The Role of Blood–Brain Barrier Disruption in Epilepsy: Mechanisms and Consequences

The blood-brain barrier (BBB) is essential for maintaining cerebral homeostasis, and its dysfunction is increasingly recognized as an active driver of epilepsy. This review explores the mechanisms by which BBB disruption contributes to seizures and the development of chronic epilepsy. Potentially epileptogenic insults, including traumatic brain injury, stroke, and status epilepticus, induce acute and often persistent BBB leakage. This breach permits the extravasation of serum albumin, which activates transforming growth factor-beta (TGF-β) signaling in astrocytes. This cascade leads to astrocytic dysfunction, impaired potassium buffering, neuroinflammation, and synaptic remodeling, collectively fostering neuronal hyperexcitability. Furthermore, BBB disruption facilitates the infiltration of peripheral immune cells, amplifying neuroinflammation and propagating a pathologic cycle of BBB damage and seizure activity. BBB damage is mediated by multiple processes, including the activation of the plasminogen activation (PA) system. Furthermore, these processes of BBB disruption and neuroinflammation provide a shared pathological basis for neuropsychiatric disorders like depression and anxiety, which are common comorbidities of epilepsy, through shared mechanisms of neuroinflammation and neurovascular unit (NVU) dysregulation. BBB dysfunction can also contribute to the resistance to antiepileptic drugs. Finally, we discuss the therapeutic potential of stabilizing the BBB as a viable strategy for developing disease-modifying therapies for epilepsy.