Journal of Alzheimer's Disease - Volume 99, issue s1

Authors: Zhou, Moran | Jiao, Qian | Wu, Zengrui | Li, Weihua | Liu, Guixia | Wang, Rui | Tang, Yun

Article Type: Research Article

Abstract: Background: The oxidative stress hypothesis is challenging the dominant position of amyloid-β (Aβ ) in the field of understanding the mechanisms of Alzheimer’s disease (AD), a complicated and untreatable neurodegenerative disease. Objective: The goal of the present study was to uncover the oxidative stress mechanisms causing AD, as well as the potential therapeutic targets and neuroprotective drugs against oxidative stress mechanisms. Methods: In this study, a systematic workflow combining pharmacological experiments and computational prediction was proposed. 222 drugs and natural products were collected first and then tested on SH-SY5Y cells to obtain phenotypic screening data …on neuroprotection. The preliminary screening data were integrated with drug-target interactions (DTIs) and multi-scale biomedical data, which were analyzed with statistical tests and gene set enrichment analysis. A polypharmacology network was further constructed for investigation. Results: 340 DTIs were matched in multiple databases, and 222 cell viability ratios were calculated for experimental compounds. We identified significant potential therapeutic targets based on oxidative stress mechanisms for AD, including NR3C1, SHBG, ESR1, PGR, and AVPR1A, which might be closely related to neuroprotective effects and pathogenesis. 50% of the top 14 enriched pathways were found to correlate with AD, such as arachidonic acid metabolism and neuroactive ligand-receptor interaction. Several approved drugs in this research were also found to exert neuroprotective effects against oxidative stress mechanisms, including beclometasone, methylprednisolone, and conivaptan. Conclusion: Our results indicated that NR3C1, SHBG, ESR1, PGR, and AVPR1A were promising therapeutic targets and several drugs may be repurposed from the perspective of oxidative stress and AD. Show more

Keywords: Alzheimer’s disease, computational systems pharmacology, oxidative stress hypothesis, phenotypic screening, polypharmacology networks, therapeutic targets

DOI: 10.3233/JAD-220727

Citation: Journal of Alzheimer's Disease, vol. 99, no. s1, pp. S139-S156, 2024

Authors: Lazarova, Maria I. | Tsvetanova, Elina R. | Georgieva, Almira P. | Stefanova, Miroslava O. | Uzunova, Diamara N. | Denev, Petko N. | Tasheva, Krasimira N.

Article Type: Research Article

Abstract: Background: The cholinergic neuronal loss in the basal forebrain and increasing brain oxidative stress are one of the main features of the brain suffering from Alzheimer’s disease. Marrubium vulgare (M. vulgare ), commonly known as ‘white horehound,’ possesses a variety of valuable properties, such as antioxidative, anti-inflammatory, and antidiabetic activities. Moreover, it possesses neuromodulatory properties that could potentially impact short-term memory functions. Objective: The present study was undertaken to investigate the preventive effects of water M. vulgare extract on working memory, cholinergic neurotransmission, and oxidative stress in rats with scopolamine (Sco)-induced dementia. Methods: Male …Wistar rats (200–250 g) were divided into four experimental groups. The plant extract was administered orally for 21 days, and Sco (2 mg/kg) was administered intraperitoneally for 11 consecutive days. The behavioral performance of the animals was evaluated by the T-maze test. The effect of the extract on acetylcholinesterase (AChE) activity and antioxidant status in cortex and hippocampus were also monitored. Results: Our experimental data revealed that treatment with M. vulgare significantly increased the percentage of correct choices of rats with Sco-induced dementia in the T maze test (by 38%, p  < 0.05). Additionally, it reduced AChE activity in the hippocampus (by 20%, p  < 0.05) and alleviated oxidative stress induced by Sco, particularly in the cortex. Conclusions: M. vulgare water extract demonstrated working memory preserving effect in rats with Sco-induced dementia, AChE inhibitory activity and in vivo antioxidant potential, and deserve further attention. Show more

Keywords: Acetylcholinesterase, Alzheimer’s disease, Marrubium vulgare, oxidative stress, scopolamine-induced dementia, T-maze test

DOI: 10.3233/JAD-231011

Citation: Journal of Alzheimer's Disease, vol. 99, no. s1, pp. S157-S169, 2024

Authors: Daly, Timothy

Article Type: Review Article

Abstract: Maintaining diversity in drug development in research into Alzheimer’s disease (AD) is necessary to avoid over-reliance on targeting AD neuropathology. Treatments that reduce or prevent the generation of oxidative stress, frequently cited for its causal role in the aging process and AD, could be useful in at-risk populations or diagnosed AD patients. However, in this review, it is argued that clinical research into antioxidants in AD could provide more useful feedback as to the therapeutic value of the oxidative stress theory of AD. Improving comparability between randomized controlled trials (RCTs) is vital from a waste-reduction and priority-setting point of view …for AD clinical research. For as well as attempting to improve meaningful outcomes for patients, RCTs of antioxidants in AD should strive to maximize the extraction of clinically useful information and actionable feedback from trial outcomes. Solutions to maximize information flow from RCTs of antioxidants in AD are offered here in the form of checklist questions to improve ongoing and future trials centered around the following dimensions: adhesion to reporting guidelines like CONSORT, biomarker enrichment, simple tests of treatment, and innovative trial design. Show more

Keywords: Alzheimer’s disease, antioxidants, biomarkers, clinical trials, drug pipeline, information flow, oxidative stress, standardization, trial innovation

DOI: 10.3233/JAD-230308

Citation: Journal of Alzheimer's Disease, vol. 99, no. s1, pp. S171-S181, 2024