Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease

Ageing Research Reviews, Год журнала: 2023, Номер 89, С. 101979 - 101979

Опубликована: Июнь 15, 2023

Therapeutic strategies for neurodegenerative disorders have commonly targeted individual aspects of the disease pathogenesis to little success. Neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's (PD), are characterized by several pathological features. In AD PD, there is an abnormal accumulation toxic proteins, increased inflammation, decreased synaptic function, neuronal loss, astrocyte activation, perhaps a state insulin resistance. Epidemiological evidence has revealed link between AD/PD type 2 diabetes mellitus, with these sharing some commonalities. Such opened up promising avenue repurposing antidiabetic agents in treatment disorders. A successful therapeutic strategy would likely require single or which target separate processes disease. Targeting cerebral signalling produces numerous neuroprotective effects preclinical brain models. Clinical trials shown promise approved diabetic compounds improving motor symptoms PD preventing decline, further phase II III underway populations. Alongside signalling, targeting incretin receptors represents one most currently available AD/PD. Most notably, glucagon-like-peptide-1 (GLP-1) receptor agonists displayed impressive clinical potential early studies. GLP-1 agonist, liraglutide, been demonstrated improve glucose metabolism functional connectivity small-scale pilot trials. Whilst agonist exenatide effective restoring function cognition. reduces inhibits apoptosis, prevents protein aggregation, enhances long-term potentiation autophagy as well restores dysfunctional signalling. Support also increasing use additional treatments, intranasal insulin, metformin hydrochloride, peroxisome proliferator-activated nuclear γ agonists, amylin analogs, tyrosine phosphatase 1B inhibitors investigation deployment treatment. As such, we provide comprehensive review anti-diabetic PD.

Язык: Английский

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Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Molecular Medicine, Год журнала: 2024, Номер 30(1)

Опубликована: Март 20, 2024

Abstract The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads stress (ER stress). As ER ensues, protein response (UPR), comprising three signaling pathways—inositol-requiring enzyme 1, kinase R-like kinase, activating transcription factor 6 promptly activates enhance ER’s protein-folding capacity restore homeostasis. However, prolonged levels propels UPR towards cellular demise subsequent inflammatory cascade, contributing development human diseases, including cancer, neurodegenerative disorders, diabetes. Notably, increased expression all pathways has been observed in these pathologies, reduction molecule correlates with decreased proliferation disease-associated target cells. Consequently, therapeutic strategies targeting stress-related interventions have attracted significant research interest. In this review, we elucidate critical role metabolic, offering novel approaches for conditions.

Язык: Английский

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Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Nervous System Disorders: A Systematic Review and Meta-Analysis

Annals of Pharmacotherapy, Год журнала: 2025, Номер unknown

Опубликована: Фев. 23, 2025

Background: Adults with type 2 diabetes mellitus (T2DM) are at an increased risk for certain brain or psychiatric disorders, as those without chronic kidney disease heart failure. Whether sodium-glucose cotransporter (SGLT2) inhibitors associated these diseases is unclear. Objective: This systematic review and meta-analysis aimed to investigate the effects of SGLT2 on nervous system disorders. Methods: We searched PubMed, ClinicalTrials.gov, Web Science randomized, double-blind placebo-controlled trials least ≥24 weeks. used Mantel–Haenszel statistical method, ratio (RR), 95% confidence interval (CI) dichotomous variables. Results: included 52 publications/trials covering 111 376 participants (SGLT2 62 192; Placebo 49 184). Sodium-glucose had no significant effect ischaemic stroke (RR = 0.97; CI 0.87-1.09; P 0.64), cerebrovascular accident 1.05; 0.91-1.22; 0.50), dementia 1.29; 0.78-2.12; 0.32), carotid artery occlusion/carotid stenosis 1.18; CI: 0.92-1.53; 0.20), haemorrhagic 0.84; 0.62-1.12; 0.23), transient attack 0.82-1.15; 0.73) compared placebo. No heterogeneity was observed. However, showed slight reduce Parkinson’s (major failure subgroup). Empagliflozin dapagliflozin significantly syncope 1.65; 1.15-2.38; < 0.01) 1.04-2.61; 0.03), respectively. Conclusion Relevance: disorders There reduced Disease observed in some specific populations. In addition, risks empagliflozin concerning worth attention.

