WO2023139514A1 - Composition à composants multiples comprenant du gallate d'épigallocatéchine et un extrait sec de safran, et son utilisation dans la prévention et le traitement de la maladie de parkinson - Google Patents
Composition à composants multiples comprenant du gallate d'épigallocatéchine et un extrait sec de safran, et son utilisation dans la prévention et le traitement de la maladie de parkinson Download PDFInfo
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- WO2023139514A1 WO2023139514A1 PCT/IB2023/050466 IB2023050466W WO2023139514A1 WO 2023139514 A1 WO2023139514 A1 WO 2023139514A1 IB 2023050466 W IB2023050466 W IB 2023050466W WO 2023139514 A1 WO2023139514 A1 WO 2023139514A1
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- Prior art keywords
- vitamin
- extract
- mixture
- titrated
- crocus sativus
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Definitions
- the present invention relates to multicomponent compositions comprising an epigallocatechin gallate (EGCG) and/or an extract of Camellia sinensis, titrated in EGCG epigallocatechin gallate, an extract of Crocus sativus, and optionally, a lipoic acid or a pharmaceutical or food grade salt thereof, and optionally, at least one omega-3 fatty acid, said mixture being capable of treating, preventively and/or curatively, Parkinson's disease, particularly with a focus on non-motor symptoms of both the prodromal and full-blown stages of the disease.
- EGCG epigallocatechin gallate
- Camellia sinensis titrated in EGCG epigallocatechin gallate
- an extract of Crocus sativus an extract of Crocus sativus
- a lipoic acid or a pharmaceutical or food grade salt thereof optionally, at least one omega-3 fatty acid
- Parkinson's disease is the second-largest neurodegenerative disease in the world, affecting 100 to 200 people per 100,000, and is characterized by a rapid incidence above age 60. Generally, it is diagnosed on average at age 70, when the disease is well established and neurodegeneration has been in progress for some time. Parkinson's disease is an extremely complex disease that includes neuropsychiatric and non-motor manifestations in addition to motor neuron degeneration and death.
- Parkinson's The cardinal symptomatic features of Parkinson's are tremor (resting tremor), bradykinesia and rigidity.
- tremor resting tremor
- bradykinesia and rigidity.
- neuropsychiatric symptoms such as depression, hallucinations, and cognitive malaise also occur concurrently with the motor symptoms.
- Parkinson's disease is also characterized by a rather long prodromal period, which can begin up to 20 years before diagnosis.
- This early phase of the disease is mainly characterized by the onset of various non-motor symptoms including hyposmia, RBD (rapid eye movement sleep behavior disorder), constipation (due to altered bowel motility, worsened later by medication use), urinary disorders, sleep disorders (difficulty in falling asleep and staying asleep), mood disorders (apathy, anger, moodiness, sadness, pessimism, anxiety), and leg pain of both muscular and neuropathic origin. All these symptoms are perceived by patients to be the most disabling in the early period of the disease.
- the present invention addresses and solves the aforementioned technical problem by providing a product for the treatment, preventive and/or curative, of Parkinson's disease, particularly of non-motor symptoms in both the prodromal phase and the full-blown phase and/or to support the treatment of motor and non-motor symptoms in the full-blown phase.
- the present invention provides a product with strong antioxidant action, considering that oxidative stress is the primary cause of neuronal degeneration (and thus of motor symptoms), and comprising active ingredients that can alleviate non-motor symptoms, such as peripheral neuropathic pain, constipation, sleep disorders, and/or mood disorders.
- the present invention provides multi-component mixtures or compositions (mixtures or compositions of the invention) comprising, (b) an epigallocatechin gallate (EGCG) and/or an extract of Camellia sinensis (L.) (green tea) titrated in epigallocatechin gallate (EGCG), (c) an extract of Crocus sativus, optionally, (a) a lipoic acid or a salt thereof, optionally (d) at least one omega-3 fatty acid (EPA- DHA), and optionally, (e) at least one vitamin, and/or (f) at least one strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus, and/or (g) at least one prebiotic, as set forth in this description and in the attached claims.
- EGCG epigallocatechin gallate
- Camellia sinensis L.
- EPA- DHA omega-3 fatty acid
- the present invention provides multi-component mixtures or compositions (mixtures or compositions of
- Said preventive and/or curative treatment activity of the mixtures or compositions of the invention is due to the specific and innovative combination of the active components (as defined in this description) in that each component acts through complementary and/or synergistic and/or cooperative mechanisms of action (e.g., with antioxidant, anti-inflammatory, mood-modulating, or gut-regulating activity), making the mixtures and compositions of the invention particularly effective in their action.
- each component acts through complementary and/or synergistic and/or cooperative mechanisms of action (e.g., with antioxidant, anti-inflammatory, mood-modulating, or gut-regulating activity), making the mixtures and compositions of the invention particularly effective in their action.
- lipoic acid has demonstrated anti-inflammatory and antioxidant action at the level of the central nervous system in both in vitro and in vivo studies.
- a supplement comprising lipoic acid has shown efficacy in the treatment of peripheral neuropathy, particularly peripheral neuropathy caused by long-term use of L-dopa.
- Green tea extract is also known for its strong antioxidant action, and in several observational studies its consumption has been associated with a reduced risk of Parkinson's disease onset.
- epigallocatechin gallate has been found to be effective in in vivo/ex-vivo studies in reducing neuronal death by apoptosis, as it is able to interfere with pathways that regulate the cell cycle, such as mTOR/p- AKT/P-GSK3p.
- Crocus sativus extract has properties of mood modulation (maintenance of normal mood) and improvement of sleep quality.
- omega-3 fatty acids especially DHA
- DHA is known to be associated with the maintenance of normal brain function.
- DHA is able to repair brain damage by significantly increasing the amount of TH-positive neurons at the level of the gray substantia in animal models of Parkinson's disease.
- the administration of omega-3 fatty acids in Parkinson's patients appears to act on an improvement of depressive symptoms.
- mixtures and compositions of the invention showing a high safety profile, are easy to prepare and cost-effective.
- Figure 1 shows the results of the dose-response study of cell viability on N27 cells related to the compounds EGCG (from Camellia sinensis extract, referred to as “green tea") (a), decosahexanoic acid (DHA) (b) and Crocus sativus extract (referred to as “saffron”) (c) at different concentrations (between 200 and 25, e.g., 50 piM or 100 piM).
- the lipoic acid assay was replicated based on a previously published study, and was maintained in all subsequent tests (Molinari, Claudio, et al.
- Figure 2 shows the results of permeability analysis by the experimental blood-brain barrier (BBB) model.
- the test results are expressed as the mean ⁇ SD (%) of 5 biological replicates normalized against the control, the p-value, calculated according to statistical analysis, is in all cases ⁇ 0.05 against the control. All concentrations are expressed as piM.
