l-3-n-Butylphthalide Activates Akt/mTOR Signaling, Inhibits Neuronal Apoptosis and Autophagy and Improves Cognitive Impairment in Mice with Repeated Cerebral Ischemia–Reperfusion Injury

Abstract

L-3-n-Butylphthalide (L-NBP) exerts neuroprotective effects in animal models of cerebral ischemia, but its potential benefits in repeated cerebral ischemia-reperfusion (RCIR) injury remain unknown. We investigated the effect of L-NBP on cognitive impairment induced by RCIR in mice. Male C57Bl/6 mice received sham surgery or bilateral common carotid artery occlusion (3 times, 20 min each) and were orally administered preoperative L-NBP (30 mg/kg/day, 7 days), postoperative L-NBP (30 or 60 mg/kg/day, 28 days) or postoperative vehicle (28 days). Learning and memory were assessed by the Morris water maze task and step-down passive avoidance test. Nissl staining was used to identify pathologic changes in the hippocampal CA1 region. The expressions of proteins associated with signaling, apoptosis and autophagy were assessed by quantitative PCR and western blot. RCIR induced deficits in learning and memory that were alleviated by preoperative or postoperative L-NBP administration. Pathologic lesions in the hippocampal CA1 region induced by RCIR were less severe in mice treated with L-NBP. Preoperative or postoperative L-NBP administration in mice receiving RCIR promoted hippocampal expression of phospho-Akt and phospho-mTOR (suggesting activation of Akt/mTOR signaling), increased the Bcl-2/Bax ratio (indicating suppression of apoptosis) and reduced the LC3-II/LC3-I ratio (implying inhibition of autophagy). Preoperative or postoperative L-NBP administration also depressed hippocampal levels of beclin-1 mRNA (indicating suppression of autophagy). These findings suggest that the effect of L-NBP to alleviate learning and memory deficits in mice following RCIR may involve activation of Akt/mTOR signaling and regulation of the expressions of proteins related to apoptosis and autophagy.

Effects of dl‐3‐n‐butylphthalide on serum lipoprotein‐associated phospholipase A2 and hypersensitive C‐reactive protein levels in acute cerebral infarction

“…Some Chinese scholars (Wang, Ma, et al, ) have summarized the research progress of NBP in the treatment of ischemic stroke in the past 20 years, and it was considered as a promising drug for ischemic stroke. A large number of experiments at home and abroad have revealed that NBP can regulate brain energy metabolism (Yan, Wang, Yao, Liu, & Xiao, ), protect the mitochondria (Min et al, ), promote normal blood flow in the ischemic area (Xu et al, ), inhibit oxidative stress and platelet aggregation (Li et al, ; Zhao, Li, Zhang, Chen, & Li, ), and prevent the vigorous apoptosis of cells (Min et al, ). In addition, Chinese scholars found that NBP plays a neuroprotective role by acting on multiple active targets (Wang et al, ; Zhao et al, ).…”

Pharmacological Modulation of Autophagy for Neuroprotection in Ischaemic Stroke

“…L-NBP is a clinically approved drug for treating ischaemic stroke in China (Abdoulaye and Guo, 2016). In cerebral ischemia, L-NBP improved neurological functions and reduced brain injuries in mice with repeated cerebral ischaemia/reperfusion by activating Akt/mTOR signalling resulting in inhibition of neuronal apoptosis and autophagy (Xu et al, 2017).…”

Efficacy of aspirin and clopidogrel combined with Butylphthalide on frequent transient ischemic attack of middle-aged and elderly patients with ABCD2

“…NBP,as an emerging anti-ischemic drug,inhibits platelet aggregation,reduces thrombosis,improves microcirculation,reduces cerebral infarction volume,resists oxidative stress,protects mitochondrial function,reduces neuronal apoptosis,and reduces in ammation,response and mediate autophagy of neurons,promote neurogenesis,etc in stroke animal models.It exerts multitargeting effects on a variety of pathophysiological mechanisms and shows obvious neuroprotective effects [7][8][9][10][11][12][13][14][15][16][17][18][19][20] .It has been found that its bene cial effect is far beyond the therapeutic scope of stroke [21,22] after further research and application of its application.Especially in the eld of neurodegenerative diseases,people have found that NBP and its derivatives are used in AD,VD,Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) all have unique effects and e cacy [7,[23][24][25] .…”