Browsing by Author "Adesh K. Saini"

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Dimethyl-2-oxoglutarate but not antioxidants prevents glucose hypometabolism induced neural cell death: implications in the pathogenesis and therapy of Alzheimer's disease
(Elsevier B.V., 2025) Aman Chauhan; Karanpreet Bhutani; Aritri Bir; Ajay Singh; Sankha Shubhra Chakrabarti; Adesh K. Saini; Sasanka Chakrabarti; Arindam Ghosh
Cerebral glucose hypometabolism is a cardinal molecular signature of Alzheimer's disease, and its role in the pathogenesis of this disorder is under intensive study in both animal and cell-based models. In the current study, we exposed SH-SY5Y cells (human neuroblastoma cell line) over a period of 48 h to DRB18, an inhibitor of multiple glucose transporters, in different concentrations to develop a state of glucose hypometabolism. Under this metabolic insult, in SH-SY5Y cells a profound dose-dependent neural cell death, an increased production of reactive oxygen radicals, mitochondrial membrane depolarization and a depletion of cellular ATP content were noted; these effects were not prevented by lipid-soluble novel antioxidants such as ferrostatin-1 and liproxstatin-1 or by a general water-soluble antioxidant like N-acetylcysteine. However, dimethyl-2-oxoglutarate, the cell-permeable analogue of 2-oxoglutarate (α-ketoglutarate) which can serve as an alternative fuel during glucose hypometabolism partially prevented both mitochondrial impairments and neural cell death. Thus, dimethyl-2-oxoglutarate may be explored further as a potential neuroprotective compound for Alzheimer's disease, and its effect on amyloid beta metabolism and homeostasis should be examined under glucose hypometabolic stress. © 2025 The Authors
GLUT inhibitor WZB117 induces cytotoxicity with increased production of amyloid-beta peptide in SH-SY5Y cells preventable by beta-hydroxybutyrate: implications in Alzheimer’s disease
(Springer Science and Business Media Deutschland GmbH, 2023) Gourav Chandan; Upasana Ganguly; Soumya Pal; Sukhpal Singh; Reena V. Saini; Sankha Shubhra Chakrabarti; Adesh K. Saini; Sasanka Chakrabarti
Background: Inhibitors of glucose transporters are being explored as potential anti-cancer drugs. Decreased cerebral glucose utilization with reduced levels of several glucose transporters is also an important pathogenic signature of neurodegeneration of Alzheimer’s disease, but its exact role in the pathogenesis of this disease is not established. We explored in an experimental model if inhibitors of glucose transporters could lead to altered amyloid-beta homeostasis, mitochondrial dysfunction, and neuronal death, which are relevant in the pathogenesis of Alzheimer’s disease. Methods: SH-SY5Y cells (human neuroblastoma cell line) were exposed to an inhibitor (WZB117) of several types of glucose transporters. We examined the effects of glucose hypometabolism on SH-SY5Y cells in terms of mitochondrial functions, production of reactive oxygen species, amyloid-beta homeostasis, and neural cell death. The effect of β-hydroxybutyrate in ameliorating the effects of WZB117 on SH-SY5Y cells was also examined. Results: We observed that exposure of SH-SY5Y cells to WZB117 caused mitochondrial dysfunction, increased production of reactive oxygen species, loss of cell viability, increased expression of BACE 1, and intracellular accumulation of amyloid β peptide (Aβ42). All the effects of WZB117 could be markedly prevented by co-treatment with β-hydroxybutyrate. Cyclosporine A, a blocker of mitochondrial permeability transition pore (mPTP) activation, could not prevent cell death caused by WZB117. Conclusion: Results in this neuroblastoma model have implications for the pathogenesis of Alzheimer’s disease and warrant further explorations of WZB117 in primary cultures of neurons and experimental animal models. © 2023, The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.