- Figure 3 shows data related to the validation of the Parkinson's disease (PD) model using 6-OHDA (6- hydroxydopamine) at different concentrations (between 200 and 25 piM) and successive times (1 and 6 hours (a), 12 and 24 hours (b)).
- MTT test results are expressed as mean ⁇ SD (%) of 5 biological replicates normalized against the control.
- Asterisks above histogram bars indicate p-values calculated according to statistical analysis, specifically: * p ⁇ 0.05 vs control. All concentrations are expressed as pi M.
- Figure 4 shows data related to the evaluation of neuroprotective effects under PD condition, specifically with respect to the measurement of cell viability by analysis of mitochondrial metabolism.
- MTT test results are expressed as mean ⁇ SD (%) of 5 biological replicates normalized against the control. Symbols above histogram bars indicate p-values calculated according to statistical analysis, specifically: * p ⁇ 0.05 vs control; ** p ⁇ 0.05 vs 6-OHDA; * ** p ⁇ 0.05 vs both (control and 6-OHDA); lines p ⁇ 0.05 vs mixture 1 (MIX 1); # p ⁇ 0.05 vs mixture 3 (MIX 3). All concentrations are expressed as pi M.
- Figure 5 shows data related to the evaluation of neuroprotective effects under PD condition, specifically with respect to the measurement of ROS (reactive oxigen species) production.
- ROS production test results are expressed as mean ⁇ SD (%) of 5 biological replicates normalized against the control.
- Symbols above histogram bars indicate p-values calculated according to statistical analysis, specifically: * p ⁇ 0.05 vs control; **p ⁇ 0.05 vs 6-OHDA; * ** p ⁇ 0.05 vs both (control and 6-OHDA); # p ⁇ 0.05 vs single substances; lines p ⁇ 0.05 vs mixture 1 (MIX 1); p ⁇ 0.05 vs mixture 3 (MIX 3). All concentrations are expressed as pi M.
- Figure 6 shows data related to the evaluation of neuroprotective effects under PD condition, particularly with respect to lipid peroxidation activity.
- Lipid peroxidation test results are expressed as mean ⁇ SD (%) of 5 biological replicates normalized against the control. Symbols above histogram bars indicate p-values calculated according to statistical analysis, specifically: * p ⁇ 0.05 vs control; **p ⁇ 0.05 vs 6-OHDA; * ** p ⁇ 0.05 vs both (control and 6-OHDA); # p ⁇ 0.05 vs single substances; lines p ⁇ 0.05 vs mixture 1 (MIX 1); p ⁇ 0.05 vs mixture 3 (MIX 3). All concentrations are expressed as pi M.
- Figure 7 shows data related to the evaluation of neuroprotective effects under PD condition; specifically with respect to nitric oxide (NO) production. NO production test results are expressed as mean ⁇ SD (%) of 5 biological replicates normalized against the control. Symbols above histogram bars indicate p-values calculated according to statistical analysis, specifically: * p ⁇ 0.05 vs control; **p ⁇ 0.05 vs 6-OHDA; * ** p ⁇ 0.05 vs both (control and 6-OHDA); # p ⁇ 0.05 vs single substances; lines p ⁇ 0.05 vs mixture 1 (MIX 1); p ⁇ 0.05 vs mixture 3 (MIX 3). All concentrations are expressed as pi M.
- Figure 8 shows data related to the evaluation of neuroprotective effects under PD condition, specifically with respect to the measurement of inflammatory markers TFNo (a), IL1b (b) and IL6 (c). TNFo and Interleukins production test results are expressed as mean ⁇ SD (%) of 5 biological replicates normalized against the control. Symbols above histogram bars indicate p-values calculated according to statistical analysis, specifically: * p ⁇ 0.05 vs control; **p ⁇ 0.05 vs 6-OHDA; * ** p ⁇ 0.05 vs both (control and 6-OHDA); # p ⁇ 0.05 vs single substances; lines p ⁇ 0.05 vs mixture 1 (MIX 1); p ⁇ 0.05 vs mixture 3 (MIX 3). All concentrations are expressed as piM.
- Figure 9 shows data related to the evaluation of neuroprotective effects under PD condition, specifically with respect to PINK1 (a) and Parkin (b) activity.
- the results of PINK1 and Parkin activity assay are expressed as mean ⁇ SD (%) of 5 biological replicates normalized against the control. Symbols above histogram bars indicate p-values calculated according to statistical analysis, specifically: * p ⁇ 0.05 vs control; **p ⁇ 0.05 vs 6-OHDA; * ** p ⁇ 0.05 vs both (control and 6-OHDA); # p ⁇ 0.05 vs single substances; lines p ⁇ 0.05 vs mixture 1 (MIX 1); p ⁇ 0.05 vs mixture 3 (MIX 3). All concentrations are expressed as pi M.
- a first aspect of the present invention relates to a mixture (in short, mixture of the invention) comprising or alternatively consisting of (b) an epigallocatechin gallate (EGCG) and/or an extract of Camellia sinensis (L.) (or green tea extract), (c) an extract of Crocus sativus (L), optionally, (a) a lipoic acid, optionally, (d) at least one omega-3 fatty acid, and optionally, (e) at least one vitamin (a vitamin D, a vitamin E, and/or at least one B group vitamin), and/or (f) at least one strain of bacteria belonging to the genus Bifidobacterium and/or Lactobacillus, and/or (g) at least one prebiotic.
- a second aspect of the present invention relates to a composition (in short, composition of the invention) comprising said mixture of the invention and at least one pharmaceutical or food grade acceptable additive and/or excipient.
- a third aspect of the present invention relates to said mixture or composition of the invention containing said mixture, for use in a method of treatment, preventive and/or curative, of Parkinson's disease (PD), particularly of non-motor symptoms in both the prodromal phase and the full-blown phase and/or to support the treatment of motor and non-motor symptoms in a subject in need thereof.
- PD Parkinson's disease
- a fourth aspect of the present invention relates to a method of treatment, preventive and/or curative, of Parkinson's disease (PD), specifically a method of treatment of non-motor symptoms in both the prodromal phase and the full-blown phase and/or to support the treatment of motor and non-motor symptoms, in a subject in need thereof, by administering to said subject a therapeutically effective amount of the mixture or composition of the invention, containing said mixture.
- PD Parkinson's disease
- a fifth aspect of the present invention relates to the use of said mixture, or composition of the invention containing said mixture, to reduce oxidative stress conditions in healthy subjects.
- a mixture comprising or alternatively consisting of: (b) an epigallocatechin gallate (EGCG) and/or a green tea extract titrated in EGCG, (c) an extract of Crocus sativus (L.) (e.g., commercial product Affron® or Satiereal®), optionally, (a) a lipoic acid or a pharmaceutical or food grade salt thereof, and optionally (d) at least one omega-3 fatty acid or a pharmaceutical or food grade salt thereof or a precursor thereof (preferably EPA-DHA).
