Pathogenesis of Stroke-Like Episodes in MELAS: Analysis of Neurovascular Cellular Mechanisms

Takahiro      Iizuka; Fumihiko      Sakai

doi:10.2174/1567202052773544

Abstract

The pathogenesis of stroke-like episodes in mitochondrial encephalopathy, myopathy, lactic acidosis and stroke-like episodes (MELAS) is not fully understood although two main theories have been proposed; ischemic vascular hypothesis caused by “mitochondrial angiopathy” and generalized cytopathic hypothesis caused by “mitochondrial cytopathy”. Crucial molecular mechanism includes the lack of taurine modification at the wobble uridine of mutant transfer RNAsLeu(UUR) resulting in defective translation of cognate codons due to a defect in codon-anticodon interaction. Whereas recent clinical studies have shed light on the neuronal hyperexcitability, which may potentially initiate a cascade of stroke-like events. Stroke-like episodes are characterized by neuronal hyperexcitability, neuronal vulnerability, increased capillary permeability, and focal hyperaemia. It is recognized that stroke-like lesions not only evolve in the area incongruent to a vascular territory, but also potentially spread into the surrounding cortex with concomitant vasogenic edema presumably provoked by prolonged epileptic activities. Based on the clinical observations, we speculate that stroke-like episodes appear to be non-ischemic neurovascular events; once neuronal hyperexcitability developed in a localized brain region as a result from either mitochondrial dysfunction in the capillary endothelial cells, or in neurons or astrocytes, epileptic activities may depolarize the adjacent neurons leading to propagation of epileptic activities in the surrounding cortex. Increased capillary permeability provoked by epileptic activities in the presence of mitochondrial capillary angiopathy may cause unique edematous brain lesions predominantly involving the cortex. As a consequence, susceptible neuronal population in the cortex may result in neuronal loss with a laminar or pseudo-laminar distribution.

Keywords: melas, stroke-like episodes, neuronal hyperexcitability, pathogenesis

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