WO2024084290A1 - Composition destinée à être utilisée dans une methode de prévention et de traitement d'un déclin cognitif et/ou de formes de démence - Google Patents
Composition destinée à être utilisée dans une methode de prévention et de traitement d'un déclin cognitif et/ou de formes de démence Download PDFInfo
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- WO2024084290A1 WO2024084290A1 PCT/IB2023/053342 IB2023053342W WO2024084290A1 WO 2024084290 A1 WO2024084290 A1 WO 2024084290A1 IB 2023053342 W IB2023053342 W IB 2023053342W WO 2024084290 A1 WO2024084290 A1 WO 2024084290A1
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- dementia
- vitamin
- extract
- cognitive decline
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Definitions
- Composition for use in a method for the prevention and treatment of cognitive decline and/or forms of dementia is a subject of the art.
- compositions and a formulation containing said composition and, optionally, additives or excipients or carriers of acceptable food or pharmaceutical grade relate to a composition and a formulation containing said composition and, optionally, additives or excipients or carriers of acceptable food or pharmaceutical grade for use in a method for the prevention and/or treatment of cognitive decline and/or forms of dementia.
- a composition for use in a method for the prevention and treatment of cognitive decline and/or forms of dementia particularly a composition to counteract inflammation, oxidative stress, and cerebrovascular damage at the level of the central nervous system as causes of neurodegeneration leading to the onset of cognitive decline and development of dementia.
- NDs Neurodegenerative Diseases
- Neurodegenerative diseases are debilitating and untreatable conditions; they are caused by the progressive functional and structural degeneration and/or death of nerve cells. Depending on where the degeneration is localized, disorders in movement (ataxias) or cognitive disorders (dementias) result. For example, if the involvement is at the encephalic level, Alzheimer's disease or Parkinson's disease may develop; if, on the other hand, the degeneration is at the motor neuron level, amyotrophic lateral sclerosis will be found; if the degeneration affects the myelin sheath of the axon, manifestations such as multiple sclerosis will occur. All neurodegenerative diseases, indiscriminately, have a significant public health impact in terms of incidence, disability, complexity of disease management, and need for ongoing treatment and care.
- Factors such as age, sex, conditions associated with metabolic syndrome (e.g., hypertension, obesity, and diabetes), and the presence of comorbidities that already alter the inflammatory profile may increase the risk of neurodegeneration onset and thus constitute risk factors to be monitored.
- WHO there were 35.6 million people with dementia worldwide in 2010, a number that is expected to triple by 2050. In fact, an average of 7.7 million new cases of dementia are diagnosed each year, with the cost attributable to medical expenses increasing. In Italy, it is estimated that the number of people diagnosed with dementia exceeds 1 million, while there are about 3 million people involved in caring for loved ones with the disease.
- AD Alzheimer's disease
- DLB Lewy body dementia
- FDD frontotemporal dementia
- VaD vascular dementia
- AD-related dementia is the most common form of dementia, and is characterized by distinctive neuropathological features such as senile plaque formation at the extracellular level and intraneuronal accumulation of neurofibrillar clusters.
- the formation of senile plaques is due to the accumulation of p-amyloid peptide (Ap), especially its isoform Ap42, which originates from amyloid precursor protein (APP), a transmembrane protein that can be processed, at the physiological level, by a-, p- and y-secretases through two pathways: amyloidogenic and non-amyloidogenic.
- Ap amyloid precursor protein
- p-secretase processes APP near the N-terminal region of its amyloid domain (Ap), causing the formation of a C-terminal fragment, called p-CTF, which is released into the extracellular space.
- p-CTF is processed by y-secretase at the C- terminal region of the Ap domain, causing the formation of the peptide Ap42 and its extracellular accumulation.
- the processing of APP by o-secretase which occurs in the central region of the Ap domain of APP, precludes the possibility of generating the amyloid peptide.
- all characteristic markers of Alzheimer's disease are associated with neurodegeneration, neuroinflammation, microglia activation, and blood-brain barrier (BBB) malfunction, leading to cognitive decline and memory impairment.
- BBB blood-brain barrier
- DLB Lewy body dementia
- frontotemporal dementia denotes a large and heterogeneous group of neurodegenerative dementias that can have different clinical and pathological profiles and are characterized by atrophy of the frontal and temporal lobes, accompanied by neuronal loss, gliosis, and spongiosis, resulting in aphasia, severe personality disorders, memory loss, and language difficulties.
- many cognitive disorders share a vascular origin and are grouped under the classification of vascular dementias (VaDs). Specifically, VaDs are characterized by reduced cerebral blood flow, which can cause hypoxic states and altered blood-brain barrier (BBB) permeability, with neurotoxic effects that promote neurodegeneration and amyloid protein accumulation.
- BBB blood-brain barrier
- the cognitive decline experienced by patients with dementia is often accompanied by secondary disorders, which can negatively affect the patient's quality of life.
- secondary disorders which can negatively affect the patient's quality of life.
- very common are states of anxiety and depression.
- depression is considered a risk factor for the development and progression of the disease and is observed in nearly 50 percent of cases.
- depression and anxiety have an endogenous component, related to the physiological changes in the brain caused by neurodegeneration, and a reactive component, in response to the awareness of the pathology and the gradual loss of independence.
- sleep disorders are also very common. Neurodegenerative diseases, in fact, can alter sleep architecture, affecting patients' state of fatigue and apathy, even to the point of causing acute confusional states ⁇ delirium).
- sleep deprivation is itself one of the risk factors related to dementia, especially Alzheimer's disease, as it can afflict cognitive functions.
