Neurodegeneration associated with oxidative stress limits recovery from stroke and other pathophysiological challenges. There are many physiological factors that play a role in recovery from oxidative stress and survival such as those related to stabilization of energy metabolism and vascular integrity. For example, prolonged mild hypoxia initiates a sequence of vascular and metabolic adaptations in brain. Angiogenesis and the resultant increased capillary density is a fundamental aspect of the hypoxic adaptation process. In the aged brain, however, there is an apparent deficiency in glucose metabolism and lack of hypoxic response. Cerebral blood flow (CBF) and metabolic rate for glucose (CMRglu) as well as the coupling between CBF and CMRglu are known to decline as a function of age, suggesting dysfunction of the neurovascular unit. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates adaptive responses to the lack of oxygen in mammalian cells and has multiple functions related to cellular homeostasis and survival, such as the upregulation of VEGF and EPO, known neuroprotective molecules. In the aged brain, the HIF-1 response to hypoxia is severely attenuated. The inability to stabilize HIF-1 is consistent with the deleterious outcomes with even mild hypoxia suffered by the aged brain that the young adult brain can overcome. We have recently shown accumulation of HIF-1a (without hypoxic stimulation) and increased vascular density in young mature rat brain in rats made ketotic through a ketogenic diet. The increased blood ketones were accompanied by up-regulation of the primary substrate transporters for glucose (GLUT1) and ketones (monocarboxylates;MCT1) at the blood-brain barrier. We intend to determine if similar responses can be elicited in the ketotic, aged rat brain. Ketone bodies are alternate energy substrates to glucose and are signaling molecules that stabilize glucose metabolism by relieving metabolic blocks. We will investigate if ketosis (via a ketogenic diet) in the aged rat results in a similar angiogenic response as the younger adult brain and test if there is improved adaptation response to hypoxia. The common mechanism by which ketones act is most likely related through the stabilization of glucose metabolism and citric acid cycle intermediates resulting in increased brain succinate levels. Increased succinate levels result in inhibition of prolyl-hydroxylase (PHD), a key enzyme of the HIF-1a degradation pathway. Inhibition of PHD will result in greater accumulation of HIF-1a and should result in better tolerance to hypoxia as measured by molecular, structural and behavioral responses.
Neurodegeneration as a result of stroke and other pathophysiological challenges related to aging remains to be explored. We propose to investigate if ketosis, induced by ketogenic diet (low carbohydrate, high fat) results in improved adaptation response to hypoxia in aged rat brain. The ability to alter brain metabolism and produce neuroprotection by dietary adjustments would be a significant new strategy for stroke prevention and recovery.
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