WO2012170657A1 - Ciblage de gsk-3 bêta pour le traitement de la maladie de parkinson - Google Patents

Ciblage de gsk-3 bêta pour le traitement de la maladie de parkinson Download PDF

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WO2012170657A1
WO2012170657A1 PCT/US2012/041292 US2012041292W WO2012170657A1 WO 2012170657 A1 WO2012170657 A1 WO 2012170657A1 US 2012041292 W US2012041292 W US 2012041292W WO 2012170657 A1 WO2012170657 A1 WO 2012170657A1
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lithium
disease
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parkinson
gsk
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Anita Sidhu
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Georgetown University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • a method for treating Parkinson's Disease involves the use of Lithium (Li) to inhibit GSK-3P, and simultaneously stimulate autophagy to clear protein aggregates of a-synuclein (a-Syn) and hyperphosphorylated Tau.
  • Li Lithium
  • a-Syn a-synuclein
  • Parkinson's Disease is the second-most common
  • PMCID PMC2922478; Haggerty T, Credle J, Rodriguez O, Wills J, Duka V, Oaks AW, Masliah E, Sidhu A. Hyperphosphorylated Tau in an a- synuclein overexpressing transgenic model of Parkinson's disease. 33(9) Eur. J. Neurosci. 1598-610 (201 1 May); Wills J, Credle J, Haggerty T, Lee J- H, Oaks AW, Sidhu A. Tauopathic changes in the striatum of A53T a- synuclein mutant mouse model of Parkinson's disease.
  • Treatment of PD primarily consists of l-dopa therapy to replace dopamine [Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson's disease.Mov Disord. 2010 Nov 15;25(15):2649-53. Review; Perez-Lloret S, Rascol O. Dopamine receptor agonists for the treatment of early or advanced Parkinson's disease. CNS Drugs. 2010 Nov 1 ;24(1 1):941 - 68. Review.].
  • Lithium is already FDA-approved for treatment of bipolar disorder, and it is safe for long-term use in humans [Kwok JB, Hallupp M, Loy CT, Chan DK, Woo J, Mellick GD, Buchanan DD, Silburn PA, Halliday GM, Schofield PR. GSK3B polymorphisms alter transcription and splicing in Parkinson's disease. Ann Neurol. 2005 Dec;58(6):829-39]. The method described herein demonstrates that lithium treats and prevents PD-like pathology in vivo, and can be immediately used in clinical trials.
  • Lithium is inexpensive and acts in a manner different from l-dopa, and will not have the same side-effects as L-DOPA, such as dyskinesias and desensitization.
  • the present invention envisions the development of an entirely new family of novel, non-dopaminergic therapeutic tools to treat PD.
  • Lithium is useful in the treatment of Alzheimer's disease, multiple system atrophy and Lewy body disease with dementia, which are all characterized by high levels of a-Syn, p-Tau and activated GSK-3p.
  • the discovery of the signaling cascade comprising a-Syn/GSK-3p/p- Tau in the genesis of PD is a highly innovative and important finding.
  • a-Syn is mandatory for observing tauopathy— in a-Syn-/- mice or cells lacking a-Syn, tauopathy and GSK-3 activation is not observed upon treatment with the potent neurotoxin MPTP/MPP+; a-Syn recruits and activates GSK-3p through its hyperphosphorylation at Tyr216; GSK-3 is the primary kinase involved in hyperphosphorylation of Tau in PD; protein phosphatase levels and activity are unchanged in postmortem PD striata and in mice; blockade of GSK-3P activation with lithium or with selective inhibitors (TDZD-8 and methylmaleimide compounds) prevents synucleinopathy and tauopathy in cells and neurons [Alan P.
  • PD Parkinson's disease
  • Drugs used for treatment of PD are not curative, and moreover, are of limited long-term use due to development of resistance and/or adverse side-effects in patients. While the genesis of PD is not known, a-synuclein (a-Syn) overexpression through gene duplication and multiplication is causal in sporadic PD.