- the aforementioned disorders related to anxiety, depression, and sleep deprivation can, in very severe cases, result in true neuropsychiatric disorders, which manifest themselves in patients in the form of illusions, especially of a paranoid nature, and hallucinations, often visual.
- patients with dementia may suffer from agitation and aggression, mainly due to confusion resulting from the inability to fully comprehend what is happening to them. This condition can lead to dangerous behaviors for caregivers and the patient himself.
- Treatments currently employed in the field of dementia focus on slowing the progression of cognitive decline and restoring function by attempting to remedy the damage already suffered by the brain.
- several therapeutic strategies have been developed, both pharmacological and nonpharmacological.
- the first approach used to slow the progression of the disease is to have the patient follow an appropriate diet, such as MIND (Mediterranean -DASH Intervention for Neurodegenerative Delay), accompanied, if possible, by the performance of exercise and the implementation of strategies to intervene on cardiovascular risk factors.
- MIND Mediterranean -DASH Intervention for Neurodegenerative Delay
- the main drugs used to treat dementia are cholinesterase inhibitors, which have proven useful because they can increase levels of acetylcholine, which plays a key role in memory and attention processes.
- NMDA receptor antagonists such as memantine, which prevent pathological overactivation of NMDA receptors.
- memantine which prevent pathological overactivation of NMDA receptors.
- side effects including nausea, vomiting, loss of appetite and diarrhea, headache, and confusion.
- Cognitive interventions which can help mitigate some of the cognitive-related symptoms of dementia, are often added to drug therapy.
- the main ones are environmental enrichment, defined as creating a stimulating environment for the patient, and cognitive neurorehabilitation, conducted by speech therapists and neuropsychologists.
- Pharmacological therapies are also often used to counter symptoms related to secondary disorders associated with the disease, such as anxiety, depression, sleep disorders, agitation, and aggression.
- drugs are selective serotonin reuptake inhibitors (SSRIs), which are considered useful both for states of anxiety and depression and to mitigate agitation and aggression.
- SSRIs are often accompanied by major side effects, and in the case of depression associated with dementia, some studies find their use to be ineffective.
- antipsychotics which, however, can cause very serious side effects
- mood stabilizers although there is no evidence regarding their effectiveness in dementia-related cases
- benzodiazepines to be administered only in cases where the patient actually becomes dangerous to himself or herself and others
- sleep disorders when necessary, patients can be treated with antidepressants, such as trazodone and mirtazapine, or low-dose nonbenzodiazepines.
- MCI mild cognitive impairment
- MCI cases can be classified as amnestic or nonamnestic, depending on whether the memory sphere is involved or not.
- both classes of MCI can be further divided into single-domain or multiple-domain cases, depending on the number of cognitive areas involved. Accordingly, single-domain amnestic MCI refers to a condition, often a precursor to Alzheimer's disease, in which subjects have memory impairment but have not yet reached the state of dementia.
- Multiple-domain amnestic MCI also a precursor to Alzheimer's disease, includes those cases in which, in addition to memory-related problems, other alterations in other cognitive domains also occur.
- non-amnestic MCI cases on the other hand, single-domain MCI cases are characterized by disorders affecting a single cognitive domain other than memory, while multiple-domain MCI cases manifest alterations in multiple cognitive domains, such as those related to language, visual-spatial abilities, and executive functions.
- Mild cognitive decline in general, is a common disorder in the elderly population with the following current prevalence estimates in relation to age groups: 6.7% between 60 and 64 years, 8.4% between 65 and 69 years, 10.1% between 70 and 74 years, 14.8% between 75 and 79 years, and 25.2% between 80 and 84 years.
- Risk factors associated with MCI are comparable to those for dementia and include, in addition to age, poor education, vascular risk factors, hypertension, diabetes, obesity, history of heart attack or heart disease, and genetic factors. It has also been estimated that the risk of a patient with MCI worsening to a state of dementia is 10% each year in individuals over 65. Those diagnosed with MCI are three times more likely to develop dementia in the 5 years after diagnosis than healthy individuals.
- Diagnosis which is often difficult because of the heterogeneity and complexity of MCI cases, usually, is based on the patient's own or close people's report of a disorder and objective evidence of alterations in one or more cognitive domains, which can be assessed through clinical interviews, validated scales, such as MoCA ⁇ Montreal Cognitive Assessment) and MMSE (Mini-Mental State Examination), and neuropsychological tests.
- MoCA ⁇ Montreal Cognitive Assessment MoCA ⁇ Montreal Cognitive Assessment
- MMSE Mini-Mental State Examination
- MCI mood-related alterations
- depression with a prevalence of 25-40%.
- the relationship between MCI and depression is complicated: on the one hand, cognitive impairment could be a consequence of depression; on the other hand, depression could be an early manifestation of cognitive decline. Other widespread symptoms are anxiety, irritability, aggression, and apathy.
- the main challenge for the treatment of patients with MCI is to be able to act early on risk factors to slow the progression of neurodegenerative processes and avoid or delay the onset of dementia. This is complemented, where necessary, by interventions to counter depression and sleep disorders, taking special care to ensure that the therapies used do not have side effects that worsen patients' quality of life.
- cholinesterase inhibitors normally used in dementia cases, fail to prevent or slow the progression of cognitive decline and the transition from MCI to dementia.
- One purpose of the present invention is to make available a composition and a formulation, containing said composition and, optionally, additives or excipients or carriers of acceptable food or pharmaceutical grade.
