Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury

Abstract

The cerebral ischemia injury can result in neuronal death and/or functional impairment, which leads to further damage and dysfunction after recovery of blood supply. Cerebral ischemia/reperfusion injury (CIRI) often causes irreversible brain damage and neuronal injury and death, which involves many complex pathological processes including oxidative stress, amino acid toxicity, the release of endogenous substances, inflammation and apoptosis. Oxidative stress and inflammation are interactive and play critical roles in ischemia/reperfusion injury in the brain. Oxidative stress is important in the pathological process of ischemic stroke and is critical for the cascade development of ischemic injury. Oxidative stress is caused by reactive oxygen species (ROS) during cerebral ischemia and is more likely to lead to cell death and ultimately brain death after reperfusion. During reperfusion especially, superoxide anion free radicals, hydroxyl free radicals, and nitric oxide (NO) are produced, which can cause lipid peroxidation, inflammation and cell apoptosis. Inflammation alters the balance between pro-inflammatory and anti-inflammatory factors in cerebral ischemic injury. Inflammatory factors can therefore stimulate or exacerbate inflammation and aggravate ischemic injury. Neuroprotective therapies for various stages of the cerebral ischemia cascade response have received widespread attention. At present, neuroprotective drugs mainly include free radical scavengers, anti-inflammatory agents, and anti-apoptotic agents. However, the molecular mechanisms of the interaction between oxidative stress and inflammation, and their interplay with different types of programmed cell death in ischemia/reperfusion injury are unclear. The development of a suitable method for combination therapy has become a hot topic.

Keywords: cerebral ischemia/reperfusion injury; inflammation; neuroprotective; oxidative stress; signaling pathways.

Figure 1

The pathophysiological mechanisms of cerebral ischemia/reperfusion injury. The main pathophysiological mechanisms include: energy metabolism disorders, cellular acidosis, synthesis or release of excitotoxic amino acids into doubling, intracellular calcium homeostasis, free radical production, activation of apoptotic genes. These factors interacted and formed a complex regulatory network, and then lead to a series of pathological cascade reactions. It lead directly or indirectly nerve cells apoptosis/death, damage the blood-brain barrier and cause brain edema, and eventually lead to neural dysfunction.

Figure 2

The toxic mechanisms of cerebral ischemia/reperfusion injury. The toxic mechanisms of reactive oxygen species (ROS) in ischemia/reperfusion injury are mainly as follows: (1) nerve cell necrosis: ROS can lead to protein degeneration and enzyme inactivation, which can lead to damage of mitochondrial respiratory chain, energy generation barrier and cell death. ROS reacts with cell membrane lipids to produce lipids peroxide. After lipid peroxide degradation, the toxic products such as 4-hydroxyl can be formed, thus damaging neurons and causing neuronal cell necrosis. (2) neuronal apoptosis: ROS can induce neuronal apoptosis through activation of multiple pathways, such as mitochondrial pathway and endoplasmic reticulum pathway, and involves multiple signaling pathways. ① the mitochondria pathway: ROS attacks mitochondria to cause the cytochrome C oxidase phosphorylation, mitochondrial transmembrane potential rising, MPTP remains open and release. Through activation of apoptotic protease activating factor 1, apoptosis inducing factor, apoptotic protease activating factor, the Bcl-1 family proteins, ROS starts the cascade activation of apoptosis pathway to promote cell apoptosis, ② the endoplasmic reticulum stress (ERS) pathway: the ERS refers to lack of oxygen, glucose, or lack of nutrients or lipids, virus infection, toxin and excessive load drug harmful factors such as steady and smooth endoplasmic reticulum, Ca²⁺ balance disorders and non-folded protein misfolding then gathered in the endoplasmic reticulum. ERS can activate the apoptotic signaling pathway, and eventually induce apoptosis, thereby aggravating cerebral ischemia/reperfusion injury (CIRI).