Язык: Английский

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Empagliflozin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats by Modulating Sesn2/AMPK/Nrf2 Signaling and Targeting Ferroptosis and Autophagy

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(11), С. 9481 - 9481

Опубликована: Май 30, 2023

Pulmonary fibrosis (PF) is a life-threatening disorder that severely disrupts normal lung architecture and function, resulting in severe respiratory failure death. It has no definite treatment. Empagliflozin (EMPA), sodium-glucose cotransporter 2 (SGLT2) inhibitor, protective potential PF. However, the mechanisms underlying these effects require further elucidation. Therefore, this study aimed to evaluate ameliorative effect of EMPA against bleomycin (BLM)-induced PF mechanisms. Twenty-four male Wister rats were randomly divided into four groups: control, BLM treated, EMPA+BLM treated. significantly improved histopathological injuries illustrated by both hematoxylin eosin Masson's trichrome-stained tissue sections, as confirmed electron microscopic examination. reduced index, hydroxyproline content, transforming growth factor β1 levels rat model. had an anti-inflammatory effect, evidenced decrease inflammatory cytokines' tumor necrosis alpha high mobility group box 1, cell infiltration bronchoalveolar lavage fluid, CD68 immunoreaction. Furthermore, mitigated oxidative stress, DNA fragmentation, ferroptosis, endoplasmic reticulum up-regulation nuclear erythroid 2-related expression, heme oxygenase-1 activity, glutathione peroxidase 4 levels, C/EBP homologous protein levels. This could be explained on basis autophagy induction via up-regulating sestrin2 expression LC3 II immunoreaction observed study. Our findings indicated protected BLM-induced PF-associated cellular stress enhancing modulating sestrin2/adenosine monophosphate-activated kinase/nuclear 2/heme oxygenase 1 signaling.

Язык: Английский

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ncRNAs and their impact on dopaminergic neurons: Autophagy pathways in Parkinson's disease

Ageing Research Reviews, Год журнала: 2024, Номер 98, С. 102327 - 102327

Опубликована: Май 10, 2024

Язык: Английский

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The microRNA-211-5p/P2RX7/ERK/GPX4 axis regulates epilepsy-associated neuronal ferroptosis and oxidative stress

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Янв. 8, 2024

Abstract Ferroptosis is an iron-dependent cell death mechanism involving the accumulation of lipid peroxides. As a critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be downregulated in epilepsy. However, ferroptosis epilepsy remains unclear. In this study, bioinformatics analysis, analysis patient blood samples and mouse experiments revealed strong associations among epilepsy, ferroptosis, microRNA-211-5p purinergic receptor P2X 7 (P2RX7). P2RX7 nonselective ligand-gated homotrimeric cation channel, its activation mainly increases neuronal activity during epileptic seizures. our upregulation was attributed downregulation microRNA (miR)-211-5p. Furthermore, found regulate GPX4/HO-1 by alleviating peroxidation induced suppression MAPK/ERK signaling pathway murine models. The dynamic decrease miR-211-5p expression induces hypersynchronization both nonconvulsive convulsive seizures, forebrain exacerbates long-lasting pentylenetetrazole-induced Additionally, induction or genetic-silencing significantly reduced seizure score duration models through abovementioned pathways. These results suggest that miR-211-5p/P2RX7 axis novel target for suppressing

Язык: Английский

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MicroRNAs in Parkinson’s disease: From pathogenesis to diagnostics and therapeutic strategies

Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Empagliflozin repurposing in Parkinson’s disease; modulation of oxidative stress, neuroinflammation, AMPK/SIRT-1/PGC-1α, and wnt/β-catenin pathways

Inflammopharmacology, Год журнала: 2023, Номер 32(1), С. 777 - 794

Опубликована: Дек. 1, 2023

Abstract Parkinson's disease is a neuroprogressive disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta. Empagliflozin (EMPA), SGLT-2 inhibitor, an oral hypoglycemic agent with reported anti-inflammatory and antioxidant effects. The current study aimed to evaluate the neuroprotective effect EMPA rotenone-induced disease. Rats were randomly distributed among five groups as follows: control, rotenone (2 mg/kg), + (10 (20 mg/kg) groups. They treated for 30 consecutive days. Rotenone reduced locomotor activity retention time on rotarod performance test while elongated descent latency time. On other side, corrected these behavioral changes. These results confirmed histological examination number intact neurons. Moreover, induced alpha-synuclein accumulation, tyrosine hydroxylase expression, dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid concentrations. reversed such effects rotenone. Depending previous results, was selected further mechanistic studies. ameliorated superoxide dismutase catalase activities enhanced lipid peroxidation, interleukin-1β, tumor necrosis factor-α levels. By contrast, opposed oxidative stress inflammation. Besides, expression pAMP-activated protein kinase (pAMPK), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), Sirtuin-1 (SIRT-1), well abrogated NAD /NADH ratio. However, activated AMPK/SIRT-1/PGC - 1α pathway. hindered wnt/β-catenin pathway reducing wnt-3a level β-catenin expression. triggered activation Collectively, may provide promising solution patients worldwide.