- EGCG epigallocatechin gallate
- L. an extract of Crocus sativus
- L. e.g., commercial product Affron® or Satiereal®
- at least one omega-3 fatty acid or a pharmaceutical or food grade salt thereof or a precursor thereof preferably EPA-DHA
- Lipoic acid (or alpha-lipoic acid or (R)(+)alpha-lipoic acid, IUPAC name (R)-5-(1,2-dithiolane-3- yl)pentanoic acid) is a small amphipathic molecule (empirical formula C8H14O2S2); example of CAS no. 1077-28-7. It exists in nature in two forms, as a cyclic disulfide (oxidized form) or as an open chain under the name dihydrolipoic acid, showing two sulfhydryl groups at positions 6 and 8; the two forms are easily interconverted by redox reactions.
- Epigallocatechin gallate is a type of catechin (example of CAS no. 989-51-5) abundant in tea, particularly in green tea (e.g., Camellia sinensis (L.)), with high antioxidant properties.
- the mixture according to the present invention comprises (b) and (c), as described in the present context.
- the mixture of the present invention comprises (a), (b), and (c), as described in the present context.
- the mixture of the present invention comprises (a), (b), (c) and (d), as described in the present context.
- Said (b) epigallocatechin gallate may be an extract of a tea plant (e.g., Camellia sinensis) comprising EGCG, preferably an extract (or dry extract) of Camellia sinensis (L.) Kuntze titrated in EGCG at a percentage by weight in the range from 5% or 10% to 95% with respect to the total weight of the extract (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%), preferably from 20% to 45% (e.g., about 40%).
- a tea plant e.g., Camellia sinensis
- an extract (or dry extract) of Camellia sinensis (L.) Kuntze titrated in EGCG at a percentage by weight in the range from 5% or 10% to 95% with respect to the total weight of the extract (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%), preferably from 20% to 45% (e.g., about 40%).
- Said extract of Camellia sinensis comprising EGCG usable in the context of the present invention may advantageously be an extract obtained and titrated according to standard procedures known to a person skilled in the art and/or reported in the literature, e.g., a dry extract of Camellia sinensis leaves with hydroalcoholic extraction solvent (e.g., ethanol/water) with titration in EGCG by spectroscopic method, e.g., HPLC.
- hydroalcoholic extraction solvent e.g., ethanol/water
- Dry extract in the context of the present invention is understood to mean an extract in a powder form having a water content by weight percentage from 0.05% to 15% (e.g., 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, or 14%), preferably from 0.05% to 10% or from 0.05% to 5%.
- Said (c) extract of Crocus sativus (L.) or saffron (dry saffron extract) used in the context of the present invention is preferably a dry extract of Crocus sativus stigmas.
- the Crocus sativus extract used in the present invention comprises (is titrated in) safranal, preferably in a weight percentage of at least 2% or greater (titration performed in UV-visible) with respect to the total weight of the extract (e.g., from 2% to 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, or 50%; preferably from 2% to 10%).
- said (c) extract of Crocus sativus (L.) or saffron (dry extract of saffron) used in the context of the present invention comprises (is titrated in) safranal, in a weight percentage from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3% (titration performed in UV-visible, e.g., at 330 nm).
- Crocus sativus extract used in the present invention may comprise (be titrated in) safranal and additional components such as crocin and/or picrocrocin.
- said (c) extract of Crocus sativus is an extract of Crocus sativus (or dry extract of stigmas) titrated in Lepticrosalides® (or mixture comprising safranal crocin, and picrocrocin) from 0.5% to 15% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%, preferably about 3.5%) and titrated in safranal from 0.5% to 10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, or 8%, preferably about 2%), wherein said percentages are weight percentages with respect to the total weight of Crocus sativus extract.
- said (c) extract of Crocus sativus (L.) or saffron (saffron dry extract) used in the context of the present invention comprises (is titrated in) safranal, in a weight percentage from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3% (titration performed in UV-visible, e.g., at 330 nm).
- a preferred example of said (c) extract of Crocus sativus is an extract (or dry extract of stigmas) titrated in Lepticrosalides® (comprising safranal, crocin and picrocrocin) to at least 3.5%, and in safranal from 0.1% to 5%, or to at least 2%.
- Lepticrosalides® comprising safranal, crocin and picrocrocin
- An example of a commercial product of Crocus sativus extract that can be used in the context of the present invention is the Affron-labeled product® having the technical characteristics given in the examples, such as Lepticrosalide (HPLC-DAD method) greater than 3.5%; bulk density (Eur. Pharm. (2.9.34)/USP, 616)) greater than 0.3 g/ml; particle size (Eur. Pharm. (2.9.12)/USP34, 786)) 240 pim/60 mesh.
- omega-3 fatty acids are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
- ALA alpha-linolenic acid
- EPA eicosapentaenoic acid
- DHA docosahexaenoic acid
- said (d) at least one omega-3 fatty acid used in the context of the present invention comprises or, alternatively, consists of eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) or salts thereof, EPA-DHA for short.
- EPA eicosapentaenoic acid
- DHA docosahexaenoic acid
- At least one omega-3 fatty acid used in the context of the present invention may be a derivative or precursor (of the synthesis) of said omega-3 fatty acid.
- the mixture of the present invention may comprise or alternatively consist of: (a) a lipoic acid or a salt thereof, (b) an epigallocatechin gallate (EGCG) or a green tea extract (e.g., Camellia sinensis) titrated in EGCG (e.g.
- Crocus sativus extract preferably titrated in safranal from 2% to 10% (e.g., commercial product Affron®), (d) at least one omega-3 fatty acid or a salt thereof (preferably EPA-DHA), and (e) at least one vitamin selected from the group comprising or alternatively consisting of: (e.1) a vitamin D (or D3), (e.2) a vitamin E, (e.3) at least one B group vitamin (such as B1, B2, B3, B5, B6, B9 and/or B12) and a mixture thereof (such as (e.i) and (e.2) and (e.3)).
- said (c) extract of Crocus sativus (L.) or saffron (saffron dry extract) used in the context of the present invention comprises (is titrated in) safranal, in a weight percentage from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3% (titration performed in UV-visible, e.g., at 330 nm).
- said mixture of the present invention comprises or alternatively consists of: (a) a lipoic acid or a salt thereof, (b) an epigallocatechin gallate (EGCG) or a green tea extract (e.g., Camellia sinensis) titrated in EGCG (e.g., about 40%), (c) Crocus sativus extract, preferably titrated in safranal from 2% to 10% (e.g., Affron®), (d) at least one omega-3 fatty acid or a salt thereof (preferably EPA-DHA), (e.1) a vitamin D (or D3), (e.2) a vitamin E, and (d.3) at least one B group vitamin selected from B1, B2, B3, B5, B6, B9, B12, and a mixture thereof (preferably a mixture thereof, such as B1, B2, B3, B5, B6, B9, and B12).