  • a-Syn a-synuclein
  • p-Tau hyperphosphorylated Tau
  • SNCA a-Syn gene
  • MAT Tau gene
  • Li overexpressing a-Syn
  • Li is approved by the FDA for treatment of bipolar disorders.
  • the off-label use of Li to treat PD is demonstrated by data showing that treatment of a- Syn overexpressing Tg mice with low levels of Li reverses synucleinopathy and tauopathy of dopaminergic neurons enervating the striatum (see
  • Li suppresses the overexpression of a-Syn and reduces aggregates of both a-Syn and p-Tau to levels seen in non-Tg wild type mice. This is the first evidence of a small molecule directly preventing the overexpression and accumulation of a-Syn.
  • Li The actions of Li are two-fold: Inhibition of the Tau kinase, GSK-3p, whose activation is entirely dependent on a-Syn, and stimulation of autophagy, a pathway central for clearing aggregates of a-Syn and p-Tau.
  • Example 1 extensive studies in vivo using different doses of Li in aged mice are performed to estimate efficacy of treatment in reversing PD- like pathology. The lowest dose of Li that can be used to reverse both synucleinopathy and tauopathy is identified.
  • Example 2 pre-symptomatic mice are treated with different doses of Li to determine if long-term use of low levels of Li will prevent onset of PD-like pathology. This allows the development of the first therapy for the prevention of sporadic PD, and is useful in individuals who carry multiplications of SNCA and are at high risk for developing PD.
  • Detailed analyses measuring the efficacy of each treatment is performed, including biochemical, behavioral and immunohistochemical analyses. Since Li is already FDA approved, and its toxicity and side-effects are well documented in both humans and mice, the drug can be readily used in other PD animal models, and ultimately, in clinical trials in humans.
  • Figure 1 shows coexpression of a-Syn/pTau in a-Syn overexpressing mice (OEM) mice and reinforces the choice of PDGF-a-Syn as a model system to analyze lithium treatments.
  • FIG 2 details blood plasma levels of lithium in wild-type (WT) and transgenic (Tg) mice following the development and execution of the lithium treatment paradigm.
  • Figure 3 quantifies the treatment of a-Syn overexpressing mice (OEM) following lithium treatment and shows a reversal of motor impairment seen in PDGF-a-Syn transgenic mice.
  • OEM a-Syn overexpressing mice
  • Figure 4 illustrates that lithium reduces high levels of a-Syn and activated p-GSK-3p in striatum of PDGF-a-Syn overexpressing mice and has no effect on wild-type mice fed lithium.
  • Sal saline
  • X lithium
  • Tg transgenic
  • WT wild-type
  • +Cpd.X lithium.
  • FIG. 5 illustrates that lithium reverses tauopathy in striatum of PDGF-a-Syn transgenic mice.
  • Sal saline
  • X lithium
  • Tg transgenic
  • WT wild-type
  • +Cpd.X lithium.
  • a novel method for treating Parkinson's Disease involves the administration of therapeutically effective amounts of Lithium (Li) to inhibit GSK-3 and simultaneously stimulate autophagy to clear protein aggregates of a-synuclein (a-Syn) and hyperphosphorylated Tau.
  • Li Lithium
  • a-Syn a-synuclein
  • Genomics Consortium Nails MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simon-Sanchez J, Schulte C, Lesage S,
  • Alpha-synuclein locus triplication causes Parkinson's disease. Science. 2003; 302(5646): 841. Crews L, Tsigelny I, Hashimoto M, Masliah E. Role of Synucleins in Alzheimer's Disease. Neurotox Res. 2009; 16(3): 306-317].
  • a-Syn is misfolded into oligomers, aggregates and accumulates into neuronal inclusion bodies, Lewy bodies (LBs), that are the pathological hallmarks of PD and other synucleinopathies [Forno LS. Neuropathology of Parkinson's disease. J. Neuropathol Exp Neurol.
