Sodium valproate (VPA), a widely used antiepileptic drug with good safety profile since many decades. It has increasingly demonstrated therapeutic potential in treating neurological disorders and offering neuroprotection. However, there are neurotoxic properties, underscoring its complex pharmacological profile. VPA works by boosting GABA, the brain's main inhibitory neurotransmitter to reduce nerve excitability and prevent seizures. In bipolar disorder, VPA stabilizes mood by modulating intracellular signaling pathways, including inhibition of histone deacetylases and modulation of G-protein-coupled receptor systems, which influence mood regulation and neuronal plasticity. VPA also prevents migraines by blocking sodium channels and pausing the brain wave disruptions that trigger migraine attacks. Emerging preclinical data suggest that VPA also plays a broader role in promoting neuronal survival, enhancing neuroplasticity, and protecting against neurodegenerative processes. However, despite its therapeutic efficacy, VPA's broad spectrum of action is accompanied by potential neurotoxicities. Chronic use of VPA is associated with adverse effects, including cognitive impairment, memory deficits, and motor dysfunction. Mitochondrial dysfunction, oxidative stress, excessive inhibition of histone deacetylase, imbalance in neurotransmitters and altered expression of neurotrophic factors are attributed to valproate-induced neurotoxicity. This review explores the neuroprotective effects as well as neurotoxic effects, with a focus on the molecular mechanisms underlying these diverse roles. Additionally, we discuss the challenges behind the failure of preclinical neuroprotective data to translate into successful clinical trials. This review aims to provide valuable insights for preclinical researchers designing future studies on VPA.
Keywords: Cognition; Memory; Neurogenesis; Neuroinflammation; Oxidative stress; Traumatic brain injury and Valproate.
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