- EGCG epigallocatechin gallate
- a green tea extract e.g., Cam
- said (c) extract of Crocus sativus (L.) or saffron (saffron dry extract) used in the context of the present invention comprises (is titrated in) safranal, in a weight percentage ranging from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3% (titration performed in UV-visible, e.g., at 330 nm).
- the mixture of the present invention may comprise or alternatively consist of: (a) a lipoic acid or a salt thereof, (b) an epigallocatechin gallate (EGCG) or a green tea extract (e.g., Camellia sinensis) titrated in EGCG (e.g., about 30%), (c) Crocus sativus extract, preferably titrated in safranal from 2% to 10% (e.g., Affron®), (d) at least one omega-3 fatty acid or a salt thereof (preferably EPA-DHA), (f) at least one strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus, preferably belonging to the species Lactobacillus rhamnosus and/or Lactobacillus plantarum, more preferably Lactobacillus plantarum LP01 (LMG P-21021) and/or Lactobacillus rhamnosus LR06 (DSM 21981); and optionally, (g
- said (c) extract of Crocus sativus (L.) or saffron (saffron dry extract) used in the context of the present invention comprises (is titrated in) safranal, in a weight percentage from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3% (titration performed in UV-visible, e.g., at 330 nm).
- said mixture of the present invention comprises or alternatively consists of: (a) a lipoic acid or a salt thereof, (b) an epigallocatechin gallate (EGCG) or a green tea extract (e.g., Camellia sinensis) titrated in EGCG (e.g., about 30%), (c) Crocus sativus extract, preferably titrated in safranal from 2% to 10% (e.g., Affron®), (d) at least one omega-3 fatty acid or a salt thereof (preferably EPA-DHA), (f) Lactobacillus plantarum LP01 (LMG P-21021) and/or Lactobacillus rhamnosus LR06 (DSM 21981), and optionally, (g) at least one prebiotic, preferably an inulin.
- EGCG epigallocatechin gallate
- a green tea extract e.g., Camellia sinensis
- Crocus sativus extract
- said (c) extract of Crocus sativus (L.) or saffron (saffron dry extract) used in the context of the present invention comprises (is titrated in) safranal, in a weight percentage from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3% (titration performed in UV-visible, e.g., at 330 nm).
- the mixture of the present invention may comprise or alternatively consist of: (a) a lipoic acid or a salt thereof, (b) an epigallocatechin gallate (EGCG) or a green tea extract (e.g., Camellia sinensis) titrated in EGCG (e.g., about 30%), (c) Crocus sativus extract, preferably titrated in safranal from 2% to 10% (e.g., Affron®), (d) at least one omega-3 fatty acid or a salt therteof (preferably EPA-DHA), (e) at least one vitamin selected from the group comprising or, alternatively, consisting of: (e.1) a vitamin D (or D3), (e.2) a vitamin E, (d.3) at least one B group vitamin (such as B1, B2, B3, B5, B6, B9 and/or B12) and a mixture thereof (such as (e.i) and (e.2) and (e.3)), (f) at least
- said (c) extract of Crocus sativus (L.) or saffron (saffron dry extract) used in the context of the present invention comprises (is titrated in) safranal, in a weight percentage from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3% (titration performed in UV-visible, e.g., at 330 nm).
- said mixture of the present invention comprises or alternatively consists of: (a) a lipoic acid or a salt thereof, (b) an epigallocatechin gallate (EGCG) or a green tea extract (e.g., Camellia sinensis) titrated in EGCG (e.g., about 30%), (c) Crocus sativus extract, preferably titrated in safranal from 2% to 10% (e.g., Affron®), (d) at least one omega-3 fatty acid or a salt thereof (preferably EPA-DHA), (e.1) a vitamin D (or D3), (e.2) a vitamin E, (e.3) at least one B group vitamin selected from B1, B2, B3, B5, B6, B9, B12, and a mixture thereof (preferably a mixture of B1, B2, B3, B5, B6, B9, and B12), (f) Lactobacillus plantarum LP01 (LMG P-21021) and/or Lactobacillus
- said (c) extract of Crocus sativus (L.) or saffron (saffron dry extract) used in the context of the present invention comprises (is titrated in) safranal, in a weight percentage from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3% (titration performed in UV- visible, e.g., at 330 nm).
- said mixture of the present invention comprises or alternatively consists of: (a) a lipoic acid or a salt thereof, (b) an epigallocatechin gallate (EGCG) or a green tea extract (e.g., Camellia sinensis) titrated in EGCG (e.g., about 30%), (c) Crocus sativus extract, preferably titrated in safranal from 2% to 10% (e.g., Affron®), (d) at least one omega-3 fatty acid or a salt thereof (preferably EPA-DHA), (e.1) a vitamin D (or D3), (e.2) a vitamin E, (e.3) at least one B group vitamin selected from B1, B2, B3, B5, B6, B9, B12, and a mixture thereof (preferably a mixture of B1, B2, B3, B5, B6, B9, and B12), (f) Lactobacillus plantarum LP01 (LMG P-21021) and Lac
- said (c) extract of Crocus sativus (L.) or saffron (saffron dry extract) used in the context of the present invention comprises (is titrated in) safranal, in a weight percentage from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3% (titration performed in UV-visible, e.g., at 330 nm).
- Examples of the mixture of the present invention comprise a mixture comprising: (b), (c), or alternatively,
- the mixture or composition of the invention is advantageously formulated for oral (or sublingual) administration.
- the dosage form of the mixture or composition 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 orosoluble granules or powder), or a semi-solid form, such as soft-gel, or a liquid form, such as solution, suspension, dispersion, emulsion or syrup; preferably the composition of the invention is in a solid form for oral use, more preferably in tablet or powder/granule form to be dispensed in sachets to be dissolved in water.
- composition of the invention comprising (b), (c), optionally (a), and optionally (d), and/or (e) and/or (f), according to any one of the described embodiments or aspects
- composition of the invention can be formulated in a solid form of multilayer tablet or multilayer tablet with a differentiallyrelease of the multicomponents (two- or three-layer tablet).
- the amount and weight ratios of the various components and additives and/or excipients in each layer of said multilayer formulation can be determined and varied by the person skilled in the art in order to achieve the desired release timing, according to known methodologies from the solid oral formulation industry.
