Dexmedetomidine Protects Against Neurological Dysfunction in a Mouse Intracerebral Hemorrhage Model by Inhibiting Mitochondrial Dysfunction-Derived Oxidative Stress.

BACKGROUND

Intracerebral hemorrhage (ICH) is a subtype of stroke with high disability and mortality. Dexmedetomidine (Dex) has been shown to provide neuroprotection in several neurological diseases. The aim of present study was to investigate the effects of Dex on ICH-induced neurological deficits and brain injury and the underlying mechanisms.

METHODS

ICH mouse model was established by intracerebral injection of autologous blood, followed by Dex or vehicle treatment. Neurological function, brain water content, neuronal activity, and oxidative parameters were determined. The protein expressions of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), uncoupling protein 2, and manganese-dependent superoxide dismutase were examined by western blotting.

RESULTS

Dex administration significantly inhibited ICH-induced the memory impairment, dyskinesia, brain edema, and neuron loss. In addition, ICH-induced the increase in brain oxidative stress level was markedly attenuated after Dex treatment, as evidenced by increased glutathione peroxidase and superoxide dismutase levels and reduced malondialdehyde and nitric oxide levels. Compared with vehicle-treated ICH mice, Dex-treated ICH mice showed significantly decreased intracellular reactive oxygen species (ROS) and mitochondrial ROS (mROS) production in brain, but had no effects on the increased nicotinamide-adenine dinucleotide phosphate oxidase activity. However, stimulation of mROS abrogated the inhibitory effects of Dex on neurological deficits and oxidative stress. The decrease in production of adenosine triphosphate and the expressions of PGC-1α, uncoupling protein 2, and manganese-dependent superoxide dismutase induced by ICH was restored by Dex treatment.

CONCLUSIONS

Our results reveal that Dex improves ICH-induced neurological deficits and brain injury by inhibiting PGC-1α pathway inactivation and mitochondrial dysfunction-derived oxidative stress.