Protective effects of luteolin against amyloid beta-induced oxidative stress and mitochondrial impairments through peroxisome proliferator-activated receptor γ-dependent mechanism in Alzheimer's disease

Redox Biology, Journal Year: 2023, Volume and Issue: 66, P. 102848 - 102848

Published: Aug. 12, 2023

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) peptides and dysfunction mitochondrion, which result in neuronal apoptosis ultimately cognitive impairment. Inhibiting Aβ generation repairing mitochondrial damage are prominent strategies AD therapeutic treatment. Luteolin, flavonoid compound, exhibits anti-inflammatory neuroprotective properties mice. However, it still unclear whether luteolin has any effect on pathology dysfunction. In this study, beneficial underlying mechanism were investigated triple transgenic (3 × Tg-AD) mice primary neurons. Our study showed that supplement significantly ameliorated memory impairment exerted neuroprotection inhibiting generation, reducing apoptosis. Further research revealed could directly bind with peroxisome proliferator-activated receptor gama (PPARγ) to promote its expression function. culture hippocampus-derived neurons, addition PPARγ antagonist GW9662 or knockdown siRNA eliminate pathologies. summary, work for first time effectively improved deficits 3 Tg-AD inhibited Aβ-induced oxidative stress, via PPARγ-dependent mechanism. Hence, potential serve as agent against AD.

Language: Английский

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Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Alternatives to Laboratory Animals, Journal Year: 2023, Volume and Issue: 51(2), P. 102 - 135

Published: March 1, 2023

The failure rate for the translation of drugs from animal testing to human treatments remains at over 92%, where it has been past few decades. majority these failures are due unexpected toxicity — that is, safety issues revealed in trials were not apparent tests or lack efficacy. However, use more innovative tools, such as organs-on-chips, preclinical pipeline drug testing, tools able predict events prior clinical and so can be used this, well efficacy testing. Here, we review several disease areas, consider how models failed offer effective new treatments. We also make some suggestions human-relevant approach methodologies might applied address this.

Language: Английский

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Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 3, 2023

Abstract Stroke and late-onset Alzheimer’s disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge basic research clinical practice. The similarities differences between stroke AD terms pathogenesis pathophysiology, however, have rarely been comparably reviewed. Here, we discuss background recent progresses that important informative related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity NMDAR-mediated Ca 2+ influx essential neuronal function cell survival. An ischemic insult, can cause rapid increases glutamate concentration excessive activation NMDARs, leading to swift overload cells acute excitotoxicity within hours days. On other hand, mild upregulation NMDAR activity, commonly seen animal models patients, is not immediately cytotoxic. Sustained hyperactivity dysregulation lasting from months years, nevertheless, be pathogenic slowly evolving events, i.e. degenerative excitotoxicity, development AD/ADRD. Specifically, mediated by extrasynaptic NMDARs (eNMDARs) downstream pathway transient potential cation channel subfamily M member (TRPM) primarily responsible excitotoxicity. subunit GluN3A plays “gatekeeper” role neuroprotective against both chronic Thus, share an NMDAR- -mediated mechanism provides common target preventive possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs was approved Federal Drug Administration (FDA) symptomatic treatment moderate-to-severe with variable efficacy. According eNMDARs, it conceivable MEM eNMDAR antagonists should administered much earlier, preferably during presymptomatic phases This anti-AD could simultaneously serve as preconditioning strategy attacks ≥ 50% patients. Future on regulation enduring control homeostasis, events will provide promising opportunity understand treat AD/ADRD stroke.

Language: Английский

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Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 13900 - 13900

Published: Sept. 9, 2023

In an ever-increasing aged world, Alzheimer’s disease (AD) represents the first cause of dementia and one chronic diseases in elderly people. With 55 million people affected, WHO considers AD to be a with public priority. Unfortunately, there are no final cures for this pathology. Treatment strategies aimed mitigate symptoms, i.e., acetylcholinesterase inhibitors (AChEI) N-Methyl-D-aspartate (NMDA) antagonist Memantine. At present, best approaches managing seem combine pharmacological non-pharmacological therapies stimulate cognitive reserve. Over last twenty years, number drugs have been discovered acting on well-established biological hallmarks AD, deposition β-amyloid aggregates accumulation hyperphosphorylated tau protein cells. Although previous efforts disappointed expectations, new era treating has working its way recently. The Food Drug Administration (FDA) gave conditional approval disease-modifying therapy (DMT) treatment aducanumab, monoclonal antibody (mAb) designed against Aβ plaques oligomers 2021, January 2023, FDA granted accelerated second antibody, Lecanemab. This review describes ongoing clinical trials DMTs therapies. We will also present future scenario based biomarkers that can detect preclinical or prodromal stages, identify at risk developing allow early curative treatment.

Language: Английский

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Passive immunotherapy for Alzheimer's disease

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 94, P. 102192 - 102192

Published: Jan. 14, 2024

Alzheimer's disease (AD) is the most common neurodegenerative characterized by cognitive impairment with few therapeutic options. Despite many failures in developing AD treatment during past 20 years, significant advances have been achieved passive immunotherapy of very recently. Here, we review characteristics, clinical trial data, and mechanisms action for monoclonal antibodies (mAbs) targeting key players pathogenesis, including amyloid-β (Aβ), tau neuroinflammation modulators. We emphasized efficacy lecanemab donanemab on cognition amyloid clearance patients phase III trials discussed factors that may contribute to side effects anti-Aβ mAbs. In addition, provided important information mAbs or inflammatory regulators trials, indicated against mid-region pathogenic potential AD. conclusion, pathogenesis offers a promising strategy effective treatment.

Language: Английский

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