- the mixture or composition of the invention may advantageously comprise per "dosage unit" in solid form (e.g. of tablet or powder/granules in sachet), the following amounts:
- epigallocatechin gallate e.g., from Camellia sinensis extract
- 50 mg to 1000 mg e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg
- 250 mg to 350 mg or up to 700 mg in the case of powder/granules e.g., about 200, or 250, or 280, or 300 mg per tablet or from 200 mg to 600 mg per powder/granule sachet
- Crocus sativus extract preferably titrated in safranal from 0.1 % to 10%, preferably from 0.2% to 10%, more preferably from 2% to 10% (e.g.
- Affron® from 1 mg to 100 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, or 90 mg), preferably from 20 mg to 30 mg or up to 60 mg in the case of powder/granules (e.g., about from 20 to 30 mg per tablet or from 20 mg to 50 mg per powder/granule sachet).
- the mixture or composition of the invention may advantageously comprise per "dosage unit" in solid form (e.g. of tablet or powder/granules in sachet), the following amounts:
- epigallocatechin gallate e.g., from Camellia sinensis extract
- 50 mg to 1000 mg e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg
- 250 mg to 350 mg or up to 700 mg in the case of powder/granules e.g., about 200, or 250, or 280, or 300 mg per tablet or from 200 mg to 600 mg per powder/granule sachet
- powder/granules e.g., about 200, or 250, or 280, or 300 mg per tablet or from 200 mg to 600 mg per powder/granule sachet
- Crocus sativus extract preferably titrated in safranal from 0.1 % to 10%, preferably from 0.2% to 10%, more preferably from 2% to 10% (e.g. Affron®) from 1 mg to 100 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, or 90 mg), preferably from 20 mg to 30 mg or up to 60 mg in the case of powder/granules (e.g., about from 20 to 30 mg per tablet or from 20 mg to 50 mg per powder/granule sachet); and
- (a) lipoic acid or a salt thereof from 50 mg to 1000 mg (e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg), preferably from 250 mg to 350 mg or up to 700 mg in the case of powder/granules (e.g., about 300 mg per tablet or from 300 mg to 600 mg per powder/granule sachet).
- 50 mg to 1000 mg e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg
- 250 mg to 350 mg or up to 700 mg in the case of powder/granules (e.g., about 300 mg per tablet or from 300 mg to 600 mg per powder/granule sachet).
- the mixture or composition of the invention may advantageously comprise per "dosage unit" in solid form (e.g. of tablet or powder/granules in sachet), the following amounts:
- lipoic acid or a salt thereof from 50 mg to 1000 mg (e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg), preferably from 250 mg to 350 mg or up to 700 mg in the case of powder/granules (e.g., about 300 mg per tablet or from 300 mg to 600 mg per powder/granule sachet); and
- epigallocatechin gallate e.g., from Camellia sinensis extract
- 50 mg to 1000 mg e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg
- 250 mg to 350 mg or up to 700 mg in the case of powder/granules e.g., about 200, or 250, or 280, or 300 mg per tablet or from 200 mg to 600 mg per powder/granule sachet
- powder/granules e.g., about 200, or 250, or 280, or 300 mg per tablet or from 200 mg to 600 mg per powder/granule sachet
- Crocus sativus extract preferably titrated in safranal from 0.1 % to 10%, preferably from 0.2% to 10%, more preferably from 2% to 10% (e.g. Affron®) from 1 mg to 100 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, or 90 mg), preferably from 20 mg to 30 mg or up to 60 mg in the case of powder/granules (e.g., about from 20 to 30 mg per tablet or from 20 mg to 50 mg per powder/granule sachet); and
- At least one omega-3 fatty acid or a salt thereof from 50 mg to 1000 mg (e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg), preferably from 200 mg to 300 mg or up to 600 mg in case of powder/granules (e.g., about 250 mg per tablet or from 250 mg to 500 mg per powder/granule sachet); and, optionally,
- a vitamin D according to the RDIs (Reference Daily Intake), such as in an amount from 0.5 pig to 50 pig (e.g., 1 pig, 10 pig, 15 pig, 20 pig, 25 pig, 30 pig, 35 pig, 40 pig, or 45 pig), preferably from 20 pig to 50 pig (e.g., about 15 pig or 300% RDI, Reference Daily Intake);
- a vitamin E according to RDIs, such as in an amount from 300 IU to 500 IU or from 5 mg to 60 mg (e.g., about 400 IU), where 1 IU (IU: International Units) is the biological equivalent of about 0.667 mg of D-o-tocopherol (2/3 of mg), or 0.45 mg or 50 mg of DL-o-tocopherol (or tocopheryl) acetate, e.g., 50 mg of DL-alpha-tocopheryl acetate (about 50 IU of vitamin E); and/or
- one strain of bacteria belonging to the genus Bifidobacterium or Lactobacillus preferably Lactobacillus plantarum LP01 (LMG P-21021) and/or Lactobacillus rhamnosus LR06 (DSM 21981)) in an amount for each strain of bacteria ranging from 10 7 CFU to 10 12 CFU, preferably from 1x10 9 CFU to 5x10 10 CFU, more preferably about 1-2 x 10 9 CFU for each strain of bacteria (CFU: Colony Forming Units); and/or
- inulin in an amount from 10 mg to 2500 mg, preferably from 25 mg to 2000 mg, even more preferably from 400 mg to 1500 mg (e.g., about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 800 mg, or 1200 mg), preferably about 1000 mg.
- One or more B group vitamins may be included in a "dosage unit" (such as a tablet or sachet comprising powders or granules) of the mixtures or compositions of the present invention in the following amounts:
- Vitamin B1 0.05 mg - 50 mg, e.g., 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg, 30 mg, or 40 mg (preferably about 1.60-1.70 mg - or 150% RDI); and/or
- Vitamin B2 0.05 mg - 50 mg, e.g. 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 40 mg (preferably 2.0-2.2 mg - 150%(??) RDI); and/or Vitamin B3: 1 mg - 100 mg (preferably 23-25 mg - or 150% RDI); and/or
- Vitamin B5 0.5 mg - 50 mg, e.g., 1 mg, 2 mg, 4 mg, 5 mg, 7 mg, 8 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 40 mg (preferably 8-10 mg - or 150% RDI); and/or
- - Vitamin B6 0.05 mg - 50 mg, e.g., 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 40 mg (preferably 2.0-2.2 mg - or 150% RDI); and/or - Vitamin B9: 10 ug - 1000 ug, e.g., 50 ug, 100 ug, 150 ug, 200 ug, 250 ug, 300 ug, 400 ug, 500 ug, 600 ug, 700 ug, 800 ug, or 900 ug (preferably about 300 ug - or 150% RDI); and/or
- Vitamin B12 0.1 ug - 50 ug, e.g. 0.5 ug, 1 ug, 1.5 ug, 2 ug, 2.5 ug, 3 ug, 4 ug, 5 ug, 10 ug, 20 ug, 30 ug, or 40 ug (preferably 3.7-3.8 ug - or 150% RDI).
