SCAN:Carbon monoxide and cerebral ischemia: challenging cell signaling

ITQB Scan Seminar

Title: Carbon monoxide and cerebral ischemia: challenging cell signaling

Speaker: Helena L. A. Vieira

Affiliation: CEDOC-Biology of Cytoprotection Lab

 Abstract:

For more than one decade it has been known that low doses of the endogenously produced carbon monoxide (CO) has beneficial effects on several tissues, acting, as an anti-inflammatory, anti-proliferative or anti-apoptotic.Furthermore, reactive oxygen species (ROS) are important signalling molecules for the cytoprotective role of CO. Cerebral hypoxia-ischemia and reperfusion (HIR) is the main cause of brain damage leading to mortality and morbility. In adults HIR is mainly due to ischemic stroke whether, in newborns is caused by perinatal complications. Recently, we have demonstrated in an in vivo model of perinatal ischemia that CO is neuroprotective in the hippocampus. Still, low doses of exogenous CO present anti-apoptotic functions using in vitro approaches: primary cultures of neurons and astrocytes.  In astrocytes, CO anti-apoptotic role is clearly attributed to inhibition of mitochondrial membrane permeabilisation and the release of pro-apoptotic factors. In isolated non-synaptic mitochondria, CO inhibits loss of potential, inner membrane permeabilisation, swelling and cytochrome c release. Yet, CO increases mitochondrial ROS generation, which are essential signalling molecules. Moreover, CO also modulates astrocytic metabolism and reinforces oxidative phosphorylation. This gaseoustransmitter enhances ATP production, cytochrome c oxidase (COX) activity and mitochondrial biosynthesis. Furthermore, the anti-apoptotic protein Bcl-2 appears to modulate COX activity since CO-induced physical interaction between COX and Bcl-2 improves oxidative metabolism. Therefore, CO targets and controls mitochondrial function at two distinct levels: (i) modulation of oxidative metabolism and (ii) prevention of the mitochondrial pathways involved in intrinsic apoptosis.
Although many different beneficial effects of CO has been described in several tissues/organs and pathological models, the actual intracellular target is still a matter of discussion and a great challenge for research.