Repurposing Prasugrel: A Neuroprotective Strategy Against Pentylenetetrazol-Induced Kindling in Mice

Epilepsy is a multifaceted brain disorder associated with frequent seizures arising from prolonged neuronal activity caused by an imbalance between neurotransmitters. Despite the availability of anti-epileptic drugs, patients develop resistance, highlighting the need to explore non-classical therapeutic targets. Thus, this study has repurposed prasugrel for anti-epileptic potential against pentylenetetrazol (PTZ) induced kindling epilepsy in mice.

Thirty Swiss albino mice were included to establish PTZ-induced kindling. Animals received sub-convulsive doses of PTZ (35 mg/kg/i.p.) on alternate days for 27 days (14 injections). The treatment group received prasugrel (5 and 10 mg/kg, p.o.) for 33 days, administered 30 minutes before PTZ injection. PTZ challenge test was performed on 33^rd day to assess seizure susceptibility. Animals were euthanized, and brain tissues were isolated for neurochemical analysis of GABA and glutamate, gene (P2ry12, IL-1β, TNF-α, NF-κB), and protein expression analysis of the P2Y₁₂ receptor, NF-κB, Caspase 8, and Caspase 3.

PTZ successfully induced kindling in animals, indicated by higher seizure severity scores. However, treating PTZ-kindled animals with prasugrel significantly and dose-dependently reduced seizure severity by improving inhibitory and excitatory neurotransmitter homeostasis. Prasugrel significantly reduced PTZ-induced neuroinflammation, reflected by downregulated P₂Y₁₂R, IL-1β, TNF-α and NF-κB gene activity. Likewise, decreased protein expression of P₂Y₁₂ receptor, NF-κB, Caspase-8, and Caspase-3.

The current study suggests that prasugrel exhibits neuroprotective effects in the PTZ-induced kindling model, via modulating the P₂Y₁₂ receptor mediated neuroinflammatory and apoptotic pathways. These findings support the repurposing of prasugrel as a promising therapeutic approach for the treatment of epilepsy.