- the mixture or composition of the invention preferably in a solid form (e.g., tablet or powder/granules in sachet), comprises the following amounts per "dosage unit.”
- epigallocatechin gallate e.g., from Camellia sinensis extract
- epigallocatechin gallate from Camellia sinensis extract
- Crocus sativus extract preferably titrated in safranal from 0.1% to 10%, preferably from 0.2% to 10%, more preferably from 2% to 10% (e.g., Affron®) from 20 mg to 35 mg or up to 50 in case of powder/granules;
- omega-3 fatty acid or a salt thereof preferably EPA-DHA
- a vitamin D from 10 pig to 20 pig e.g., about 15 ug (300% RDI)
- a vitamin E from 300 IU to 500 IU pig (e.g., about 400 IU (50 mg; 416.67%);
- Lactobacillus plantarum LP01 LMG P-21021
- Lactobacillus rhamnosus LR06 DSM 21981 in an amount for each strain of bacteria ranging from 1 x10 9 CFU to 5x10 9 CFU;
- Said "dosage unit” e.g., tablet or powder or granules sachet
- Said "dosage unit” of the composition of the invention may be administered to a subject in need thereof in the 24-hour interval 2, 3, or 4 times at intervals from 4 hours to 12 hours apart, depending on the type of dosage form and the needs of the subject.
- said "dosage unit" of the composition of the invention is administered to a subject in need thereof once or twice a day (e.g., away from meals), preferably once a day.
- the mixture or composition of the invention comprising (b), (c), optionally (a), optionally (d), and optionally (e), and/or (f) and/or (g), according to any one of the described embodiment or aspects) for use as a medicament.
- the mixture or composition of the invention (comprising (b), (c), optionally (a), optionally (d), and optionally (e), and/or (f) and/or (g), according to any one of the described embodiments or aspects) for use in a method of treatment, preventive and/or curative, of Parkinson's disease in both the prodromal phase and the full-blown phase to support the treatment of motor symptoms and/or non-motor symptoms, in a subject in need thereof, by administering to said subject a therapeutically effective amount of the mixture or composition of the present invention.
- the mixture or composition of the present invention (comprising (b), (c), optionally (a), optionally (d), and optionally (e), and/or (f) and/or (g), according to any one of the described embodiments or aspects) is effective, for example, for use in a method of treatment, preventive and/or curative, of non-motor symptoms of Parkinson's disease, particularly non-motor symptoms of the prodromal phase of Parkinson's disease and/or non-motor symptoms of the full-blown phase of Parkinson's disease.
- the mixture or composition of the present invention (comprising (b), (c), optionally (a), optionally (d), and optionally (e), and/or (f) and/or (g), according to any one of the described embodiments or aspects) is effective, for example, for use in a method of treatment, preventive and/or curative, of the motor symptoms of Parkinson's disease, preferably as an adjunct to a therapy for the treatment of Parkinson's disease.
- Said motor symptoms can be selected from the group comprising or alternatively consisting of: tremor or resting tremor, bradykinesia, and rigidity.
- Said non-motor symptoms can be selected from the group comprising or alternatively consisting of: sleep disorders (difficulty in falling asleep and staying asleep), mood disorders (apathy, anger, moodiness, sadness, pessimism, anxiety), peripheral neuropathic pain (particularly of the legs), muscle pain (particularly of the legs), bowel constipation, urinary disorders, hyposmia (decreased ability to perceive all or part of odors), RBD (rapid eye movement (REM) sleep behavior disorder).
- sleep disorders difficulty in falling asleep and staying asleep
- mood disorders apathy, anger, moodiness, sadness, pessimism, anxiety
- peripheral neuropathic pain particularly of the legs
- muscle pain particularly of the legs
- bowel constipation urinary disorders
- hyposmia decreased ability to perceive all or part of odors
- RBD rapid eye movement
- the mixtures or compositions of the present invention may be for use in a method of treatment of Parkinson's disease (as defined in the present description) when administered to a subject as the sole therapy or when administered as an adjunctive therapy to at least one other therapy or composition capable of treating Parkinson's disease (motor symptoms and/or non-motor symptoms, e.g., a dopamine drug therapy).
- the active compounds of the mixture or composition of the present invention can also be administered separately or in groups (preferably in a time interval of 30 minutes up to 2-3 hours) and in any order.
- Said at least one additive and/or excipient of pharmaceutical or food grade, included in the composition of the invention together with the mixture of (a), (b), (c), (d), and optionally (e) and/or (f) and/or (g), consists of a substance without therapeutic activity suitable for pharmaceutical or food use selected from auxiliary substances known to the person skilled in the art such as, e.g., diluents, solvents (including water, glycerin, ethyl alcohol), solubilizers, thickeners, sweeteners, flavoring agents, dyes, lubricants, surfactants, antimicrobials, antioxidants, preservatives, pH-stabilizing buffers, and mixtures thereof.
- auxiliary substances known to the person skilled in the art such as, e.g., diluents, solvents (including water, glycerin, ethyl alcohol), solubilizers, thickeners, sweeteners, flavoring agents, dyes, lubricants, surfact
- Non-limiting examples of such substances are phosphate buffers (e.g., dicalcium phosphate), stearate of an alkaline or alkaline earth metal (e.g., magnesium), silicon dioxide, mono- and diglycerides of fatty acids, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch or corn starch, natural or artificial flavorings (e.g., iron oxides).
- phosphate buffers e.g., dicalcium phosphate
- stearate of an alkaline or alkaline earth metal e.g., magnesium
- silicon dioxide e.g., silicon dioxide
- mono- and diglycerides of fatty acids e.g., microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch or corn starch
- natural or artificial flavorings e.g., iron oxides
- Said composition of the invention can be a pharmaceutical composition, a medical device composition (Medical Device Regulation (EU) 2017/745 (MDR)), a dietary supplement and/or a food for special medical purposes (FSMP).
- EU Medical Device Regulation
- MDR Medical Device Regulation
- FSMP food for special medical purposes
- subject(s) in the context of the present invention refers to mammals (animal and human), preferably human subjects.
- terapéuticaally effective amount refers to the amount of mixture or compound or formulation that elicits biological or medicinal response in a tissue, system, or subject that is researched and defined by an expert in the field.
- the expression mixture or composition comprising a component in an amount "within a range from x to y" means that said component may be present in the composition in all amounts present in said range, even if not made explicit, extremes of the range included.
- Examples of active components that can be used in the context of the present invention are given below.
- An example of (a) lipoic acid extract usable in the present invention may be that marketed under the name M.A.T.R.I.S.
- Crocus sativus extract usable in the present invention is the product with trade name Affron® (trade mark), as the dry extract of stigmas of Crocus sativus L. titrated to about 3.5% (minimum titer) in Lepticrosalides® (trade mark for a compound comprising at least safranal, crocin, picrocrocin) and about 2% safranal (percentages w/w of total extract); titer standardized by HPLC.
