Mitochondrial bioenergetic deficits in the hippocampi of rats with chronic ischemia-induced vascular dementia

Vascular dementia (VD), defined as a loss of memory and cognitive function resulting from vascular lesions in the brain, is the second-most-common cause of dementia in the elderly, after Alzheimer's disease. In recent years, research has focused on the pathogenesis of VD, and mitochondrial bioenergetic deficits have been suggested to contribute to VD onset. To further investigate the role of mitochondria in VD, we used a rat model of VD, which involved permanent bilateral occlusion of the common carotid arteries (with a 1-week interval between artery occlusion to avoid an abrupt reduction in cerebral blood flow) leading to chronic cerebral hypoperfusion. Prior to occlusion, male Wistar rats underwent 7 days of Morris water maze training. Only animals that could swim and passed the Morris water maze test were chosen for the study. After 5 days of Morris water maze training, mitochondria from the hippocampi of rats, which were randomly selected from animals that could complete the Morris water maze test, were isolated for functional assessment.Mitochondria isolated from the hippocampi of rats from the ischemia group had decreased pyruvate dehydrogenase protein levels, and increased oxidative stress, as manifested by increased hydrogen peroxide production. The ischemia group mitochondria also exhibited decreased respiration coupled to decreased expression and activity of the electron transport chain complex IV (cytochrome c oxidase). These results indicate that the mitochondrial oxidative metabolism is inhibited in the hippocampi of rats following chronic ischemia-induced VD. As the mitochondrial oxidative metabolism deficits, namely mitochondrial bioenergetic deficits directly affect the functions of neurons, it may contribute to VD onset.

73Highlights► A higher survival rate VD model was established using a modified protocol of 2VO. ► Activity of COX and the expression of COX IV in VD rats decreased. ► Expression of PDH A1 in VD rats decreased. ► The rate of state 4 respiration H2O2 production in VD rats increased. ► Oxygen consumption of state 3 respiration in VD rats decreased.