MITOCHONDRIAL DYSFUNCTION AFTER EXPERIMENTAL AND HUMAN BRAIN INJURY AND ITS POSSIBLE REVERSAL WITH A SELECTIVE N-TYPE CALCIUM-CHANNEL ANTAGONIST (SNX-111)

have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload oi cytosolic calcium and excessive calcium adsorbed on the mitochondri al membrane, consequently the mitochondrial respiratory chain-linked o xidative phosphorylation was impaired. We report the effect of a selec tive N-type calcium channel blocker, SNX-111 on mitochondrial dysfunct ion induced by a controlled cortical impact. Intravenous administratio n of SNX-111 al varying times post injury was made. The concentration titration profile revealed SNX-111 at 4 mg kg(-1) to be optimal, and t he time window to De administration at 4 h post-injury, in line with t hat reported on the effect of SNX-111 in experimental stroke. Under op timal conditions, SNX-111 significantly improved the mitochondrial res piratory chain-linked functions, such as the electron transfer activit ies with both succinate and NAD-linked substrates, and the accompanied energy coupling capacities measured as respiratory control indices (R CI) and ATP synthesis (P/O ratio), and the energy linked Ca2+ transpor t in order to assess the applicability of these data to the clinical s etting, we have initiated studies with brain tissue which has to be re sected during surgical treatment. Five patients suffered from brain tr auma, one from intracranial hypertension due to stroke (noninfarcted t issue was taken), and one from epilepsy. Our data revealed that brain mitochondria derived from the patient with intracranial hypertension a nd the patient with epilepsy were tightly coupled with good respirator y rates with glutamate and malate as substrates, and high P/O ratios. The rates of respiration and A TP synthesis were severely impaired in the brain mitochondria isolated from traumatized patients. These resul ts indicate that investigation of brain mitochondrial functions can be used as a measure for trauma-induced impairment of brain energy metab olism. The rime window for the effect of SNX-111 in mitochondrial func tion and the (preliminary) similarity between mitochondrial dysfunctio n in experimental animals and humans make the drug appear to be well s uited for clinical trials in severe head injury.