- Affron® trade mark
- Lepticrosalides® trade mark for a compound comprising at least safranal, crocin, picrocrocin
- 2% safranal percentages w/w of total extract
- (c) extract of Crocus sativus usable in the present invention e.g., comprising (titrated in) safranal, in a weight percentage from 0.1% to 10%, preferably from 0.2% to 5%, e.g., 0.3%-titration performed in UV-visible, e.g., at 330 nm
- Satiereal® is the product with trade name Satiereal®.
- At least one omega-3 fatty acid preferably EPA-DHA
- An example of vitamin D usable in the present invention is a vitamin D3 having CAS No. 67-97-0, min. 90,000 IU vitamin D3/g (equivalent to 2250 pig cholecalciferol/g), density (bulk density) ⁇ 0.6 g/mL.
- vitamin E or tocopherol or compound comprising tocopherol
- An example of a vitamin E (or tocopherol or compound comprising tocopherol) usable in the present invention is a commercially available and publicly available vitamin E.
- vitamin B1 usable in the present invention is a vitamin B1 (thiamine chlorohydrate) with a purity of 98.5-101.0% w/w (Ph.Eur. method) or 98.0-102.0% w/w (USP method), pH 2.7-3.3 (Ph.Eur.) or 2.7-3.4 (USP), water max. 5.0% w/w (Ph.Eur, USP), sulfated ash max. 0.1% w/w (Ph.Eur.), residues on ignition max. 0.2% w/w (USP), residual solvents (USP): methanol max. 0.3% w/w and ethanol max. 0.5%.
- vitamin B2 usable in the present invention is a vitamin B2 (riboflavin high flow 100 (HF)) having CAS No. 83-88-5.
- HF riboflavin high flow 100
- vitamin B3 usable in the present invention is vitamin B3 (niacinamide food grade FCC) having CAS No. 98-92-0 purity 99.0-101.0% w/w (HPLC), obtained from 3-cyanopyridine as starting material by the following steps: hydrolysis of 3-cyanopyridine on bio-catalyst on fixed bed to obtain crude niacinamide solution, purification on activated carbon on fixed bed, nanofiltration, evaporation, and lyophilization (spray drying).
- vitamin B5 that can be used in the present invention is a calcium D-pantothenate having CAS No. 137-08-6.
- vitamin B6 usable in the present invention is a vitamin B6 (pyridoxine chlorohydrate food grade) purity 99.0-101.0% w/w (Ph.Eur. method) or 98.0-102.0% w/w (USP method), pH 2.4 ⁇ 3.0(Ph.Eur.), chlorine (in anhydrous compound) 16.9% ⁇ 17.6% w/w (USP), sulfated ash max. 0.1% w/w (Ph.Eur.), drying loss max. 0.5% w/w (Ph.Eur.), residual solvents (Ph.Eur.): ethanol max. 0.5%.
- vitamin B9 that can be used in the present invention is a vitamin B9 (folic acid) having CAS No. 59-30-3 and molecular weight 441.40, IR identification, Residue on ignition ⁇ 0.30 % w/w, specific absorbance ratio 256/365 nm 2.80-3.00, water ⁇ 8.50% w/w, titer (on anhydrous) 95.00-102.00 % w/w.
- vitamin B12 that can be used in the present invention is a vitamin B12 (Dry vitamin B12 0.1% GFP) having CAS No. 68-19-9.
- Table 1 shows an example embodiment of the composition of the invention comprising (a), (b), (c) and (d) formulated for oral use in solid form (in short, dose).
- Table 1A shows an example embodiment of the composition of the invention comprising (a), (b), (c) and (d) formulated for oral use in solid form of granules/powder packaged in sachet (in short, dose).
- Table 2 shows an example embodiment of the composition of the invention comprising (a), (b), (c), (d), (e), (f) and (g) formulated for oral use in solid form of tablet (in short, dose).
- ⁇ b >example of additives/excipients: Mg stearate, Si dioxide, dicalcium phosphate, mono and diglycerides of fatty acids, microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, flavoring, and/or corn starch.
- Table 2A shows an example embodiment of the composition of the invention comprising (a), (b), (c), (d), (e), (f) and (g) formulated for oral use in solid form of granules/powder packaged in sachets (in short, dose).
- the astrocytic cell line CCF-STTG1 was grown in flask in RPMI medium (Merck, Milan, Italy) supplemented with 10% FBS (Merck, Milan, Italy) with the addition of Hepes 2 mM (Merck, Milan, Italy), L- glutamine 2 mM (Merck, Milan, Italy) and 1% penicillin-streptomycin (P/S, Merck, Milan, Italy) and maintained in a 37°C incubator with 95% humidity and 5% CO 2 [Jogalekar, M. P. et al. "Total RNA isolation from separately established monolayer and hydrogel cultures of human glioblastoma cell line" Bio-protocol 9- 4 (2019), e3305-e3305],
- Huvec cells were cultured in 0.1% gelatin-coated flask and grown with Endothelial Growth Medium-2 (EGM-2) medium containing 2% fetal bovine serum (FBS), 0.04% hydrocortisone, 0.4% hFGF-B, 0.1% VEGF, 0.1% R3-IGF-1, 0.1% ascorbic acid, 0.1% hEGF, 0.1% GA-1000, 0.1% heparin (all produced by Lonza, Walkersville, MD, USA) and maintained at 37 °C and 5% CO 2 as previously described [Molinari, C. et al. "The role of BDNF on aging-modulation markers" Brain Sciences 10-5 (2020), 285], For all experiments, passage from 3 to 6 cells were used.
- MTT assay was performed as described in the literature [Uberti, F. et al. "Iron absorption from three commercially available supplements in gastrointestinal cell lines” Nutrients 9-9 (2017), 1008] to determine cell viability after stimulations.
- Cells were incubated in DMEM without Red phenol 0% FBS with 1% of the MTT probe for 2 hours at 37°C in an incubator, then, cell viability was determined by measuring the absorbance through a spectrometer (Infinite 200 Pro MPlex, Tecan, Mannedorf, Switzerland) at 570 nm with correction at 690 nm. The results were obtained by comparing them with control cells (100% viable).
- Absorbance was measured by a spectrometer (Infinite 200 Pro MPlex, Tecan, Mannedorf, Switzerland), at 550 nm, and the O 2 was expressed as nanomoles (nM) of reduced cytochrome C per microgram (pig) of protein with respect to the control, as percentage (%).
- Lipid peroxidation in cells was estimated using the thiobarbituric acid assay (TBARS) [Han, F. et al. "Interleukin-6 promotes ferroptosis in bronchial epithelial cells by inducing reactive oxygen speciesdependent lipid peroxidation and disrupting iron homeostasis" Bioengineered 12-1 (2021), 5279-5288], Briefly, 10Opi of sample or standard was added into a 5ml vial and then 10Opi of SDS solution was added. In each vial, 4ml of dye reagent was added and boiled for 1 hour.