- Another purpose of the present invention is to make available a composition and a formulation, containing said composition and, optionally, additives or excipients or carriers of acceptable food or pharmaceutical grade, that counteracts the onset and/or slows the progression of dementia and/or cognitive decline states.
- a further purpose of the present invention is to make available a composition and a formulation, containing said composition and, optionally, additives or excipients or carriers of acceptable food or pharmaceutical grade, that improves the quality of life of patients with cognitive decline and/or dementia.
- Still another purpose of the present invention is to make available a composition and a formulation, containing said composition and, optionally, additives or excipients or carriers of acceptable food or pharmaceutical grade, which can be employed, without causing side effects, as a support or complement to conventional therapy of neurodegenerative diseases, particularly cognitive decline and/or dementia, that acts on the underlying causes of the neurodegenerative disease, and thus is capable of preventing and/or slowing down the disease itself.
- a composition and a formulation containing said composition and, optionally, additives or excipients or carriers of acceptable food or pharmaceutical grade
- a composition and a formulation containing said composition and, optionally, additives or excipients or carriers of acceptable food or pharmaceutically grade, for use in a method for the prevention and treatment of cognitive decline and/or forms of dementia, in particular a composition and a formulation, containing said composition and, optionally, additives or excipients or carriers of acceptable food or pharmaceutically grade, to counteract inflammation, oxidative stress and cerebrovascular damage at the level of the central nervous system.
- composition comprising or alternatively consisting of:
- an epigallocatechin gallate preferably an epigallocatechin-3-gallate (EGCG)
- an extract of Camellia sinensis L. titrated in epigallocatechin gallate (EGCG) or, preferably, titrated in epigallocatechin-3- gallate (EGCG)
- EGCG epigallocatechin gallate
- EGCG epigallocatechin-3-gallate
- Camellia sinensis L.
- said (i) may be a green tea extract, e.g., of the type 90%P (total Polyphenols) 60%C (total Catechins) 40E (EGCG -epigallo-catechine-gallate) or similar, e.g., an extract from green tea leaves made with an extraction solvent, e.g., water/ethyl acetate.
- a green tea extract e.g., of the type 90%P (total Polyphenols) 60%C (total Catechins) 40E (EGCG -epigallo-catechine-gallate) or similar, e.g., an extract from green tea leaves made with an extraction solvent, e.g., water/ethyl acetate.
- said (i) may be a green tea extract that, for example, may comprise or, alternatively, consist of polyphenols, catechins, EGCG and/or caffeine, e.g. said (i) may be a green tea extract that, for example, may comprise or, alternatively, consist of from 90% to 98% of total polyphenols, from 60% to 90% of total catechins, from 40% to 55% of EGCG and from 5% to 15% of caffeine, as measured by HPLC method.
- said (i) can also be a green tea extract with reduced caffeine content or without caffeine (decaffeinated green tea) e.g., it can be a green tea extract that comprises or alternatively consists of from 90% to 98% of total polyphenols, from 60% to 90% of total catechins and from 40% to 55% of EGCG as measured by HPLC method.
- a dry extract of Green Tea leaves with added caffeine may be of the type:
- said (ii) may be, for example, a dry extract of Crocus sativus L, Iridaceae, e.g., a dry saffron extract or saffron powder capable of containing safranal in an amount from 0.1% to 50% by weight (UV-visible ISO 3632 analytical method; UHPLC), preferably from 0.2% to 30% by weight, even more preferably from 0.3% to 15%, e.g., from 0.35% to 5%.
- Saffron is made from the stigmas of the crocus.
- the actives are, for example, safranal, crocine and/or picrocrocrocine.
- harvested saffron stigmas are dried and then extracted in water.
- said (ii) may be an extract of Crocus sativus (L.), and/or tryptophan.
- said composition may also comprise (iii) a trans-resveratrol, or resveratrol, preferably from Polygonum cuspidatum or Vitis vinifera, to give a (i)+(ii)+(iii) composition.
- a trans-resveratrol or resveratrol, preferably from Polygonum cuspidatum or Vitis vinifera, to give a (i)+(ii)+(iii) composition.
- said component (iii) may be, for example, a trans-resveratrol or resveratrol, e.g. it may have formula C14H12O3 and/or molecular weight of about 228.24 g/mol and/or CAS No. 501-36-0, preferably it may be from Polygonum cuspidatum or Vitis vinifera,' said component (iii) may give a (i)+(ii)+(iii) composition, where said (ii) can be an extract of Crocus sativus (L), and/or tryptophan.
- a trans-resveratrol or resveratrol e.g. it may have formula C14H12O3 and/or molecular weight of about 228.24 g/mol and/or CAS No. 501-36-0, preferably it may be from Polygonum cuspidatum or Vitis vinifera,' said component (iii) may give a (i)+(ii)+
- said composition may also comprise (iv) citicoline or other sources of choline, to give a (i)+(ii)+(iv) composition, or (i)+(ii)+(iii)+(iv) composition, where said (ii) may be an extract of Crocus sativus (L), and/or tryptophan.
- citicoline or other sources of choline, to give a (i)+(ii)+(iv) composition, or (i)+(ii)+(iii)+(iv) composition, where said (ii) may be an extract of Crocus sativus (L), and/or tryptophan.
- Said component (iv) may, for example, currently be marketed under the trade name Cognizin ®.
- said composition also may comprise (v) at least one compound selected from the group comprising or, alternatively, consisting of selenium, zinc, vitamin C, vitamin D, vitamin E, or vitamin B12, to give a (i)+(ii)+(v), or (i)+(ii)+(iii)+(v), or (i)+(ii)+(iv)+(v), or (i)+(ii)+(iii)+(iv)+(v) composition.
