Hyperbaric Oxygen Reduces Infarction Volume and Hemorrhagic Transformation Through ATP/NAD ⁺ /Sirt1 Pathway in Hyperglycemic Middle Cerebral Artery Occlusion Rats

Abstract

Background and purpose Energy depletion is a critical factor leading to cell death and brain dysfunction after ischemic stroke. In this study we investigated whether energy depletion is involved in hyperglycemia-induced hemorrhagic transformation (HT) after ischemic stroke and determined the pathway underlying the beneficial effects of hyperbaric oxygen (HBO). Methods After 2 hours MCAO, hyperglycemia was induced by injecting of 50% dextrose (6 ml/kg) intraperitoneally at the onset of reperfusion. Immediately after it rats were exposed to HBO at 2 atmospheres absolutes (ATA) for 1 hour. ATP synthase inhibitor Oligomycin A (Olig A), NAMPT inhibitor FK866 or Sirt1 siRNA was administrated for interventions. Infarct volume, hemorrhagic volume, neurobehavioral deficits were recorded; the level of blood glucose, ATP and NAD+ and the activity of NAMPT were monitored; the expression of Sirt1, acetylated P53, acetylated NF-κB and cleaved caspase 3 were detected by western blots; the activity of MMP-9 was assayed by zymography. Results Hyperglycemia deteriorated energy metabolism and reduced the level of ATP and NAD+, exaggerated hemorrhagic transformation, blood-brain barrier disruption and neurological deficits after MCAO. HBO treatment increased the levels of the ATP and NAD+ and consequently increased Sirt1, resulting in attenuation of hemorrhagic transformation, brain infarction as well as improvement of neurological function in hyperglycemic MCAO rats. Conclusion HBO induced activation of ATP/NAD+/Sirt1 pathway and protected blood-brain barrier in hyperglycemic MCAO rats. HBO might be promising approach for treatment of acute ischemic stroke patients, especially patients with diabetes or treated with rtPA.

Ginsenoside-Rb1 for Ischemic Stroke: A Systematic Review and Meta-analysis of Preclinical Evidence and Possible Mechanisms

“…Improvement of energy metabolism Neurons have higher energy expenditure and lower reserves compared to other cell types (Belanger et al, 2011). After cerebral ischemia a lack of glucose and oxygen, and consequently adenosine triphosphate, is one of the major events that results in energy failure (Hu et al, 2017). Numerous interactions of transporters, enzymes, and intracellular signaling processes within the neurovascular unit at the BBB participate in glucose transport, where GLUT1 and GLUT3 are regarded as the major glucose transporters (Patching, 2017).…”

Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5' adenosine monophosphate-activated protein kinase and sirtuins

“…SIRT1 knockdown decreases Nrf2 expression while Nrf2 knockdown does not affect the expression of SIRT1. [ 45 ] This directly supports Nrf2 as a downstream effector in the SIRT1 signaling pathway. In addition, SIRT1 has been shown to protect against ischemic injury through its deacetylase activity.…”

“…[ 44 ] Similarly, HBO-induced neuroprotection against MCAO is lost after SIRT1 knockdown by shRNA in the rat brain. [ 45 ] It is evident that SIRT1 and its activity is required for numerous IPC and RPC models, suggesting that SIRT1 is an essential regulator of ischemic neuroprotection.…”

“…This suggests HBO-induced neuroprotection is dependent on SIRT1 deacetylase activity. [ 45 ] In addition, resveratrol-induced SIRT1 activity has been shown to decrease the expression of mitochondrial uncoupling protein two (UCP2). In rat hippocampus mitochondria, UCP2 protein levels were downregulated 48 h after resveratrol treatment.…”

Combination therapy for ischemic stroke: Novel approaches to lengthen therapeutic window of tissue plasminogen activator

“…Additional well-designed clinical studies are necessary to further assess the safety and efficacy of NBO and HBO as treatments to be used to mitigate adverse complication associated with tPA. [ 29 49 59 60 61 ]…”