Mechanistic Insights into metformin's neuroprotective effects against drug-induced neurotoxicity
Abstract
Drugs contribute to one of the most harmful contributors to neurotoxicity as they stimulate multiple neurotransmitter systems, inculcating oxidative damage, cell death, and glutamate excitotoxicity, which together contribute to brain injury. Common drugs capable of causing neurotoxicity include methylglyoxal, chemotherapy agents, aluminium, glutamate, Lipopolysaccharide (LPS), and aggregated proteins such as Amyloid β1-40, which can lead to neuronal cell damage, cognitive impairment, altered gene expression, and impaired neurogenesis. Metformin, a widely used anti-diabetic medication and first-line treatment, is a biguanide exhibiting several properties, including antioxidant, anti-inflammatory, and anti-apoptotic effects across various tissues. It activates adenosine monophosphate-activated protein kinase (AMPK) and inhibits hepatic gluconeogenesis. Both in vitro and in vivo research has explored its potential neuroprotective mechanisms in cerebral ischaemic injury and other neurodegenerative conditions. However, despite these benefits, long-term use of metformin may cause adverse effects such as the development of dementia and Parkinsonism, as well as accelerated oxidative damage. This highlights the need for further well-designed preclinical and clinical studies to determine the optimal dosing, treatment duration, and patient selection for metformin. This knowledge would help identify key molecular pathways and biomarkers influenced by metformin, enabling exploration of…
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