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

Background

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. MATERIALS &

Methods

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 33rd 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. RESULT 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.

Conclusion

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.