- at least one compound selected from the group comprising or, alternatively, consisting of selenium, zinc, vitamin C, vitamin D, vitamin E, or vitamin B12 to give a (i)+(ii)+(v), or (i)+(ii)+(iii)+(iv)+(v) composition.
- said composition also may comprise (vi) an oleuropein, preferably obtained from a dry extract of the olive tree Olea europaea (L), to give a (i)+(ii)+(vi), or (i)+(ii)+(iii)+(vi), or (i)+(ii)+(iv)+(vi), or (i)+(ii)+(iii)+(iv)+(vi), or (i)+(ii)+(v)+(vi), or (i)+(ii)+(iii)+(v)+(vi), or (i)+(ii)+(iv)+(v)+(vi), or (i)+(ii)+(iii)+(iv)+(v)+(vi) composition.
- an oleuropein preferably obtained from a dry extract of the olive tree Olea europaea (L)
- said composition also comprises (vii) at least one substance selected from the group comprising or, alternatively, consisting of a dry extract of Bacopa monnieri, a dry extract of Curcuma longa (L), omega-3 fatty acids, preferably DHA or docosahexaenoic acid, or phosphatidylserine, to give a (i)+(ii)+(vii), or (i)+(ii)+(vi)+(vii), or (i)+(ii)+(iii)+(vi)+(vii), or (i)+(ii)+(iv)+(vi)+(vii), or (i)+(ii)+(iii)+(iv)+(vi)+(vii), or (i)+(ii)+(v)+(vi)+(vii), or (i)+(ii)+(v)+(vi)+(vii), or (i)+(ii)+(v)+(vi)+(vii), or
- compositions for use as a medicament; preferably, said composition is for use in the prevention and/or treatment of neurodegenerative diseases; preferably, said neurodegenerative diseases are selected from cognitive decline and/or dementia.
- a formulation comprising a composition, among those mentioned above, for use as a medicament; preferably, said formulation is for use in the prevention and/or treatment of neurodegenerative diseases; preferably, said neurodegenerative diseases are selected from cognitive decline and/or dementia.
- the composition object of the present invention comprises or alternatively consists of (I) an epigallocatechin gallate (EGCG), preferably an epigallocatechin-3-gallate, preferably derived or obtained from dry extract of green tea Camellia sinensis (L.) titrated in epigallocatechin gallate (EGCG), preferably titrated in epigallocatechin-3- gallate, and/or (II) a saffron extract (Crocus sativus), preferably a saffron dry extract or a saffron powder (Crocus sativus), and/or tryptophan.
- EGCG epigallocatechin gallate
- EGCG epigallocatechin-3-gallate
- EGCG epigallocatechin-3-gallate
- EGCG epigallocatechin-3-gallate
- EGCG epigallocatechin-3-gallate
- EGCG epigallocatechin-3-gallate
- EGCG epigallocatechin-3-gal
- said (I) is a green tea extract of the type 90%P (total Polyphenols) 60%C (total Catechins) 40E (EGCG -epigallo-catechine-gallate) or similar, e.g., from green tea leaves with an extraction solvent, e.g., water/ethyl acetate.
- an extraction solvent e.g., water/ethyl acetate.
- said (I) is a green tea extract that may comprise or, alternatively, consist of polyphenols, catechins, EGCG and/or caffeine, e.g. said (I) may be a green tea extract that, for example, may comprise or, alternatively, consist of from 90% to 98% of total polyphenols, from 60% to 90% of total catechins, from 40% to 55% of EGCG and from 5% to 15% of caffeine, as measured by HPLC method.
- said (I) can also be a green tea extract with reduced caffeine content or without caffeine (decaffeinated green tea) e.g., it can be a green tea extract that comprises or alternatively consists of from 90% to 98% of total polyphenols, from 60% to 90% of total catechins and from 40% to 55% of EGCG as measured by HPLC method.
- said (II) may be a dry extract, or powder, of saffron (Crocus sativus) titrated in safranal, for example, at 0.2%; or 0.3%; or 0.4%; 0.5%; or 1%; or 1.5%; or 2%; or 3%; or 4%; or 5%, by weight.
- saffron Crocus sativus
- it is an extract that is marketed by the company Inoreal having the name Satiereal WS.
- a solid/liquid extraction can be made with an extraction solvent containing from 30% to 50% of ethanol and fom 70% to 50% of water, the extract is supported on acacia gum, for example.
- the composition may comprise in addition to (I) and (II) also (ill) a trans-resveratrol, or resveratrol, from Polygonum cuspidatum or Vitis vinifera, where said (II) may be an extract of Crocus sativus (L), and/or tryptophan.
- a trans-resveratrol, or resveratrol from Polygonum cuspidatum or Vitis vinifera, where said (II) may be an extract of Crocus sativus (L), and/or tryptophan.
- the composition may comprise in addition to (I), (II) and (ill) also (iv) a citicoline or other source of choline such as phosphatidylcholine, where said (II) may be an extract of Crocus sativus (L), and/or tryptophan.
- the composition may comprise in addition to (I), (II), (ill), and (iv) also (v) a source of selenium such as, for example, an L-selenomethionine obtained from Saccharomyces cerevisiae strains, and/or a source of zinc such as, for example, a zinc bis-glycinate, and/or one or more vitamins such as, for example, a vitamin C (CAS No.
- a vitamin D preferably a vitamin D3 (CAS No. 67-97-0), a vitamin E (CAS No. 7695-91-2) or a vitamin B, preferably a vitamin B12 (CAS No. 68-19-9).
