Abstract
Autophagic/lysosomal dysfunction is a critical pathogenesis of neuronal injury after ischemic stroke. Trehalose has been validated to restore the impaired autophagy flux by boosting transcription factor EB (TFEB) nuclear translocation, but orally administrated trehalose can be greatly digested by intestinal trehalase before entering into brain. Melibiose (MEL), an analogue of trehalose, may thoroughly exert its pharmacological effects through oral administration due to absence of intestinal melibiase. The present study was to investigate whether melibiose could also confer a neuroprotection by the similar pharmacological mechanism as trehalose did after ischemic stroke. The rats were pretreated with melibiose for 7 days before middle cerebral artery occlusion (MCAO) surgery. Twenty-four hours following MCAO/reperfusion, the cytoplasmic and nuclear TFEB, and the proteins in autophagic/lysosomal pathway at the penumbra were detected by western blot and immunofluorescence, respectively. Meanwhile, the neurological deficit, neuron survival, and infarct volume were assessed to evaluate the therapeutic outcomes. The results showed that the neurological injury was significantly mitigated in MCAO+MEL group, compared with that in MCAO group. Meanwhile, nuclear TFEB expression in neurons at the penumbra was significantly promoted by melibiose. Moreover, melibiose treatment markedly enhanced autophagy flux, as reflected by the reinforced lysosomal capacity and reduced autophagic substrates. Furthermore, the melibiose-elicited neuroprotection was prominently counteracted by lysosomal inhibitor Bafilomycin A1 (Baf-A1). Contrarily, reinforcement of lysosomal capacity with EN6 further improved the neurological performance upon melibiose treatment. Our data suggests that melibiose-augmented neuroprotection may be achieved by ameliorating autophagy flux via facilitation of TFEB nuclear translocation in neurons after ischemic stroke.
Highlights
Ischemic stroke caused by cerebrovascular occlusion is a serious disease, resulting in millions of death throughout the world [1]
Autophagic/lysosomal dysfunction has been investigated to be an important cause of neuronal injury after ischemic stroke [30]
Numerous reported investigations determined the roles of autophagy in ischemic stroke only by evaluation of autophagic activity [34,35]
Summary
Ischemic stroke caused by cerebrovascular occlusion is a serious disease, resulting in millions of death throughout the world [1]. Pharmacological administration with the recombinant tissue plasminogen activator (rt-PA) is an effective thrombolysis therapy at the early stage of stroke, within 4.5 h after the insult, but this narrow therapeutic time window greatly limits its application, leading to only about 5% of the patients can benefit from this treatment [3]. Mechanical thrombectomy is another efficacious approach for cerebrovascular complete recanalization, but the sudden blood resupply may lead to more serious brain damage due to the ischemia/reperfusion injury [4]. Understanding the pathological mechanism of neuronal injury may be a fundamental way to seek novel clues for stroke treatment
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