Abnormal Capillary Vasodynamics Contribute to Ictal Neurodegeneration in Epilepsy

Abstract

Seizure-driven brain damage in epilepsy accumulates over time, especially in the hippocampus, which can lead to sclerosis, cognitive decline, and death. Excitotoxicity is the prevalent model to explain ictal neurodegeneration. Current labeling technologies cannot distinguish between excitotoxicity and hypoxia, however, because they share common molecular mechanisms. This leaves open the possibility that undetected ischemic hypoxia, due to ictal blood flow restriction, could contribute to neurodegeneration previously ascribed to excitotoxicity. We tested this possibility with Confocal Laser Endomicroscopy (CLE) and novel stereological analyses in several models of epileptic mice. We found a higher number and magnitude of NG2+ mural-cell mediated capillary constrictions in the hippocampus of epileptic mice than in that of normal mice, in addition to spatial coupling between capillary constrictions and oxidative stressed neurons and neurodegeneration. These results reveal a role for hypoxia driven by capillary blood flow restriction in ictal neurodegeneration.

Seizure‐induced microvascular injury is associated with impaired neurovascular coupling and blood–brain barrier dysfunction

“…23 Moreover, several studies implicate postseizure hypoxia and vasoconstriction in seizure-related memory and behavioral deficits 24,25 and point to pericytelike mural cells as the mediators of capillary constriction. 26 This is in line with a recent study showing a correlation between mural cell remodeling, vascular pathology, and seizure severity by monitoring pericytic coverage in vivo over the course of several days after status epilepticus. 27 Together, these studies highlight the importance of an in-depth understanding of the development of metabolic and NVC abnormalities associated with recurrent seizures.…”

“…Seizures were reported to compromise stimulus‐induced vascular reactivity, and tissue oxygenation around the epileptic focus and in deep cortical layers . Moreover, several studies implicate postseizure hypoxia and vasoconstriction in seizure‐related memory and behavioral deficits and point to pericytelike mural cells as the mediators of capillary constriction . This is in line with a recent study showing a correlation between mural cell remodeling, vascular pathology, and seizure severity by monitoring pericytic coverage in vivo over the course of several days after status epilepticus .…”

“…By studying the longitudinal changes in the hemodynamic responses to seizures, our study reveals a gradual neurovascular decoupling at both the capillary and the arteriolar level and excludes hypoxia as an immediate cause of microvascular dysfunction and cellular injury. Our findings may explain the reported disturbances in blood flow regulation and mural cell remodeling following recurrent seizures . Furthermore, our in vitro evidence of pericytic injury–associated loss of capillary response and increased microvascular permeability highlights pericyte functionality as a potential therapeutic target for seizure disorders …”

“…Our findings may explain the reported disturbances in blood flow regulation and mural cell remodeling following recurrent seizures. 20,24,26,27 Furthermore, our in vitro evidence of pericytic injury-associated loss of capillary response and increased microvascular permeability highlights pericyte functionality as a potential therapeutic target for seizure disorders. 27…”

Seven‐tesla susceptibility‐weighted analysis of hippocampal venous structures: Application to magnetic‐resonance–normal focal epilepsy

“…In analysis of sclerotic hippocampi of temporal lobe epilepsy patients, changes in permeability of the blood‐brain barrier have been reported . Although previous attempts to characterize vasculature relative to epileptogenic zones and hippocampal sclerosis have been inconsistent, an increase in hippocampal vasculature, found through examination of immunohistochemistry markers such as collagen IV and macroscopic observations of the epileptogenic zone, has been interpreted as evidence of an increase in hippocampal vasculature in MTLE . However, this pattern is discordant with histochemical labeling studies employing alkaline phosphatase, a marker of endothelial cells in the blood‐brain barrier, and both high‐magnification light and electron microscopy, which suggest a decrease of blood vessels and visual identification of atrophic blood vessels in sclerotic hippocampi .…”