustrating the number of PTZ induced severe seizures in rats exposed to 120 ⁇ g and 1.2 mg of sodium selenate (mean ⁇ SEM).
  • FIG. 8 is a graphical representation illustrating the duration of seizure activity in rats injected with PTZ exposed to 120 ⁇ g and 1.2 mg of sodium selenate (mean ⁇ SEM).
  • FIG. 9 is a graphical representation illustrating the latency to seizure onset in rats injected with PTZ exposed to 120 ⁇ g and 1.2 mg of sodium selenate (mean ⁇ SEM).
  • Wistar rat pups (8-11 days old) were decapitated and the hippocampus rapidly dissected into ice-cold Gey's balanced salt solution supplemented with 4.5 mg/mL glucose.
  • Transverse sections 400 ⁇ m were cut on a McIlwain tissue chopper and placed back into ice-cold Gey's balanced salt solution. Slices were separated and plated onto Millicell CM culture inserts (4 per well) and maintained at 37° C./5% CO 2 for 14 days.
  • Maintenance medium consists of 25% heat-inactivated horse serum, 25% Hank's balanced salt solution (HBSS) and 50% minimum essential medium with added Earle's salts (MEM), supplemented with 1 mM glutamine and 4.5 mg/mL glucose. Medium was changed every 3-4 days.
  • hypoxia was induced by transferring cultures to serum free media (SFM) (+PI) which had been saturated with 95%N 2 /5%CO 2 .
  • Culture plates (without lids) were sealed into an airtight chamber in which the atmosphere was saturated with 95%N 2 /5%CO 2 by continuously blowing through gas at 10 L/min for ten minutes before being sealed and placed in the incubator for 170 minutes (total time of hypoxia was therefore 180 minutes).
  • SFM serum free media
  • Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) at 100 ⁇ M was used as a positive neuroprotective control.
  • Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) at 100 ⁇ M was used as a positive neuroprotective control.
  • MnTBAP Mn(III)tetrakis(4-benzoic acid)porphyrin chloride
  • mice were induced by transferring cultures to glucose deficient media (GFM—75% MEM, 25% HBSS supplemented with 1 mM glutamine)+PI, which had been saturated with 95%N 2 /5%CO2.
  • Culture plates (without lids) were then sealed into an airtight chamber in which the atmosphere was saturated with 95%N 2 /5%CO 2 by continuously blowing through gas at 10 L/min for ten minutes before being sealed and placed in the incubator for 50 minutes (total time of ischaemia was therefore 60 minutes).
  • cultures were returned to normoxic SFM containing PI and placed back in the incubator for 24 hours.
  • MnTBAP at 100 ⁇ M was used as a positive neuroprotective control.
  • the efficacy of the compounds under investigation was assessed using a pre, during and post-hypoxia paradigm—compounds being present in the medium 24 hours pre-ischaemia, during the 1 hour of ischaemia and 24 hours post-ischaemia.
  • Neuronal damage was assessed using ImageJ software running on a PC. Images being captured using a monochrome CCD camera and saved for offline analysis. Light transmission images were captured prior to the addition of drugs, and PI fluorescence images recorded at the end of the 24-hour recovery period. The area of the CA1 region was then determined from the transmission image. The area of PI fluorescence in the CA1 is measured using the threshold function on ImageJ, and neuronal damage expressed as the percentage of the CA1 in which PI fluorescence is detected above background (Pringle et al., 1997).
  • a preliminary toxicity screen was carried out on the compounds to determine tissue culture exposure levels that would cause toxicity.
  • Each compound was made to 5 mM in SFM, then used at 1 ⁇ L/mL, 5 ⁇ L/mL and 20 ⁇ L/mL, to give final concentrations of 5 ⁇ M, 25 ⁇ M and 100 ⁇ M. Damage was measured after 24 hours and 48 hours.
  • FIGS. 1 and 2 Results shown in FIGS. 1 and 2 ).
  • Sodium selenite was found to be toxic above 5 ⁇ M and selenomethionine was toxic above 25 ⁇ M.
  • Sodium selenate was not found to be toxic at any concentration tested up to 100 ⁇ M.
  • the compounds were made to 10 mM in SFM.
  • Sodium selenate was serially diluted with SFM to 1 mM, 100 ⁇ M and 5 ⁇ M, each of these was used at 10 ⁇ L/mL, to give final concentrations of 50 nm, 1 ⁇ M, 10 ⁇ M and 100 ⁇ M.
  • Sodium selenite was diluted to 100 ⁇ M, selenomethionine to 500 ⁇ M. These were then used at 10 ⁇ L/mL to give final concentrations of 1 ⁇ M and 5 ⁇ M.
  • the sodium selenate was made to 50 mM in SFM, then serially diluted to 25 mM, 10 mM and 1 mM, each of these used at 10 ⁇ L/mL to give final concentrations of 10 ⁇ M, 100 ⁇ M, 250 ⁇ M and 500 ⁇ M.
  • Sodium selenite and selenomethionine as before.
  • An experiment to assess the toxicity of sodium selenate at these higher concentrations was run in parallel with the OGD (Results FIG. 4 ).
  • Pentylenetetrazol 60 mg/kg is administered intraperitoneally (i.p., 2 mL/kg in saline) to male Sprague-Dawley rats.
  • Sodium selenate is administered p.o in drinking water for 7 days prior to PTZ injection.
  • the rats have ad libitum access to water (normal daily consumption of water is 30 mL/rat/day).
  • the duration of seizure activity of animals receiving vehicle was 1443.4 ⁇ 166.3 seconds.
  • Sodium selenate treatment significantly reduced duration of seizure activity at both 120 ⁇ g (770.9 ⁇ 189.9 secs) and 1.2 mg (808.6 ⁇ 126.1 secs) ( FIG. 8 ).

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