  • PMCID PMC2922478; Haggerty T, Credle J, Rodriguez O, Wills J, Duka V, Oaks AW, Masliah E, Sidhu A. Hyperphosphorylated Tau in an a- synuclein overexpressing transgenic model of Parkinson's disease. 33(9) Eur. J. Neurosci. 1598-610 (201 1 May); Wills J, Credle J, Haggerty T, Lee J- H, Oaks AW, Sidhu A. Tauopathic changes in the striatum of A53T a- synuclein mutant mouse model of Parkinson's disease.
  • tauopathy in dopaminergic neurons in a manner strictly dependent on a-Syn has been shown.
  • a-Syn also recruits and activates the Tau kinase, ⁇ -3 ⁇ (p-GSK- 3 ⁇ , hyperphosphorylated at Tyr216), to induce the hyperphosphorylation of Tau (p-Tau) at multiple sites, leading to a toxic gain of function and microtubule destabilization, with eventual cell death.
  • GSK-3P can be targeted with lithium, providing for a novel therapeutic approach in the treatment of PD.
  • lithium is FDA-approved and has been long used in the treatment of bipolar disorders. Moreover, its use is associated with very few side effects, with no psychotropic effects in humans; it is not a sedative, depressant, or euphoriant [Marcus WL. Lithium: a review of its pharmacokinetics, health effects, and toxicology. J Environ Pathol Toxicol Oncol. 1994 -13(2):73-9].
  • Inhibitors of GSK-3 such as lithium, are a novel group of drugs for the treatment of PD.
  • tauopathies is used to refer to a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain.
  • synucleinopathies is used to name a group of neurodegenerative disorders characterized by fibrillary aggregates of alpha- synuclein protein in the cytoplasm of selective populations of neurons and glia. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA).
  • PD Parkinson's disease
  • DLB dementia with Lewy bodies
  • PAF pure autonomic failure
  • MSA multiple system atrophy
  • Parkinsonism is the predominant symptom of PD, but it can be indistinguishable from the parkinsonism of DLB and MSA.
  • Autonomic dysfunction which is an isolated finding in PAF, may be present in PD and DLB, but is usually more prominent and appears earlier in MSA.
  • DLB could be the same disease as PD but with widespread cortical pathological states, leading to dementia, fluctuating cognition, and the characteristic visual hallucinations.
  • the deposition of aggregates of synuclein in neurons and glia suggests that a common pathogenic mechanism may exist for these disorders.
  • a method of treating a mammal suffering from a malady associated with synucleinopathy and/or tauopathy involves administering to said mammal a therapeutically effective amount of lithium and/or a lithium salt.
  • the malady is Parkinson's Disease (PD)
  • the method involves the administration to a mammal suffering from a malady associated with aggregates of both a-Syn and p-Tau, and involves the administration of an aggregate-reducing or - eliminating amount of lithium.
  • the method involves the prevention and/or treatment of a mammal suffering from overproduction of GSK-3P, or from the activation of p-GSK-3p.
  • the lithium may be co-administered, complexed or covalently linked with other carriers or active agents.
  • the term “lithium” includes elemental lithium, lithium ion, lithium salts, and lithium complexed with, or covalently bonded to, other carriers or active agents.
  • lithium is co-administered (or complexed or covalently linked) with TDZD-8 or with methylmaleimide.
  • the mammal is a human, murine, porcine, bovine, ovine, equine, canine, feline, or gibbon.
  • the mammal is human, the malady is Parkinson's Disease, and the lithium is administered as a lithium salt (e.g., lithium carbonate, lithium citrate, lithium sulfonates, lithium orotate).
  • a lithium salt e.g., lithium carbonate, lithium citrate, lithium sulfonates, lithium orotate.
  • Other lithium salts are known, and may also be used in these methods.
  • the lithium-containing active agent may be administered orally, parenterally (e.g., intravenous, intramuscular, etc.), subcutaneously, transdermally, or by sublingual, intranasal, or suppository, or by any means commonly known and accepted in the art for the administration of lithium or lithium salts.
