α-lipoic acid protects against cerebral ischemia/reperfusion-induced injury in rats

Abstract

Abstract. It is well established that the brain is sensitive to ischemia/reperfusion (I/R)-induced injury. α-lipoic acid (LA), a free radical scavenger and antioxidant, has a neuroprotective effect against cerebral I/R-induced injury, however, the underlying mechanisms remain to be elucidated. Therefore, the present study was undertaken to evaluate whether LA was able to protect against cerebral I/R-induced injury and to examine the potential mechanisms. The neuroprotective effects of LA were investigated in a rat model of transient focal ischemia induced by middle cerebral artery occlusion (MCAO) followed by reperfusion. Adult male Sprague-Dawley rats were randomly assigned into the sham, cerebral I/R injury model and model plus LA groups. Cerebral I/R injury was induced by 90 min MCAO followed by reperfusion for 24 h. Cerebral infarct size was detected by 2,3,5-triphenyltetrazolium chloride staining. Neurological deficit score (NDS), brain water content and oxidative parameters, including malondialdehyde (MDA), nitric oxide (NO), total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) were measured. The expression of cleaved caspase-3, brain-derived neurotrophic factor (BDNF), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), p-Akt and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) were also analyzed using western blotting. The present study demonstrated that pretreatment with LA significantly decreased the infarction size, brain water content and improved NDS. LA reversed the levels of oxidative parameters, including MDA, NO, T-AOC and SOD to their normal state in rat brains following cerebral I/R. Furthermore, the expression of cleaved caspase-3 markedly decreased and the expression of BDNF, PI3K, p-Akt and p-ERK1/2 significantly increased following administration of LA. On the basis of these findings, it was concluded that LA protected the brain from cerebral I/R damage by attenuation of oxidative stress and caspase-dependent apoptosis. Furthermore, LA exerts its neuroprotective effects potentially through activation of the BDNF-PI3K/Akt-ERK1/2 pathway. IntroductionCerebral ischemic injury is one of the leading causes of human mortality and disability worldwide (1). Restoration of blood flow to the ischemic brain is often used to treat patients in clinical experiments. However, reperfusion itself also has the potential to produce additional injuries in the ischemic brain due to overproduction of reactive oxygen species (ROS). The potential pathological mechanisms of ischemia/reperfusion (I/R) injury include glutamate excitotoxicity, calcium overload, nitric oxide (NO) production, oxidative stress, inflammation and apoptosis, which eventually lead to cell death (2). Oxidative stress and apoptosis following cerebral I/R are the two major processes that induce neuronal injury (3,4). For this reason, multifunctional molecules with anti-oxidative and anti-apoptotic properties are ideal neuroprotective agents.α-lipoic acid (LA), an endogenous short-chain fatty acid, is a cofact...

Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury

“…Studies have confirmed that T-AOC regulation can protect neuronal damage in CIRI (Deng et al, 2015;Lin et al, 2015;Kryl'skii et al, 2019). α-lipoic acid exerted its neuroprotective effects through reversing the levels of oxidative parameters, including malondialdehyde (MDA), nitric oxide (NO), T-AOC, and SOD to their normal state in rat brains following CIRI (Deng et al, 2015). Lin et al found that neuronal damage in the hippocampal CA1 area was significantly reduced after cerebral ischemia/reperfusion in SOD transgenic mice (Lin et al, 2015;.…”

“…Non-enzymatic systems include glutathione (GSH), vitamin A, vitamin C, Vitamin E, and carotenoids (Kryl'skii et al, 2019). Studies have confirmed that T-AOC regulation can protect neuronal damage in CIRI (Deng et al, 2015;Lin et al, 2015;Kryl'skii et al, 2019). α-lipoic acid exerted its neuroprotective effects through reversing the levels of oxidative parameters, including malondialdehyde (MDA), nitric oxide (NO), T-AOC, and SOD to their normal state in rat brains following CIRI (Deng et al, 2015).…”

Rapamycin treatment increases hippocampal cell viability in an mTOR-independent manner during exposure to hypoxia mimetic, cobalt chloride

“…MAPK signaling is certainly diverse, and its functions can differ depending on the cell type and context [61], however, this pro-survival function is in line with the vast majority of studies describing pMAPK signaling in neurons [44]. It is also in line with increased MAPK signaling acting as a protective mechanism against hypoxic insults [57,62,63].…”

Pentoxifylline exerts anti-inflammatory effects on cerebral ischemia reperfusion‑induced injury in a rat model via the p38 mitogen-activated protein kinase signaling pathway

“…Male Sprague-Dawley rats weighing 260-300 g (n=36; 1.5 years old) were obtained from the Experimental Animal Centre of Zhangqiu People's Hospital (Jinan, China) and were allowed free access to laboratory chow and tap water in day-night quarters at 25˚C with 50-60% humidity and a 12-h light/dark cycle. The experiment was approved by the Committee on Animal Experiments of Zhangqiu People's Hospital (14). All rats were randomly divided into the following three experimental groups (n=12 per group): Sham, sham-operated rats pretreated intraperitoneally with normal saline for 3 days; cerebral IRI model, cerebral IRI model rats pretreated intraperitoneally with normal saline for 3 days; and pentoxifylline treatment group, cerebral IRI model rats pretreated daily with 46.7 mg/kg pentoxifylline (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) intraperitoneally for 3 days.…”