Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism

Abstract

Summary The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown. Here we report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia. This was not due to an increased collateral vessel network, nor to enhanced neurotrophin expression. Instead, PHD1−/− neurons were protected against oxygen-nutrient deprivation by reprogramming glucose metabolism. Indeed, PHD1−/− neurons enhanced glucose flux through the oxidative pentose phosphate pathway by diverting glucose from glycolysis. As a result, PHD1−/− neurons increased their redox buffering capacity to scavenge oxygen radicals in ischemia. Intracerebroventricular injection of PHD1-antisense oligonucleotides reduced the cerebral infarct size and neurological deficits following stroke. These data identify PHD1 as a novel regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke.

Spreading depolarization and repolarization during cardiac arrest as an ultra-early marker of neurological recovery in a preclinical model

“…CA), reduced oxygen metabolism and gas exchange in the brain during periods of low flow CBF may be related to the formation of harmful reactive oxygen species. [87][88][89] Evidence for this hypothesis can be found in several different measurement parameters from our data. First, metrics related to total perfusion from start of ischemia/anoxia to onset of SD (AUC of MAP and CBF) are lower in animals that recovered better post-CPR.…”

“…Recently, it has been shown that formation of these reactive oxygen species during cerebral ischemia may be mitigated through manipulation of glucose metabolism. 87 Future experiments utilizing our multimodal platform to test these concepts and maneuvers on cerebral perfusion and metabolism throughout the dynamic periods of ischemia and reperfusion can help to uncover the underlying mechanisms of how flow-metabolism dynamics during CAinduced SD affect outcome.…”

NADPH: new oxygen for the ROS theory of aging

“…Conceivably, this could be achieved by overactivation of NADPH-producing pathways, such as the PPP (as we have reported), the folate pathway or others. In agreement, prior reports in mice have observed beneficial cardiovascular effects by genetically increasing the PPP flux [6]. Interestingly, NADPH can also be interconverted to nicotinamide-adenine dinucleotide (NADH), and this could partially account for the increased lifespan observed in mice supplemented with nicotinamide riboside, an NADH precursor [7].…”

Cisplatin Toxicity in Dorsal Root Ganglion Neurons Is Relieved by Meclizine via Diminution of Mitochondrial Compromise and Improved Clearance of DNA Damage

“…Notwithstanding, recent reports revealed that sensory neurons have inherent capacity to utilize glycolytic energy for axonal transport [15] raising the question of whether metabolic reprogramming to augment glycolytic metabolism and improve redox balance might be viable strategy for protection against mitochondrial compromise-associated peripheral neurotoxicity. Specifically, whether reprogramming of energy metabolism to enhance the oxidative phase of pentose phosphate pathway to maintain favorable NADP + /NADPH ratios and preserve antioxidant defenses and thereby mitochondrial status [16,17], might serve as strategy for protection of DRG neurons from injury incidental to mitochondria-disrupting effects of chemotherapeutic drugs [1,18–20]. To examine this premise we adapted an in vitro system of cultured DRG neurons [21] to study the effects of sub lethal doses of cisplatin that support investigation of cisplatin-induced molecular, metabolic and morphologic changes without triggering significant death and loss of neurons.…”