Язык: Английский

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Apigenin Attenuates Hippocampal Microglial Activation and Restores Cognitive Function in Methotrexate-Treated Rats: Targeting the miR-15a/ROCK-1/ERK1/2 Pathway

Molecular Neurobiology, Год журнала: 2023, Номер 60(7), С. 3770 - 3787

Опубликована: Март 21, 2023

Microglial activation underpins the methotrexate (MTX)-induced neurotoxicity; however, precise mechanism remains unclear. This study appraised potential impact of apigenin (Api), a neuroprotective flavonoid, in MTX-induced neurotoxicity rats terms microglial through targeting miR-15a/Rho-associated protein kinase-1 (ROCK-1)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Male Sprague Dawley were randomly divided into 4 groups: Normal control (saline i.p. daily and i.v. on days 8 15); Api (20 mg/kg, p.o.) for 30 days; MTX-alone (75 i.v.) 15, then four injections leucovorin (LCV): 6 mg/kg after 18 h, three doses (3 mg/kg) every h post-MTX; co-treated mg/kg/day, throughout model days, with administration MTX LCV as group 3. elevated hippocampal ionized calcium-binding adaptor protein-1 (Iba-1) immunostaining, indicating activation. was accompanied by neuroinflammation, oxidative stress, enhanced apoptosis manifested interleukin-1β, malondialdehyde, caspase-3, decreased reduced glutathione levels. Concurrently, abated miR-15a expression, overexpression its target ROCK-1, diminished downstream ERK1/2 cAMP response element-binding (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) levels observed. mitigated reversing biochemical, histopathological, behavioral derangements tested novel object recognition Morris water maze tests. Conclusively, lessens boosts cognitive function inhibiting via modulating miR-15a/ROCK-1/ERK1/2/CREB/BDNF Graphical abstract showing effects co-treatment model. On left, (MTX) to resulted downregulation, which triggered an expression consequently ERK1/2/CREB/BDNF pathway, instigating state activation, apoptosis. other hand, (Api) restored miR-15a, inhibited ROCK-1 activated leading apoptosis, restoration redox balance, along improvement memory MTX-treated rats.

Язык: Английский

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Dexmedetomidine Attenuates Methotrexate-Induced Neurotoxicity and Memory Deficits in Rats through Improving Hippocampal Neurogenesis: The Role of miR-15a/ROCK-1/ERK1/2/CREB/BDNF Pathway Modulation

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(1), С. 766 - 766

Опубликована: Янв. 1, 2023

Methotrexate (MTX) is a widely used neurotoxic drug with broad antineoplastic and immunosuppressant spectra. However, the exact molecular mechanisms by which MTX inhibits hippocampal neurogenesis are yet unclear. Dexmedetomidine (Dex), an α2-adrenergic receptor agonist, has recently shown neuroprotective effects; however, its full mechanism unexplored. This study investigated potential of Dex to mitigate MTX-induced neurotoxicity memory impairment in rats possible role miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway. Notably, no former studies have linked this pathway neurotoxicity. Male Sprague Dawley were placed into four groups. Group 1 received saline i.p. daily i.v. on days 8 15. 2 at 10 μg/kg/day for 30 days. 3 75 mg/kg 15, followed doses leucovorin 6 after 18 h 26, 42, 50 h. 4 as group dosages 2. Bioinformatic analysis identified association miR-15a ROCK-1/ERK1/2/CREB/BDNF neurogenesis. lowered doublecortin Ki-67, two markers was associated downregulation miR-15a, upregulation target ROCK-1, reduction downstream ERK1/2/CREB/BDNF pathway, along disturbed redox state. Novel object recognition Morris water maze tests demonstrated deficiencies. co-treatment reversed behavioral, biochemical, histological alterations rats. These actions could be partly mediated through modulating enhances

Язык: Английский

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