COULD RLIP76 BE THE KEY TO UNLOCKING NOVEL THERAPEUTIC AVENUES IN EPILEPSY?

Epilepsy is a debilitating neurological disorder characterized by recurrent seizures that is associated with significant cognitive and physical impairments. Several important factors, including oxidative stress, metabolic imbalances, and genetic mutations, contribute to the etiopathology of epilepsy, and its gradual progression leads to neurodegeneration. The traditional antiepileptic drugs (AEDs) cannot cure drug resistance in epilepsy, which is a challenge in current research. Overcoming such difficulties creates a necessity to develop new therapeutic methods. Ral interacting protein 76 (RLIP76), an ATP-dependent transporter, is essential for cellular homeostasis through modulation of oxidative stress and promoting the removal of toxic metabolites like 4-hydroxynonrenal linked with neuronal injury. It controls proteins like c-Jun N-terminal kinases (JNK) and extracellular signal-regulated kinases (ERK), controlling cell survival, apoptosis, and drug resistance. It also regulates neuronal excitability and synaptic plasticity, crucial determinants of seizure susceptibility, along with its function in cell detoxification. Its multifaceted functions in neuron stability, protection against oxidative stress, and restraint of pathological excitability contribute to the therapeutic potential of RLIP76. Its modulatory activity may be beneficial to improve the efficacy of AEDs through increased availability of drugs and decreased multidrug resistance, providing promise to develop more novel and effective therapeutic approaches for the management of epilepsy, particularly drug-resistant epilepsy. This review emphasizes the organization, functions, and cellular processes of RLIP76, highlighting its role in epilepsy pathophysiology as a possible biomarker for epileptic conditions and its therapeutic potential in the development of targeted therapies, including small-molecule inhibitors and gene therapy, to improve its therapeutic outcomes.

Keywords: RLIP76, Epilepsy, Oxidative stress, Neuroinflammation, Seizures