Cortical spreading depolarization (CSD) is the neuronal correlate of migraine aura and the reliable consequence of acute brain injury. The role of CSD in triggering headaches that follow migraine aura and brain injury remains to be uncertain. We examined whether a single CSD occurring in awake animals modified the expression of proinflammatory cytokines (Il1b, TNF, and Il6) and endogenous mediators of nociception/neuroinflammation-pannexin 1 (Panx1) channel and calcitonin gene-related peptide (CGRP), transforming growth factor beta (TGFb) in the cortex. Unilateral microinjury of the somatosensory cortex triggering a single CSD was produced in awake Wistar rats. Three hours later, tissue samples from the lesioned cortex, intact ipsilesional cortex invaded by CSD, and homologous areas of the contralateral sham-treated cortex were harvested and analyzed using qPCR. Three hours post-injury, intact CSD-exposed cortexes increased TNF, Il1b, Panx1, and CGRP mRNA levels. The strongest upregulation of proinflammatory cytokines was observed at the injury site, while CGRP and Panx1 were upregulated more strongly in the intact cortexes invaded by CSD. A single CSD is sufficient to produce low-grade parenchymal neuroinflammation with simultaneous overexpression of Panx1 and CGRP. The CSD-induced molecular changes may contribute to pathogenic mechanisms of migraine pain and post-injury headache.

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.