- TBARS thiobarbituric acid assay
- TNFa concentration was determined by TNFa ELISA kit (Merck Life Science, Rome, Italy) following the experimental protocol [Molinari, C. et al. "Preventing c2c12 muscle cells damage by combining magnesium and potassium with vitamin D3 and curcumin” Journal of traditional and complementary medicine 11-6 (2021), 532-544], Colorimetric intensity was measured at 450 nm by spectrophotometer (Infinite 200 Pro MPlex, Tecan, Mannedorf, Switzerland). Results were calculated by generating a calibration curve (range from 24.58 pg/ml to 6000 pg/ml) and expressed as % relative to control.
- IL-1p Quantification of IL-1p was performed with the IL-1p ELISA kit (R&D systems, MN) according to the manufacturer's instructions [Uberti, F. et al. "A combination of a-lipoic acid (ALA) and palmitoylethanolamide (PEA) blocks endotoxin-induced oxidative stress and cytokine storm: A possible intervention for COVID-19" Journal of Dietary Supplements (2021), 1-23], Absorbance was determined with a microplate reader at 450 nm with correction at 570 nm. IL-1p was quantified by relating sample readings to the generated standard curve (range from 12.5 pg/ml to 800 pg/ml) and expressed as % relative to control.
- IL-6 concentration in basolateral co-culture media was analyzed with the IL-6 ELISA kit (eBioscience, USA) [Huang, K. et al. "Effect of PM2.5 on invasion and proliferation of HeLa cells and the expression of inflammatory cytokines IL1 and IL6" Oncology Letters 16-6 (2018), 7068-7073], The plate was measured at a wavelength of 450 nm, and the data were analyzed by relating the sample readings to the generated standard curve (range from 3.1 pg/ml to 300 pg/ml) and expressed as % relative to control.
- PINK1 activity was determined in cell lysates using an ELISA kit (PINK1 ELISA kit, MyBiosource, San Diego, CA, USA) according to the manufacturer's instructions. Briefly, cells were lysed with cold 1x PBS and centrifuged at 1500* g for 10 min at 4 °C. A quantity of 100 pl of each sample was added to a well and incubated at 37 °C for 90 min; then, the contents were removed and, to each well, 100 pl of detection solution (a) was added and incubated for 45 min at 37 °C. After this time had elapsed, the wells were washed and 100 pl of detection solution (b) was added to each well and then incubated for 45 min.
- PINK1 ELISA kit PINK1 ELISA kit, MyBiosource, San Diego, CA, USA
- Parkin activity was determined in cell lysates using an ELISA kit (Parkin ELISA kit, MyBiosource, San Diego, CA, USA) according to the manufacturer's instructions. Briefly, 100 pl of each sample was added and incubated at 37 °C for 90 min; then, the material was removed and 100 pl of detection solution (a) was added and incubated for 45 min at 37 °C. After this time had elapsed, the wells were washed and 100 pl of detection solution (b) was added to each well and then incubated for 45 min.
- ELISA kit Parkin ELISA kit, MyBiosource, San Diego, CA, USA
- the tests were carried out by treating the cell cultures with the single substances, lipoic acid, EGCG (from Camellia sinensis extract, referred to as “green tea”), decosahexanoic acid (DHA) and Crocus sativus extract (referred to as “saffron”), or with three different mixtures made up as follows:
- MIX 1 lipoic acid 50piM + green tea 100piM + DHA 25piM + saffron 25piM;
- MIX 2 green tea 100piM+ saffron 25piM
- MIX 3 green tea 100piM + DHA 25piM + saffron 25piM.
- lipoic acid (indicated as “Lipo” in the figures) was derived from the study Molinari, C. et al. "Role of combined lipoic acid and vitamin D3 on astrocytes as a way to prevent brain aging by induced oxidative stress and iron accumulation” Oxidative Medicine and Cellular Longevity February (2019).
- the BBB regulates the passage of water, some gases, and some fat-soluble molecules by passive diffusion, but also the selective transport of molecules crucial for neuronal function, or of drugs and active ingredients with neuroprotective function; for this reason, it was essential to assess the rate of uptake of all test substances.
- the BBB tests showed that all test substances increased the permeability of the blood-brain barrier, peaking at 12h and maintaining their effect up to 24h (p ⁇ 0.05).
- oxidative stress represents one of the main pathogenetic mechanisms of neuronal death, as it causes damage to neurons in the Central Nervous System (CNS) by leading to hyperproduction of free radicals due to increased oxidative metabolism of dopamine, further tests were conducted to assess oxidative stress levels under PD conditions.
- CNS Central Nervous System
- nitric oxide (NO) production also confirms a negative role of 6-OHDA in neurodegenerative processes, as it is capable of causing the formation of highly reactive species that kill dopaminergic neurons and activated glial cells. Therefore, the inhibition of nitric oxide production by the tested substances, as demonstrated in Figure 7, confirms their potential usefulness for the treatment of Parkinson's disease (p ⁇ 0.05). Again, their combination, and particularly mixture 1 (MIX 1), enhances their effect, confirming that their synergistic effect plays a key role in modulating Parkinson's disease.
- MIX 1 mixture 1
- PINK1/Parkin pathway is the main molecular mechanism involved during PD. Normally, when PINK1 recognizes defective mitochondria in cells, it activates Parkin, which "cleans" the cell of defective mitochondria, protecting it. As such, research has shown that increased dopamine production leads to an imbalance in mitochondrial metabolism, activating the PINK1/Parkin pathway.
- these substances are also able to increase the BBB permeability to promote their passage.
- MIX 1 when combined together, and particularly when combined all four together (MIX 1), the positive effect on all studied neuroprotective and molecular parameters is found to be increased compared to their effect when taken individually.
- the combination of the analyzed substances is able to maintain proper mitochondrial metabolism, modulate antioxidant and anti-inflammatory effects that, in PD, are impaired, as well as inhibit the main molecular pathways involved during Parkinson's disease by maintaining proper neuronal cell homeostasis.
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Abstract
La présente invention concerne des compositions à composants multiples comprenant du gallate d'épigallocatéchine (EGCG) et/ou un extrait de Camellia sinensis, désigné par gallate d'épigallocatéchine EGCG, un extrait de Crocus sativus, et éventuellement un acide lipoïque ou un de ses sels de qualité pharmaceutique ou alimentaire, et éventuellement, au moins un acide gras oméga-3, ce mélange permettant de traiter, de manière préventive et/ou curative, la maladie de Parkinson, en particulier les symptômes non moteurs des stades prodromiques et des stades avancés de la maladie.
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