Mitochondria: A Target for Neuroprotective Interventions in Cerebral Ischemia-Reperfusion

Abstract

Evidence obtained over the past two decades shows that reactive oxygen species (ROS) are involved in brain lesions, including those due to cerebral ischemia-reperfusion. The mitochondria are the primary intracellular source of ROS, as they generate huge numbers of oxidative-reduction reactions and use massive amounts of oxygen. When anoxia is followed promptly by reperfusion, the resulting increase in oxygen supply leads to overproduction of ROS. In ischemic tissues, numerous studies have established a direct role for ROS in oxidative damage to lipids, proteins, and nucleic acids. Thus, mitochondria are both the initiator and the first target of oxidative stress. Mitochondrial damage can lead to cell death, given the role for mitochondria in energy metabolism and calcium homeostasis, as well as the ability of mitochondria to release pro-apoptotic factors such as cytochrome C and apoptosis-inducing factor (AIF). This review discusses possible mitochondrion-targeted strategies for preventing ROS-induced injury during reperfusion. The sequence of events that follow oxidative damage provides the outline for the review: thus, we will discuss protection of oxidative phosphorylation, mitochondrial membrane integrity and fluidity, and antioxidant or mild-uncoupling strategies for diminishing ROS production. Among mechanisms of action, we will describe the modulation of mitochondrial permeability transition pore (MPTP) opening, which may not only operate as a physiological Ca(2+) release mechanism, but also contribute to mitochondrial deenergization, release of pro-apoptotic proteins, and protection by ischemic preconditioning (IPC). Finally, we will review genetic strategies for controlling apoptotic protein expression, stimulating mitochondrial oxidative defences, and increasing mitochondrial proliferation.

Ischemic Postconditioning Protects Against Global Cerebral Ischemia/Reperfusion-Induced Injury in Rats

“…Previous studies have demonstrated that ischemic postconditioning reduces the overproduction of reactive oxygen species and calcium overload, both of which contribute to mitochondrial dysfunction and cytochrome c release. 7,[32][33][34][35] It has been reported that neuron death in the penumbra after focal ischemia is mainly induced via apoptosis, and ischemic postconditioning decreases terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive neurons in the penumbra. 7 Therefore, we speculate that ischemic postconditioning inhibits the release of cytochrome c and the activation of caspases and then blocks I/R-induced neuronal apoptosis.…”

Edaravone protects PC12 cells from ischemic-like injury via attenuating the damage to mitochondria

“…Although more and more studies demonstrate the ischemia mechanism, such as excessive production of free radicals (Chung et al, 2006;Margaill et al, 2005), altered calcium homeostasis (Montell, 2005) and N-methyl-D-aspartate excitotoxicity (Christophe and Nicolas, 2006), few effective therapeutic drugs have been used in clinic.…”

Leonurine Protects Middle Cerebral Artery Occluded Rats Through Antioxidant Effect and Regulation of Mitochondrial Function

“…3 Damage of mitochondria leads to cell death, because mitochondria are involved in energy metabolism and calcium homeostasis as well as the ability of mitochondria to release apoptotic-promoting proteins such as cytochrome C and apoptosis-inducing factor to initiate the intrinsic pathway of apoptosis. 5 Ample evidences have suggested that mitochondria have a central role in neurodegenerative disease.…”