- the composition may comprise in addition to (I), (II), (ill), (iv) and (v) also (vi) an oleuropein, preferably extracted from a dry extract of olive tree titrated at 40 percent oleuropein (CAS No. 32619-42-4).
- an oleuropein preferably extracted from a dry extract of olive tree titrated at 40 percent oleuropein (CAS No. 32619-42-4).
- composition may further comprise: Dry extract of Bacopa monnieri;
- said epigallocatechin-3-gallate is preferably derived from dry extract of green tea ⁇ Camellia sinensis).
- Epigallocatechin-3-gallate is a molecule with antioxidant and anti-inflammatory properties, as well as being able to cross the blood-brain barrier.
- Said dry extract of saffron ⁇ Crocus sativus is used, according to the present invention, to take advantage of its characteristic of significantly improving sleep quality and mood, as often treated subjects tend to suffer from anxiety and depression.
- said trans-resveratrol or resveratrol is preferably derived from Polygonum cuspidatum or Vitis vinifera.
- the brain requires constant blood flow through the network of cerebral veins and arteries to replenish itself with oxygen, glucose, and other essential nutrients, but also to remove waste products of metabolism.
- a source of choline is, for example, citicoline.
- Cicoline is used as a precursor to choline, an essential nutrient involved in numerous processes at the neuronal level. Choline, in cholinergic neurons, is acetylated to give acetylcholine, a key neurotransmitter involved in numerous areas, including memory. As an example, citicoline may be the one currently commercially available as Cognizin ®, in the form of a white crystalline powder.
- Vitamin E another preferred component of the composition according to the present invention, is a fat-soluble antioxidant par excellence, protecting the cell from free radical-induced damage at the level of cell membranes.
- Vitamin C contributes to the normal functioning of the nervous system and normal psychological function.
- Vitamin B12 contributes to the normal functioning of the nervous system and contributes to normal psychological function.
- Vitamin D preferably vitamin D2 and/or D3, could be useful in the composition of the present invention.
- Zinc contributes to normal cognitive function and cell protection from oxidative stress.
- said oleuropein is preferably derived from a dry extract of olive tree ⁇ Olea eurepaea L).
- Oleuropein is one of the main phenolic components of the olive tree ⁇ Olea europaea L). Specifically, the chemical structure of oleuropein contains an ortho-diphenolic group that can act as a scavenger of ROS, stabilizing free radicals via an intramolecular hydrogen bond. Tryptophan is an essential amino acid: the body is unable to ex novo synthesize it. Therefore, it must be taken through the diet. Being the precursor of serotonin (5-HT), supplementation of tryptophan, throughout the day, can increase levels of this neurotransmitter in the brain.
- 5-HT serotonin
- Bacopa monnieri extract is useful for memory and cognitive function, as well as promoting mental well-being.
- the extract derived from Bacopa monnieri due to its bioactive components, including Bacoside A, could play a role in protecting the brain from oxidative damage and cognitive impairment.
- Said omega-3 fatty acids are, for example, according to the present invention, preferably DHA or docosahexaenoic acid. DHA contributes to the maintenance of normal brain function.
- Phosphatidylserine is one of the main phospholipids that make up cell membranes and has been found, in particular, at the level of neuronal cells, where it plays an essential role related to membrane viscosity.
- the effectiveness of the composition comes from the surprising synergistic effect of its essential components in association with each other, further enhanced by the presence of its optional components, also in association with each other.
- This synergistic effect is evident from the fact that although the individual components are known as such for example to show efficacy on inflammation, oxidative stress, to have generic antioxidant activity, protective activity on the cerebrovascular system and cognitive function, and to have mood-regulating activities, their combination does not provide individual benefits on each of these aspects, but rather has an overall action in the prevention and/or treatment of neurodegenerative diseases, particularly cognitive decline and dementia.
- Figure 1 shows the results of the tests conducted for dose-response assessment with regard to cell viability for components (I), (ill), (ii);
- Figure 2 shows the results of tests conducted to evaluate the best combination of components (I), (ii), (ill) and (iv) according to the invention, excluding a cytotoxic effect;
- Figure 3 shows the results of tests conducted to evaluate the passage through the BBB (Brain Blood Barrier);
- Figure 4 shows the results of tests designed at determining the integrity of the BBB (Marveld and Claudin 5);
- Figure 5 shows the results of tests designed at evaluating the protective effect of compounds and compositions thereof according to the invention, on mitochondrial metabolism in the presence of oxidative stress;
- Figure 6 shows the results of tests designed to evaluate the antioxidant effect of the compounds and compositions of the invention, in the presence of oxidative stress
- Figure 7 shows the results of tests designed to assess nitric oxide (NO) production in the presence of oxidative stress
- Figure 8 shows the results of tests designed to assess inflammatory markers (IL-2 and TNF-a) in the presence of oxidative stress
- Figure 9 shows the results of tests designed to assess the production of BDNF (Brain Derived Neurotrophic Factor) in the presence of oxidative stress
- Figure 10 shows the results of tests designed to assess the activation of intracellular apoptotic mechanisms (p53 and Cytochrome C) activated in the presence of oxidative stress;
- BDNF Brain Derived Neurotrophic Factor
- Figure 11 shows the results of tests designed to evaluate the activation of intracellular energy metabolism mechanisms (SIRT1 and NRF2) activated in the presence of oxidative stress;
- Figure 12 shows the results of tests designed to assess the activation of intracellular mechanisms activated in the presence of oxidative stress such as APP and pTau expression;
- Figure 13 shows the results of tests designed to evaluate the protective effect of compounds and combinations thereof in compositions according to the invention in the presence of iron accumulation
- Figure 14A shows the results of tests designed to assess neurodegenerative damage caused by iron accumulation
- Figure 14B shows the results of tests designed to verify the absence of Fe 3+ accumulation in astrocytes
- Figure 15 shows the results of tests designed to evaluate lipid peroxidation in the presence of iron accumulation
- Figure 16 shows the results of tests to evaluate inflammatory markers (IL-1 and TNF-a) expressed in the presence of iron accumulation;
- Figure 17 shows the results of tests for evaluating the activation of intracellular mechanisms activated in the presence of iron accumulation (evaluated as BDNF Brain Derived Neurotrophic Factor-panel A; cytochrome C activity-panel B; p53 activity - panel C);
- Figure 18 shows the results of tests for evaluating the activation of intracellular mechanisms activated in the presence of iron accumulation (evaluated as SIRT1 - panel A; NRF2 - panel B; APP - panel C; pTAU - panel D).