  • the lithium agent is administered orally.
  • the therapeutically effective amount for treating, reversing, or preventing these maladies can be readily determined by those of ordinary skill in the art, and will vary based upon the patient and the seventy of his or her condition. The severity of the patient's condition will be affected by a constellation of factors including genetic predisposition, environmental exposure, and other factors. One skilled in the art will be able to assess the therapeutic efficacy of a particular dosage regimen based upon routine screening and diagnostic testing.
  • the lithium agent can be administered orally, with blood levels reaching therapeutic blood levels in the patient of about 0.01 - 3 mEq/L.
  • lithium is administered so as to achieve therapeutically effective blood levels of about 0.05 - 2.0 mEq/L.
  • lithium is administered to achieve patient blood levels of about 0.1-1.5 mEq/L.
  • the method is employed to administer lithium to patient blood levels of about 0.6 to about 0.8 mEq/L.
  • Patient treatment according to these methods can be achieved by repeated and routine administration of lithium.
  • the lithium may be administered daily for periods of six months or more.
  • Treatment regimens will generally be about one month or more.
  • lithium when administering lithium orally according to these methods, lithium can be combined with food for ease of administration. Dosage regimens of about 1-20 g lithium per kg food can be used. In other embodiments, about
  • lithium per kg food can be used. And in still other embodiments, about 3-6 g lithium per kg food can be used.
  • mice overexpressing human a-Syn were obtained [Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L. Dopaminergic loss and inclusion body formation in alpha- synuclein mice: implications for neurodegenerative disorders. Science. 2000 Feb 18;287(5456): 1265-9] and bred. These mice have been used in several studies and both synucleinopathy and tauopathy are well- characterized in these animals [Haggerty T, Credle J, Rodriguez O, Wills J, Duka V, Oaks AW, Masliah E, Sidhu A.
  • Hyperphosphorylated Tau in an a- synuclein overexpressing transgenic model of Parkinson's disease 33(9) Eur. J. Neurosci. 1598-610 (2011 May); Kaul T, Credle J, Haggerty T, Oaks A, Masliah E, Sidhu A (20 1 ) Region-specific tauopathic changes in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease. 12 BMC Neurosci. 79 (201 1 Aug 3)]. Accumulation of a-Syn and p-Tau develops in these mice at >8 months of age; younger mice do not show such pathology.
  • mice From IHC, it is shown that these mice have large intraneuronal aggregates of a-Syn and p-Tau in striatum, which resemble Lewy bodies, with proteins co-localizing with one another (Figure 1) and with p-GSK-3 [Haggerty T, Credle J, Rodriguez O, Wills J, Duka V, Oaks AW, Masliah E, Sidhu A. Hyperphosphorylated Tau in an a-synuclein overexpressing transgenic model of Parkinson's disease. 33(9) Eur. J. Neurosci. 1598-610 (201 1 May)]. Moreover, it has been shown that activation of p-GSK-3 (phosphorylation at Tyr216) occurs in these mice, resulting in
  • a-Syn overexpressing mice also display abnormal motor behavior, when compared to WT mice, as indexed by reduced latency to fall and latency to passive rotation (see Figure 3).
  • lithium may act to not only inhibit GSK-3P activation but also to remove existing aggregates of a-Syn and p-Tau through increase in proteasomal activity.
  • lithium is also a known activator of autophagy [Sarkar S, Rubinsztein DC. Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations. Autophagy. 2006 Apr- Jun;2(2):132-4. Epub 2006 Apr 6. Review; Pasquali L, Longone P, Isidoro C, Ruggieri S, Paparelli A, Fornai F. Autophagy, lithium, and amyotrophic lateral sclerosis. Muscle Nerve. 2009 Aug;40(2): 173-94.
