Metabolic Reprogramming: Strategy for Ischemic Stroke Treatment by Ischemic Preconditioning

Abstract

Stroke is one of the leading causes of death and permanent disability worldwide. Ischemic preconditioning (IPC) is an endogenous protective strategy, which has been reported to exhibit a significant neuroprotective effect in reducing the incidence of ischemic stroke. However, the underlying neuroprotective mechanisms of IPC remain elusive. An increased understanding of the pathogenic mechanisms of stroke and IPC serves to highlight the importance of metabolic reprogramming. In this review, we summarize the metabolic disorder and metabolic plasticity in the incidence and progression of ischemic stroke. We also elaborate how IPC fully mobilizes the metabolic reprogramming to maintain brain metabolic homeostasis, especially for energy and redox homeostasis, and finally protects brain function in the event of an ischemic stroke.

Keywords: ischemic preconditioning (IPC); ischemic stroke; metabolic reprogramming.

Figure 1

General description of ischemic preconditioning (IPC), in which several cycles of brief non-lethal ischemia and reperfusion are applied either directly, regionally, or remotely. Through neuronal, humoral, and immunological pathways, IPC confers protection against subsequent, more severe, and lethal ischemia. The ischemic protection of IPC has been applied in various organs, such as the heart, brain, kidney, liver, lungs, and intestine. For ischemic stroke, IPC can reduce the infarct size and improve prognosis, which is supported by increasing the cerebral blood flow (CBF), protecting mitochondrial function, and maintaining neuronal activity.

Figure 2

Metabolic disorder and metabolic plasticity in ischemic stroke: Upon ischemia onset, a sharp reduction of regional CBF results in oxygen and glucose deprivation, followed by excess excitatory and blood–brain barrier dysfunction. Neurons experience mitochondrial dysfunction, shifting the cellular machinery from aerobic to anaerobic metabolism, and a decrease of ATP production, directly resulting in energy failure. In the meantime, free radicals trigger oxidative stress, which further induce damage to nucleic acid bases, lipids, and proteins, ultimately leading to cell death by necrosis or apoptosis. To defend against this ischemic cascade, upon ischemia onset, brain tissues enhance their metabolic plasticity, in order to maintain the cerebral activity transiently, mainly through the regulation of CBF, extraction of oxygen and glucose, energy metabolic reprogramming, antioxidant defense, and mitophagy. However, with persistent ischemia, irreversible damage may occur in the affected brain areas.

Figure 3

Metabolic reprogramming for metabolic homeostasis maintenance. Brain, tumor, and proliferative tissues have high metabolic activity and energy requirements, necessitating that they have reliable mechanisms to adequately protect their metabolic homeostasis. Metabolic reprogramming is notably crucial in this regard, especially for energy and redox homeostasis maintenance.

Figure 4

Metabolic reprogramming by ischemic preconditioning (IPC). For blood glucose and oxygen supply, IPC increases regional CBF and regulates the oxygen-delivery ability of erythrocytes through sphingosine 1-phosphate (S1P), in order to maintain glucose and oxygen metabolic consumption. To enhance energy reserves, IPC improves mitochondrial efficiency for cellular energy metabolism, boosts glycolysis, and stockpiles and utilizes alternative energy substrates. Meanwhile, IPC also boosts the PPP, providing an essential redox equivalent for GSH regeneration and enhancing the capacity of antioxidant defense.