- the composition object of the invention is as follows:
- composition C1 -Main components 1.
- EGCG Epigallocatechin-3-gallate
- composition C2 -Main components
- EGCG Epigallocatechin-3-gallate
- -tryptophan from 50 mg to 400 mg, preferably from 100 mg to 350 mg, such as 300 mg, per daily dose.
- EGCG Epigallocatechin-3-gallate
- Saffron Crocus sativus
- -tryptophan from 50 mg to 400 mg, preferably from 100 mg to 350 mg, such as 300 mg, per daily dose.
- a trans-resveratrol or resveratrol from Polygonum cuspidatum or Vitis vinifera from 50 mg to 300 mg, preferably from 100 mg to 200 mg, e.g., 150 mg, per daily dose, and/or an Oleuropein preferably extracted from dry extract of olive tree (Olea eurepaea L.) from 10 mg to 150 mg, preferably from 30 mg to 100 mg, e.g., 70 mg, is added to the C1 , or 02, or 03 compositions.
- said epigallocatechin-3-gallate is provided in an amount from 2 mg to 500 mg, preferably from 10 mg to 300 mg, even more preferably from 25 mg to 200 mg, and is preferably derived from dry extract of green tea ⁇ Camellia sinensis).
- the amount of green tea extract will depend on the titration of the extract.
- Said saffron extract is provided in an amount from 1 mg to 50 mg, preferably from 5 mg 40 mg, even more preferably from 10 mg to 30 mg, of saffron dry extract.
- Said trans-resveratrol or resveratrol from polygonum cuspidatum is provided in an amount from 5 mg to 500 mg, preferably from 10 mg to 300 mg, even more preferably from 40 mg to 200 mg.
- Said citicoline is present in an amount from 10 mg to 5 g, preferably from 50 mg to 4 g, even more preferably from 100 mg to 3 g.
- Said vitamin E is present in an amount from 2 mg to 60 mg, preferably from 5 mg to 50 mg, even more preferably from 6 mg to 40 mg.
- Said vitamin C is present in an amount from 10 mg to 500 mg, preferably from 40 mg to 400 mg, even more preferably from 60 mg to 300 mg.
- Said vitamin B 12 is present in an amount from 0.1 ug to 1 mg, preferably from 1 ug and 0.5 mg.
- Said vitamin D preferably vitamin D2 and/or D3, is present in an amount from 1 ug to 50 ug, preferably from 2 ug to 30 ug .
- Said zinc is present in an amount from 1 mg to 15 mg, preferably from 3 mg to 12 mg, even more preferably from 5 mg to 10 mg.
- Said selenium is present in an amount from 5 ug to 100 ug, preferably from 10 ug to 70 ug, even more preferably from 25 ug to 50 ug.
- Said oleuropein and/or extract from leaf of Olea europaea L. preferably titrated at 20%, or 30% or 40% or 50% of oleuropein, is present in an amount from 5 mg to 1 g, preferably from 10 mg to 0.75 g, even more preferably from 50 mg to 0.5 g.
- Said tryptophan is present in an amount from 5 mg to 500 mg, preferably from 40 mg to 400 mg, even more preferably from 80 mg to 300 mg.
- Said Bacopa monnieri extract is present in an amount from 50 mg to 1 g, preferably from 100 mg to 600 mg, even more preferably from 200 mg to 400 mg.
- Said curcuma is present in an amount from 10 g to 500 g of extract, preferably from 25 mg to 300 mg, even more preferably from 50 mg to 200 mg.
- omega-3s they are present in an amount from 50 mg to 5 g, preferably DHA is present in an amount from 50 mg to 1 g, preferably from 100 mg to 0.5 g, of DHA.
- the composition according to the invention will provide an amount of omega-3 such that an intake of 250 mg of DHA per day is provided.
- Said phosphatidylserine is present in an amount from 50 mg to 1 g, preferably from 100 mg to 0.75 g, even more preferably from 200 mg to 0.5 g.
- composition according to the present invention may be administered according to a dosage of one or two daily administrations, such as one or two tablets per day.
- a tablet may be of the type:
- Vitamin E 6 mg
- Vitamin C 60 mg
- Vitamin B12 1.25 ug
- Vitamin D3 2.5 ug
- compositions of the invention that comprise the composition of the invention, as well as commonly used additives and formulation agents or carriers of acceptable food or pharmaceutically grade.
- Said formulations may be in tablet, pouch, orosoluble stick, stick or gel form.
