The contribution of fibronectin in epileptogenesis: therapeutic potential and mechanistic complexity

Epilepsy is a chronic neurological disorder leading to repeateduncontrollable seizures. The available armamentarium of ~ 30 antiseizure drugsis unable to control seizures in a third of the patients, which signifies the need to look for novel therapeutic targets with alternative mechanisms of action.

Fibronectin, an extracellular matrix (ECM) glycoprotein,is involved in epileptogenesis as shown by several clinical and preclinicalstudies. There is ample evidence supporting fibronectin's role in modulatingkey pathognomonic events during epileptogenesis. This review presents a conciseoverview of fibronectin's contribution to the initiation and progression ofepilepsy. Additionally, we highlight the potential of fibronectin to betargeted for developing novel anti-epileptogenic therapeutics.

Epileptogenesis involves aberrant angiogenesis,blood-brain barrier (BBB) perturbation, neuroinflammation, synaptic remodeling,and neuronal hyperexcitability, all of which are significantly regulated byfibronectin. Small-molecule inhibitors against fibronectin could disrupt the signaling pathways that influence hyperexcitability, BBB disruption, andaberrant neurogenesis during epileptogenesis. Alternatively, delivering fibronectin/nanomedicine complex to the brain could help target neuroinflammation, as demonstrated in other diseases. However, current evidence supporting fibronectin as a therapeutic target in epilepsy remains limited,highlighting the need for further research to better understand its role in epileptogenesis.