Pyrus pashia fruit extract and its major constituent chrysin attenuate seizures through GABAergic pathway modulation: Evidence from mouse models and in silico studies

Epilepsy is a chronic neurological disorder characterized by recurrent, unprovoked seizures resulting from abnormal neuronal excitability in the brain. This neurological disorder is considerably managed by the antiepileptic drugs, though they have serious limitations including significant side effects and adverse drug reactions. Hence, it is necessary to develop safer and more effective therapeutic alternatives. In this context, many traditional medicinal plants have long been explored for their anticonvulsant properties. Pyrus pashia (Wild Himalayan Pear), a member of the Rosaceae family, has been traditionally utilized in various ethnomedicinal practices for neurological disorders, including epilepsy. Our previous research demonstrated that the ethanolic fruit extract of P. pashia (EPP) and its major bioactive constituent chrysin exhibit significant anticonvulsant activity comparable to diazepam and improve memory performance in pentylenetetrazol (PTZ)-induced seizure model. In the current study, we have further investigated the molecular mechanisms underlying these effects, focusing on the modulation of GABAergic neurotransmission by chrysin in a mouse seizure model. Molecular docking and western blot analyses revealed that chrysin binds effectively to the GABA receptor α1/γ2 interface and increases synaptic protein gephyrin levels in the hippocampus. These results suggest that EPP and chrysin enhance GABAergic transmission and synaptic stability, positioning them as promising candidates for developing safer and more effective antiepileptic therapies.