Publications (2)10.01 Total impact
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Article: Interactive effects of excitotoxic injury and dietary restriction on microgliosis and neurogenesis in the hippocampus of adult mice.
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ABSTRACT: Responses to neuronal degeneration are complex, involving activation of microglia, astrocytes, and synaptic remodeling. It has also been suggested that neuronal injury stimulates neurogenesis, the production of new neurons from neural stem cells. Because dietary restriction (DR) can increase hippocampal neurogenesis and promotes the survival of neurons following injury, we determined the effects of DR on the responses of neural stem cells, microglia, and astrocytes in the hippocampus to seizure-induced hippocampal damage. Mice on ad libitum or DR diets were given an intrahippocampal injection of kainate, administered the DNA precursor bromodeoxyuridine (BrdU) during a 5-d period, and euthanized 1 d or 3 wk later. Although kainate greatly increased the numbers of BrdU-labeled cells, it did not enhance neurogenesis and damaged neurons were not replaced. Instead, most BrdU-labeled cells were either proliferating microglia or neural progenitor cells that subsequently died. Microgliosis was transient and was strongly correlated with the amount of damage to CA3 neurons, whereas astrocytosis was delayed and not correlated with neuronal loss. Surprisingly, neurogenesis was not increased in response to seizure-induced damage, and although DR increased basal neurogenesis, it did not promote neurogenesis following brain injury. DR significantly decreased seizure-induced microgliosis, but did not affect astrocytosis. Our findings show that DR suppresses injuryinduced microgliosis suggesting a contribution of a reduced microglial response to the neuroprotective effects of DR.NeuroMolecular Medicine 02/2003; 4(3):179-96. · 5.00 Impact Factor -
Article: Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome c release.
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ABSTRACT: Neurons express a variety of plasma-membrane potassium channels that play important roles in regulating neuronal excitability and synaptic transmission, but also contain mitochondrial ATP-sensitive potassium channels, the functions of which are unknown. Studies of cardiac cells suggest that similar mitochondrial ATP-sensitive potassium channels are involved in the process of ischemic preconditioning, suggesting a role in regulating cell survival. The authors report that mice given diazoxide, an activator of mitochondrial ATP-sensitive potassium channels, exhibited a large (60% to 70%) decrease in cortical infarct size after permanent occlusion of the middle cerebral artery. Diazoxide decreases neuronal apoptosis and increases astrocyte survival and activation in the penumbral region of the ischemic cortex. The neuroprotective effect of diazoxide is abolished by 5-hydroxydecanoate, a selective antagonist of mitochondrial ATP-sensitive potassium channels. Studies of cultured hippocampal neurons reveal that diazoxide depolarizes mitochondria, prevents cytochrome c release, and protects cells against death induced by staurosporine and chemical hypoxia. Diazoxide increased the levels of Bcl2 and inhibited the association of Bax with mitochondria in neurons exposed to an apoptotic insult, suggesting that activation of mitochondrial ATP-sensitive potassium channels may stabilize mitochondrial function by differentially modulating proapoptotic and antiapoptotic proteins. Collectively, the data suggest that mitochondrial ATP-sensitive potassium channels play a key role in modulating neuronal survival under ischemic conditions, and identify agents that activate mitochondrial ATP-sensitive potassium channels as potential therapeutics for stroke and related neurodegenerative conditions.Journal of Cerebral Blood Flow & Metabolism 05/2002; 22(4):431-43. · 5.01 Impact Factor