  • Example 1 To test whether long-term treatment of aged Tg mice, who have both synucleinopathy and tauopathy, with lithium will reverse PD- like pathology. PD is most commonly seen in the elderly population. In aged mice (18 months) PDGF-a-Syn is administered at different doses of lithium in chow for 2 months. Improvement in biochemical,
  • GSK-3 is central to the tauopathic process seen in PD, and that its inhibition in neurons and transfected neuronal cells with lithium, TDZD-8 or with methylmaleimide inhibitors of GSK-3 , rescues cells from MPP+-mediated cell death, with abolition of synucleinopathy and tauopathy [Duka T, Sidhu A. (2006) The neurotoxin, MPP+, induces hyperphosphorylation of Tau, in the presence of alpha- Synuclein, in SH-SY5Y neuroblastoma cells. Neurotox Res. 10: 1-10; Alan P. Kozikowski, Irina N. Gaisina, Pavel A.
  • the PDGF-a-Syn mouse is an ideal model for our studies, as it mimics the vast majority of sporadic PD, which is caused by multiplications of the SNCA [Hofer A, Berg D, Asmus F, Niwar M, Ransmayr G, et al (2005). The role of alpha-synuclein in gene multiplications in early-onset Parkinson's disease and dementia with Lewy bodies. J Neural Transm.
  • PD pathology has key features of PD pathology seen in humans: (1 ) elevation of a-Syn to levels similar to those seen in PD; (2) hyperphosphorylation of Tau at sites identical to those seen in PD striatum, namely, at Ser202, Ser262 and Ser396/404; (3) increases in p-Tau to levels similar to those seen in PD; (4) increases in p-GSK-3 to levels similar to those seen in PD [Wills J, Jones J,Haggerty T, Duka V, Joyce JN, Sidhu A (2010). Elevated taupathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia. Exp Neurol. 2010 Sep;225(1 ):210-8.
  • mice Treatment of mice. WT and a-Syn Tg mice at age 16 months are used, since this is the age which most closely models the onset of PD in humans. Mice are treated with low, medium and high levels of lithium in chow in order to obtain serum levels of ⁇ 0.2, 0.5 and 0.8 mEq/L.
  • the treatment groups are: WT + Tg mice fed normal chow; WT + Tg mice fed low levels of lithium chow; WT + Tg mice fed medium levels of lithium; WT + Tg mice fed high levels of lithium. There are 12 mice per group. After 2 months of treatments, all mice are sacrificed. Results from lithium-fed mice are compared to Tg and WT mice fed normal chow.
  • mice are induced to grip the wire screen cover from a rodent housing cage and the screen will be inverted and suspended 45 cm above an empty housing cage [Mata IF, Yearout D, Alvarez V, Coto E, de Mena L, Ribacoba R, Lorenzo-Betancor O, Samaranch L, Pastor P, Cervantes S, Infante J, Garcia-Gorostiaga I, Sierra M, Combarros O, Snapinn KW, Edwards KL, Zabetian CP. Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for
  • Dopamine metabolites are measured by HPLC, as previously described [Duka T, Sidhu A. (2006) The neurotoxin, MPP+, induces hyperphosphorylation of Tau, in the presence of alpha-
  • brains are sectioned in a 1 :2 series at 40 pm and IHC performed for TH and counterstained with a Nissl stain. Counts are made at regular predetermined intervals (x, 140 pm, y 140 pm). Systematic samples of the area occupied by the nuclei are made from a random starting point. An unbiased counting frame of known area (45 pm x 35 pm) is superimposed on the image of the tissue sections, using a 63 times oil objective NA 1 .36.
  • Active p-GSK-3 is phosphorylated at Tyr216, while inactive GSK-3p is phosphorylated at Ser9.
  • levels of p-GSK-3p and GSK-3p-Ser9 are determined by conducting Western blots. Total GSK-3 levels are
  • a-Syn levels are measured in striata of mice after lithium treatments, by Western blots.
  • p-a-Syn levels are also measured.
  • p-Tau levels are measured by Western blots.