- the composition and formulation of the invention are advantageously formulated for oral (or sublingual) administration such as in sachet or tablet form.
- the dosage form of the formulation of the invention may be a solid form, such as tablet, chewable tablet, effervescent tablet, multi-layered tablet (e.g., time-release), capsule, lozenge, granules or powder (granules or powder to be dissolved in water or granules or orosoluble powder), or a semisolid form, such as soft-gel, or a liquid form, such as solution, suspension, dispersion, emulsion, or syrup; preferably the formulation of the invention is in a solid form for oral use, more preferably in a tablet or powder/granule form to be dispensed in sachets to be dissolved in water.
- Said composition of the invention can be a pharmaceutical composition, a medical device composition (Medical Device Regulation (EU) 2017/745 (MDR)), a food supplement and/or a food for special medical purposes (FSMP).
- EU Medical Device Regulation
- MDR Medical Device Regulation
- FSMP food for special medical purposes
- the protocol generally provides, among other things:
- BBB Brain Blood Barrier
- BDNF Brain Derived Neurotrophic Factor
- Phase 1 of the experimental protocol involves:
- Phase 2 involves:
- BBB Brain Blood Barrier
- Phase 3 involves:
- Figure 1 dose-response evaluation shows the results of tests conducted to evaluate the best concentration to be used for the components shown as (I), (II) and (ill) according to the present invention.
- Figure 2 shows the results of tests performed to evaluate the best combination of individual components (I), (II), (ill) and (iv) according to the present invention, excluding a cytotoxic effect.
- the tested combinations increased cell viability compared to the control (p ⁇ 0.05), but also compared to the individual substances (p ⁇ 0.05).
- the analysis showed that the tested substances are able to stimulate cell viability excluding any cytotoxic effect and confirming the safety of all tested compositions.
- the data obtained show a synergistic effect of the tested substances suggesting that their combination is able to improve neuronal homeostasis.
- Mix 4 seems to satisfy mitochondrial metabolism better, as it increases cell viability in a statistically significant manner compared to the other combinations (p ⁇ 0.05).
- Figure 3 shows the results of tests performed to evaluate passage through the Brain Blood Barrier (BBB). Specifically, tests on the BBB identified that the compositions according to the present invention are able to pass through the blood-brain barrier with a maximum peak at 12h, maintaining their effect even at 24h. In particular, the combined effect of the substances is able to increase permeability (p ⁇ 0.05), hypothesizing a possible antioxidant and neuroprotective role.
- BBB Brain Blood Barrier
- Composition Mix4 achieves a better value at 12h than the other compositions (p ⁇ 0.05). In addition, no composition exerted barrier exchange problems.
- Figure 5 shows the results of tests designed to evaluate the protective effect of compounds and compositions thereof according to the invention in the presence of oxidative stress.
- Analysis of mitochondrial metabolism shows that brain damage induced by H2O2 reduces cell viability compared with the untreated control (p ⁇ 0.05). All test substances are able to maintain and increase normal cellular physiological conditions. This effect is amplified for the combinations according to the present invention, stimulating mitochondrial well-being (p ⁇ 0.05).
- These data demonstrate that the compositions according to the present invention are able to activate survival mechanisms more effectively than the components taken individually (p ⁇ 0.05 vs individual substances).
- the Mix4 composition according to the invention increases the antioxidant effect the most (p ⁇ 0.05).
- NO production was observed by Griess assay.
- treatment with H 2 O 2 increased NO production compared with control (p ⁇ 0.05), supporting the hypothesis of cell loss previously observed through the viability and ROS production assay.
- the harmful action of H 2 O 2 was counteracted by stimulation with the single substances and combinations (p ⁇ 0.05).
- the beneficial effect of combinations was significantly greater in reducing NO production (p ⁇ 0.05) than treatment with single substances.
- the analysis on NO production confirms its central role in neurodegenerative processes.
- Figure 8 shows the results of tests designed to assess inflammatory markers during oxidative stress. It is reported that the oxidative stress condition correlates with an increase in IL-2 and TNFa.
- the analysis of inflammatory processes confirms the data obtained previously: the compositions examined decrease inflammatory markers, decreasing the inflammation that is generated following the induction of oxidative damage. In particular, all the compositions examined were seen to decrease the production of IL-2 and TNFa compared to cells treated with H 2 O 2 (p ⁇ 0.05).
- the compositions according to the present invention were found to be more effective and provided with synergistic effect, causing a decrease in the inflammatory picture related to oxidative stress compared to the control.
- the Mix4 composition according to the invention is confirmed to have a greater effect than that attributable to the sum of the effects of the individual active ingredients composing it (p ⁇ 0.05).
- Figure 9 shows the results of tests aimed at assessing the production of BDNF (Brain Derived Neurotrophic Factor), a neurotrophin required for the survival of neurons. Its presence was assessed following damage induced by H 2 O 2 and stimulation with individual components and combinations thereof according to the compositions of the present invention. These data were also compared with respect to treatment with exogenous BDNF, which was employed as a positive control to assess whether the substances/combinations were able to act on the endogenous mechanism of neurotrophin production.
- BDNF Brain Derived Neurotrophic Factor
- Figure 10 shows the results of tests designed to assess the activation of intracellular mechanisms triggered in the presence of oxidative stress.
- Loss of mitochondrial potential under conditions of oxidative stress triggers a cascade of events that activate apoptosis.
- p53 activity as a key factor involved in aging, oxidative stress and neurodegeneration, and cytochrome C activity, as a key regulator of cellular energy metabolism and apoptosis, were studied.
