Mitochondrial Targeting for Development of Novel Drug Strategies in Brain Injury

Jean      F. Soustiel; Menashe      Zaaroor

Abstract

For years, therapeutic approach to brain injury has been mostly physiological in essence, either based on revascularization of ischemic tissue in stroke or decompression of the swollen brain in neurotrauma. Despite tremendous efforts for the development of new strategies, translational research targeting specific cellular pathophysiological processes triggered by the injury has provided deceiving results. During the past decade, disruption of mitochondrial function and structural integrity has emerged as a pivotal event in the generation of cell damage. Following the injury, a vast array of deleterious signals are generated and integrated at the mitochondrial level resulting in impairment of three major mitochondrial functions: calcium homeostasis, free radicals generation and detoxification and energy production. Increasing understanding of the biochemical complexity of these events has led to the development of new therapeutic strategies targeting mitochondrial damage that has shown encouraging data in various models of injury. Importantly, translational efforts have been already initiated with promising preliminary data in several phase II clinical studies. In this review, we will briefly describe the process of mitochondrial damage and dysfunction following brain injury and discuss the various therapeutic strategies aiming at mitochondrial protection.

Keywords: Traumatic brain injury, stroke, mitochondria, mitochondrial permeability transition pore, neuroprotection, therapeutic strategies, calcium homeostasis, neurons and glial cells