  • the epitopes examined are: Ser202, Ser262 and Ser396/404. Assessment of these sites is sufficient to determine if tauopathy is reduced. Comparison of results obtained with the lithium treated Tg and WT groups is made to controls fed normal chow.
  • Example 2 To test the ability of lithium to prevent onset of PD-like pathology and behavioral deficits in pre-symptomatic PDGF-a-Syn
  • PD the most common form of PD.
  • Pre-symptomatic adult mice (6 months of age) are continuously fed very low doses of lithium for 4 months to test the ability of lithium to prevent onset of PD-like pathology. Improvement in biochemical, neuropathological and behavioral correlates is assessed.
  • Gene multiplications of a-Syn are causal in sporadic PD, the most common form of PD. Genotyping can identify individuals carrying SNCA multiplications; as a preventive measure, administration of low levels of lithium is useful in preventing onset of PD. Moreover, other individuals identified at high risk for developing PD, particularly through work-related exposure to environmental toxins and agrichemicals, are administered low levels of lithium as a precautionary measure.
  • the a-Syn overexpressing Tg mice develop synucleinopathy and tauopathy at 8 months of age. Treatment of 6 month old pre-symptomatic mice with low levels of lithium prevents synucleinopathy and tauopathy at a later age in mice. This approach is very useful in prevention strategies aimed at individuals who carry multiplications of the a-Syn gene, and who are at the highest risk of developing PD.
  • mice with lithium Treatment of mice with lithium for 4 months. Mice 6 months of age (12/group) are treated with lithium in their chow as described above, and treatment will be continued for 4 months. As a control, a group of Tg mice will be fed normal chow and allowed to age to 10 months. Another group of WT mice will be fed normal chow and a group of WT mice will be fed lithium chow. The purpose of this study is to determine if long-term treatment of mice will prevent onset of PD-like pathology.

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Abstract

L'invention concerne un procédé de traitement de la maladie de Parkinson (MP) qui emploie du lithium (Li) pour inhiber GSK-3 bêta et stimuler simultanément l'autophagie afin d'éliminer les agrégats protéiques de a-synucléine (a-Syn) et de tau hyperphosphorylé. Le procédé inverse la synucléinopathie et la tauopathie associées aux maladies neurodégénératives, en particulier la maladie de Parkinson. Le lithium est utile dans le traitement de la maladie d'Alzheimer, de l'atrophie multisystématisée et de la démence à corps de Lewy, qui se caractérisent toutes par des teneurs élevées en a-Syn, p-Tau et GSK-3 bêta activé.
PCT/US2012/041292 2011-06-07 2012-06-07 Ciblage de gsk-3 bêta pour le traitement de la maladie de parkinson Ceased WO2012170657A1 (fr)

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Publication number Priority date Publication date Assignee Title
US9603869B2 (en) 2015-05-22 2017-03-28 University Of South Florida Lithium co-crystals and an additional neuropsychiatric agent for treatment of neuropsychiatric disorders
PL448928A1 (pl) * 2024-06-29 2026-01-05 Uniwersytet Medyczny W Lublinie Kompozycja substancji aktywnych na bazie resweratrolu oraz zastosowanie kompozycji substancji aktywnych w leczeniu chorób neurodegeneracyjnych

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US20090233971A1 (en) * 2004-04-05 2009-09-17 Noscira, S.A. GSK-3 Inhibitors
US20110136867A1 (en) * 2006-02-02 2011-06-09 Justman Craig J Treatment of Synucleinopathies
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9603869B2 (en) 2015-05-22 2017-03-28 University Of South Florida Lithium co-crystals and an additional neuropsychiatric agent for treatment of neuropsychiatric disorders
PL448928A1 (pl) * 2024-06-29 2026-01-05 Uniwersytet Medyczny W Lublinie Kompozycja substancji aktywnych na bazie resweratrolu oraz zastosowanie kompozycji substancji aktywnych w leczeniu chorób neurodegeneracyjnych

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