- the results obtained show an increase in p53 activity following induction of oxidative stress.
- There is a reduction in p53 activity after stimulation with the compounds taken individually and in combination in compositions according to the present invention (p ⁇ 0.05 compared with control).
- cytochrome C activity cells treated with H 2 O 2 showed an increase in its activity (p ⁇ 0.05) compared with control. Stimulation with compounds (i), (ii), (iii) and (iv) reduced cytochrome C activity back to basal levels. Treatment with the compositions of the invention results in a statistically significant reduction in cytochrome C activity compared to the individual actives (p ⁇ 0.05).
- FIG 11 shows the results of tests designed to assess the activation of intracellular mechanisms activated in the presence of oxidative stress .
- SIRT 1 an enzyme that deacetylates proteins that contribute to cellular regulation in response to stressors and in longevity
- PGC-1o peroxisome proliferator gamma coactivator 1
- NRF2 nuclear transcription factor erythroid-2 pathway
- the stimulus given by hydrogen peroxide decreases the activity of both SIRT1 and NRF2.
- Treatment with the single actives is able to increase the activity of these two markers.
- Treatment with the Mixtures is also found to statistically significantly increase the activity of SIRT1 and Nrf2 compared with the single actives (p ⁇ 0.05). In particular, among the Mixtures the most active appears to be Mix4.
- test substances alone and in combination, in preventing cell damage under conditions of cellular accumulation, mitochondrial metabolism, iron accumulation, and lipid peroxidation were assessed by pretreating neuronal cells with 300 pM Fe 3+ .
- Figure 13 shows the results of tests designed to evaluate the protective effect of compounds and combinations thereof in compositions according to the invention in the presence of iron accumulation.
- exposure to Fe 3+ significantly reduced mitochondrial metabolism compared with the control (p ⁇ 0.05); in contrast, all substances under investigation are able to maintain and increase normal cellular physiological conditions. In particular, this effect is amplified when the substances are combined in that they stimulate mitochondrial well-being more than control (p ⁇ 0.05) and compared with Fe 3+ Fe 3+ (p ⁇ 0.05).
- Figure 14 A and B show the results of tests designed to assess neurodegenerative damage caused by iron accumulation.
- Iron can be accumulated progressively in the brain during normal aging, and its accumulation is an important cause of brain damage. In particular, in neurodegenerative disorders, it may be stored abnormally, altering its transport mechanisms. An analysis was conducted to assess the amount of intracellular iron, and it was observed that all the compositions of the present invention are able to decrease its levels significantly (p ⁇ 0.05) compared with the control. In particular, it is evident how the synergistic action of the individual agents in the compositions according to the invention is able to further improve this condition, especially with regard to the efficacy of Mix 4.
- Figure 14A it is important to note that single actives are able to decrease iron accumulation only marginally. In contrast, treatment with the combined actives was able to modulate this accumulation. In fact, the number of positive cells decreased significantly compared with treatment with the individual agents alone ( Figure 14B).
- Figure 15 shows the results of tests designed to assess lipid peroxidation as measured by MDA levels in the presence of iron accumulation. Exposure to Fe 3+ increased MDA levels significantly compared to control (p ⁇ 0.05). Treatment with test substances (I), (ii), (ill) and (iv) was found to significantly reduce MDA levels (p ⁇ 0.05), and all combinations thereof were found to significantly increase the neuroprotective effect (p ⁇ 0.05), suggesting an active role of these new formulations in counteracting lipid peroxidation. These results confirm the ability of the combinations to counteract the oxidative condition caused by iron accumulation and indicate the ability of the combinations to counteract iron-dependent damage by preventing iron accumulation. In particular, Mix 4 composition better supports protection.
- Figure 17 A shows the test results for the evaluation of BDNF (Brain Derived Neurotrophic Factor) in the presence of damage generated by iron accumulation. All compounds considered showed the ability to induce BDNF production compared with the untreated control (X-axis) and especially compared with damage induced by Fe 3+ accumulation (p ⁇ 0.05).
- BDNF Brain Derived Neurotrophic Factor
- Mix 1 and Mix 4 had the most appreciable effects with a statistically significant reduction in P53 and cytochrome C activity compared with Fe 3+ -treated control cells and individual actives (p ⁇ 0.05).
- Figure 18 panel C shows how combinations of the test substances amplify the effect of the individual actives: APP activity decreases statistically significantly (p ⁇ 0.05) with respect to both iron-treated cells and individual actives for all mixtures considered.
- compositions according to the invention inhibit key molecular pathways involved during cognitive decline, maintaining proper homeostasis of neuronal cells.
- compositions of the invention can be freely used, having shown no inherent toxicity.
- compositions according to the invention have shown different synergies of efficacy.
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Abstract
La présente invention a pour objet une composition et une formulation contenant ladite composition et, éventuellement, des additifs ou des excipients ou des supports de qualité alimentaire ou pharmaceutique acceptable. En outre, la présente invention concerne une composition et une formulation contenant ladite composition et, éventuellement, des additifs ou des excipients ou des supports de qualité alimentaire ou pharmaceutique acceptable pour une utilisation dans une méthode de prévention et/ou de traitement du déclin cognitif et/ou des formes de démence. La présente invention a pour objet une composition destinée à être utilisée dans une méthode de prévention et de traitement du déclin cognitif et/ou des formes de démence, en particulier une composition pour contrer l'inflammation, le stress oxydatif et les lésions cérébrovasculaires au niveau du système nerveux central en tant que causes de la neurodégénérescence conduisant à l'apparition du déclin cognitif et au développement de la démence.
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