Abstracts

Rationale: Focal cortical dysplasia (FCD) is associated with compromised blood-brain barrier (BBB) function, which has clinical relevance and presents the opportunity for therapeutic intervention in patients with difficult-to-treat epilepsy. The underlying cellular and molecular factors in cortical dysplasia (CD) associated with progressive neurovascular challenges during the pro-epileptic phase, post-seizure and during epileptogenesis remain unclear.

Methods: We studied BBB function in a rat model of congenital (in utero radiation-induced, first hit) CD and longitudinally examined the baseline and progressive neurovascular alterations, glucose transporter-1 (GLUT1) expression and glucose metabolic activity at 2, 15, and 30 days following a second-hit using pentylenetetrazole-induced seizure. In the cortex, the neurovascular target proteins associated with BBB integrity, glucose metabolism and mammalian target of rapamycin (mTOR) signaling were analyzed by immunoblotting and immunohistochemistry. Cortical brain glucose-lactate levels and ATPase activity were evaluated. We also assessed the effect of lactate supplementation during glucose deprivation in human embryonic kidney cells (in vitro) on mTOR activation and monocarboxylate transporter-2 (MCT2) expression.

Results: Our study revealed that 1) altered vascular density and prolongation of BBB albumin leakages continued through 30 days post-seizure in CD rats, 2) CD brain tissues showed elevated matrix-metalloproteinase-9 levels through 15 days post-seizure and microglial overactivation through 30 days post-seizure, 3) BBB tight junction protein and GLUT1 levels were decreased and neuronal MCT2 and mTOR levels were increased in the CD rat brain, 4) ATPase activity is elevated and a low glucose/high lactate imbalance exists in the brain of CD rats, and 5) the mTOR pathway is activated and MCT2 elevated in the presence of high lactate during glucose starvation in vitro.

Conclusions: Together, this study suggests that BBB dysfunction, including decreased GLUT1 expression, may contribute to epilepsy and its progression in CD rat model through multiple mechanisms. These metabolic factors at the neurovasculature could be a potential therapeutic target for the treatment of FCD in medically refractory epilepsy.

Funding: Please list any funding that was received in support of this abstract.: This study is supported in part by NIH-NINDS grant R01NS095825 awarded to Dr. Chaitali Ghosh.