Transcriptomic Insights into Levetiracetam's Neuroprotective Mechanisms Against Lead-Induced Toxicity in SH-SY5Y Cells

Levetiracetam (LEV), an antiepileptic drug of the second generation, has shown neuroprotective activity in
addition to antiepileptic activity, in particular against oxidative stress-induced neuronal damage. The researchers
tested the effects of finding out whether LEV can reduce the neurotoxicity effects of lead acetate in human SHSY5Y
neuroblastoma cell line via a whole-transcriptome NGS. There was an interference of gene networks
concerning oxidative stress management, apoptosis, lipid metabolism, and synaptic signalling with lead acetate
exposure. LEV pretreatment significantly counteracted these changes and stimulated genes involved in
antioxidant protection, neuronal survival, extracellular component organization, and nicotinic plasticity and
inhibited the pro-apoptotic pathway and the genes related to cholesterol biosynthesis. KEGG pathway and
functional enrichment analysis showed that TGF-beta, PI3K-Akt and metal ion detoxification pathways were
notably covered, and excitation-inhibition balance restoration of gene expression was restored. PPI mapping
identified major hub genes linked to survival signalling and extracellular matrix stability, including as TIMP1,
IGFBP5, ID1/2/3, and DCN. These data imply that LEV has transcriptional neuroprotection that enables
neuroprotection due to the promotion of the detoxication processes, maintenance of synaptic integrity, and
inhibition of the metal and metabolic stress responses, which underlines its repositioning as a possible treatment
of neurodegenerative disorders linked to environmental neurotoxins.