Clinical treatments for mitochondrial dysfunctions after brain injury.
OBJECTIVE
This review provides a comprehensive look at the evidence supporting the role of mitochondrial dysfunction in promoting neuronal death after acute brain injury, and critically discusses the most recent proposed therapies that could limit the deleterious effects of such a dysfunction on neurological outcome.


RESULTS
Following acute brain injury, disruption of calcium homeostasis, overproduction of reactive oxygen species, and opening of the mitochondrial permeability transition pore, are key factors in promoting mitochondrial dysfunction, with ensuing activation of either necrotic or apoptotic cell death pathways. Growing interest has been focused on developing new therapeutic strategies able to oppose these mechanisms. Several pharmacological agents are currently under investigation, including novel calcium channel blockers and antioxidants, uncoupling proteins and mitochondrial permeability transition pore inhibitors. Although a 'magic bullet' has not yet been identified, the results of both preclinical and clinical studies are encouraging.


CONCLUSIONS
Therapeutic interventions directly targeting processes and mechanisms responsible for mitochondrial dysfunction, may offer neuroprotection in brain-injured patients. The multifactorial cause of mitochondrial dysfunction suggests, however, the need for further studies aimed at clarifying optimal dose and time for drug administration, as well as the logical combination/sequence of those approaches that may ultimately achieve improvement in neurological outcome.
Merenda
Amedeo
A
Department of Neurosurgery, University of Messina, Messina, Italy.
Bullock
Ross
R
D001794:Blood Pressure / Q000187:drug effects*; D001930:Brain Injuries / Q000150:complications*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D003422:Critical Care; D016572:Cyclosporine / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*
D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D016572:Cyclosporine