An update on drug repurposing in Parkinson’s disease: Preclinical and clinical considerations

Biomedicine & Pharmacotherapy, Год журнала: 2025, Номер 183, С. 117862 - 117862

Опубликована: Янв. 22, 2025

Язык: Английский

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Repurposing of dipeptidyl peptidase FDA-approved drugs in alzheimer’s disease using network pharmacology and in-silico approaches

Computational Biology and Chemistry, Год журнала: 2025, Номер 116, С. 108378 - 108378

Опубликована: Фев. 8, 2025

Язык: Английский

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Sitagliptin attenuates L-dopa-induced dyskinesia by regulating mitochondrial proteins and neuronal activity in a 6-OHDA-induced mouse model of Parkinson’s disease

Journal of Neural Transmission, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Язык: Английский

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Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP-4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson’s Disease Mouse Models

ACS Chemical Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Март 24, 2025

Parkinson's disease (PD) is one of the most common progressive neurodegenerative pathologies that leads to dopaminergic deficiency and motor manifestations. Alpha-synuclein aggregation a characteristic hallmark PD pathogenesis. These aggregates facilitate formation Lewy bodies degeneration. The epidemiological evidence demonstrates definitive association diabetes with risk. Considering this, many antidiabetic agents such as GLP-1 agonists DPP-4 inhibitors are being explored alternative therapeutics. This study evaluated neuroprotective effect inhibitor sitagliptin mediated by PI3K/AKT Nrf2 pathways in models. In silico studies were conducted determine binding affinity, stability, ADMET properties target proteins. Sitagliptin (15 mg/kg p.o.) was administered rotenone (30 p.o. for 28 days)-induced MPTP/P (25 i.p. MPTP 100 probenecid twice week 5 weeks)-induced mouse (C57/BL6) Neurobehavioral assessments carried out throughout study. Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β, GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological studies, immunohistochemistry at end demonstrate better binding, profile both restored cognitive deficits rotenone- MPTP/P-induced There upregulation AKT, BDNF levels downregulation alpha-synuclein models after treatment sitagliptin. However, GLP1 not significantly restored, indicating GLP1-independent mechanism. It also alterations TH+ neuronal loss induced MPTP/P. findings exhibits action PD.

Язык: Английский

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Dipeptidyl peptidase-4 inhibitors enhance memory retention via neuropeptide Y

European Journal of Pharmacology, Год журнала: 2025, Номер unknown, С. 177556 - 177556

Опубликована: Март 1, 2025

Язык: Английский

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In Vivo and Computational Studies on Sitagliptin’s Neuroprotective Role in Type 2 Diabetes Mellitus: Implications for Alzheimer’s Disease

Brain Sciences, Год журнала: 2024, Номер 14(12), С. 1191 - 1191

Опубликована: Ноя. 26, 2024

Background/Objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Effective blood glucose management is essential, sitagliptin (SITG), dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes (T2DM). Methods: T2DM was induced rats using nicotinamide (NICO) streptozotocin (STZ), biomarkers AD DM-linked enzymes, inflammation, oxidative stress, apoptosis were evaluated brain. Computational studies supported vivo findings. Results: SITG significantly reduced brain enzyme levels acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, glycogen synthase kinase-3β (GSK-3β) T2DM-induced rats. It also inflammation lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB). Additionally, improved stress markers reducing malondialdehyde (MDA) enhancing glutathione (GSH). increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while pro-apoptotic Bcl-2-associated X (BAX) Caspace-3. lowered plasma insulin levels. To explore potential molecular level mechanisms, docking performed on AChE, COX-2, GSK-3β, BACE-1, The binding affinity for above-mentioned target enzymes 10.8, 8.0, 9.7, 7.7, 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further mode analysis lowest energy conformation revealed interactions with critical residues. Conclusions: These findings highlight SITG’s targets T2DM-associated neurodegeneration its therapeutic approach AD, warranting further clinical investigations.

Язык: Английский

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Targeting Glucose Metabolism: A Novel Therapeutic Approach for Parkinson’s Disease

Cells, Год журнала: 2024, Номер 13(22), С. 1876 - 1876

Опубликована: Ноя. 13, 2024

Glucose metabolism is essential for the maintenance and function of central nervous system. Although brain constitutes only 2% body weight, it consumes approximately 20% body’s total energy, predominantly derived from glucose. This high energy demand underscores its reliance on glucose to fuel various functions, including neuronal activity, synaptic transmission, ion gradients necessary nerve impulse transmission. Increasing evidence shows that many neurodegenerative diseases, Parkinson’s disease (PD), are associated with abnormalities in metabolism. PD characterized by progressive loss dopaminergic neurons substantia nigra, accompanied accumulation α-synuclein protein aggregates. These pathological features exacerbated mitochondrial dysfunction, oxidative stress, neuroinflammation, all which influenced disruptions. Emerging suggests targeting could offer therapeutic benefits PD. Several antidiabetic drugs have shown promise animal models clinical trials mitigating symptoms progression review explores current understanding association between metabolism, emphasizing potential medications as a novel approach. By improving uptake utilization, enhancing function, reducing these address key pathophysiological mechanisms PD, offering hope more effective management this debilitating disease.

Язык: Английский

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Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders

GeroScience, Год журнала: 2024, Номер 46(5), С. 4397 - 4414

Опубликована: Март 27, 2024

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, anti-neuroinflammatory actions. dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of GLP-1 GIP, and, thereby, extends the circulation these protective peptides. current nonhuman primate (NHP) study evaluates whether human translational doses can elevate systemic central nervous system (CNS) levels GLP-1/GIP in naive, non-lesioned NHPs, line with our prior rodent studies that demonstrated efficacy preclinical models Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose treatment inadequate. Repositioning well-tolerated efficacious diabetes drug provides a rapid approach to add therapeutic armamentarium for PD. pharmacokinetics pharmacodynamics 3 oral (5, 20, 100 mg/kg), equivalent routine clinical dose, tolerated higher dose maximal monkey, were evaluated. Peak plasma aligned both reports humans administered those rodents demonstrating reduction associated neurodegeneration. Although CNS uptake was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), CSF concentrations elevated studies. Additional cellular evaluating SH-SY5Y primary rat ventral mesencephalic cultures challenged 6-hydroxydopamine, established PD, joint + GIP mitigated cell death, particularly when combined DPP-4 inhibition maintain incretin levels. In conclusion, this supportive step towards evaluation other disorders which aging, similarly, greatest risk factor.

Язык: Английский

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Exploring DPP IV inhibitors for Alzheimer’s disease: Bridging diabetes and neurodegeneration

Brain Research, Год журнала: 2024, Номер 1848, С. 149342 - 149342

Опубликована: Ноя. 19, 2024

Язык: Английский

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Effects of sitagliptin and L-theanine combination therapy on testicular tissue in rats with experimental diabetes

Toxicology and Applied Pharmacology, Год журнала: 2024, Номер 492, С. 117119 - 117119

Опубликована: Окт. 6, 2024

Язык: Английский

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