Excessive Autophagy Contributes to Neuron Death in Cerebral Ischemia

Shi, Rong; Weng, Jiequn; Zhao, Ling; Li, Xinmin; Gao, Tianming; Kong, Jiming

doi:10.1111/j.1755-5949.2012.00295.x

Cited by 237 publications

(148 citation statements)

References 45 publications

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“…The conundrum being that autophagy can be protective in neonatal hypoxic-ischemic injury (Li et al, 2010) (Koike et al, 2008) and in models of preconditioning (Sheng et al, 2010), yet cytodestructive in models of middle cerebral artery occlusion (MCAO) (Wen et al, 2008;Shi et al, 2012). Such observations support the concept that the "load" of cellular debris and damaged proteins, as influenced by stroke severity, determine the mode of autophagy and its M A N U S C R I P T…”

Section: Introductionmentioning

confidence: 90%

Evidence for the recruitment of autophagic vesicles in human brain after stroke

Frugier

McLean

et al. 2016

Neurochemistry International

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Section: Introductionmentioning

confidence: 90%

Evidence for the recruitment of autophagic vesicles in human brain after stroke

Frugier

McLean

et al. 2016

Neurochemistry International

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“…Also as a bulk cellular degradation pathway, autophagy has been widely reported in its neuroprotective potential [11][12][13] and autophagy is thought to be a protective mechanism that sustain cell survival under stress conditions. By contrast, altercation exist whether excessive autophagy activity contribute to autophagy induced cell death [14][15][16], when autophagy is excessively induced, it can result in autophagic cell death, type II programmed cell death (PCD). The majority of the cell death due to cerebral ischemia has been attributed to apoptosis; type I PCD [17].…”

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confidence: 99%

Ghrelin protects adult rat hippocampal neural stem cells from excessive autophagy during oxygen-glucose deprivation

2018

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Abstract. Ghrelin functions as a neuroprotective agent and saves neurons from various insults include ischemic injury. However, it remains to be elucidated whether ghrelin protects neuronal cells against ischemic injury-induced excessive autophagy. Autophagy is required for the maintenance of neural stem cell homeostasis. However, regarding autophagic cell death, it is commonly assumed that excessive autophagy leads to self-elimination of mammalian cells. The purpose of this study was to investigate the potential neuroprotection effects of ghrelin from excessive autophagy in adult rat hippocampal neural stem cells (NSCs). Oxygen-Glucose Deprivation (OGD) strongly induces autophagy in adult rat hippocampal NSCs. Ghrelin treatment inhibited OGD-induced cell death of adult rat hippocampal NSCs assessed by cell-counting-kit-8 assay. Ghrelin also suppressed OGD-induced excessive autophagy activity. The protective effect of ghrelin was accompanied by an increased expression levels of Bcl-2, p-62 and decreased expression level of LC3-II, Beclin-1 by Western blot. Furthermore, ghrelin reduced autophagosome formation and number of GFP-LC3 transfected puncta. In conclusion, our data suggest that ghrelin protects adult rat hippocampal NSCs from excessive autophagy in experimental stroke (oxygen-glucose deprivation) model. Regulating autophagic activity may be a potential optimizing target for promoting adult rat hippocampal NSCs based therapy for stroke.

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“…32,33) In cerebral ischemia studies, substantial evidence suggests 3-MA inhibits autophagy activation and maturation, reduces I/R injury, and improves cell survival in vivo and in vitro. 34,35) An intrathecal injection of 3-MA was administered to enable the drug to enter the cerebrospinal fluid to directly act on the injured spinal nerves. Intrathecal injections of 3-MA at the time of reperfusion significantly reduced LC3/Beclin 1 expression levels and the number of LC3-positive cells and improved neurological function.…”

Section: Discussionmentioning

confidence: 99%

Intrathecal Injection of 3-Methyladenine Reduces Neuronal Damage and Promotes Functional Recovery <i>via</i> Autophagy Attenuation after Spinal Cord Ischemia/Reperfusion Injury in Rats

Xing

Zhou

et al. 2016

Biological & Pharmaceutical Bulletin

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The present study aimed to determine the occurrence of autophagy following ischemia/reperfusion (I/R) injury in the rat spinal cord and whether autophagy inhibition contributes to neural tissue damage and locomotor impairment. A spinal cord I/R model was induced via descending thoracic aorta occlusion for 10 min using systemic hypotension (40 mmHg) in adult male Sprague-Dawley rats. Then, 600 nmol 3-methyladenine (3-MA) or vehicle was intrathecally administered. Ultrastructural spinal cord changes were observed via transmission electron microscopy (TEM) and immunofluorescent double-labeling. Western blots were used to determine the protein expression of microtubule-associated protein light chain 3 (LC3) and Beclin 1. Spinal cord ischemia/reperfusion (I/R) injury may induce paralysis, which represents the underlying pathological cause of patient mortality and morbidity.1) Spinal cord I/R injury triggers pathophysiological changes that involve excitotoxicity, free radical production, inflammation, and apoptosis.2-4) In recent years, evidence has indicated that autophagy may play an important role in various spinal disease models, including spinal cord contusion injury, spinal cord hemisection injury, and cervical spondylotic myelopathy.5-7) However, the occurrence and role of autophagy in neural tissues following spinal cord I/R injury have not been clearly illustrated.Autophagy comprises an evolutionarily conserved process wherein damaged or dysfunctional cytoplasmic components undergo autophagosomal-lysosomal pathway clearance/degradation to facilitate the maintenance of homeostasis. 8,9) Microtubule-associated protein light chain 3 (LC3) and Beclin 1 are two key proteins involved in the autophagic cascade. LC3 occurs in cytosolic (LC3-I) and membrane-bound (LC3-II) forms, and the extent of autophagosome formation is correlated with the ratio of LC3-I to LC3-II conversion. 10)Beclin 1 is a mammalian homolog of yeast Atg6 that was initially described as a Bcl-2-interacting protein and has been demonstrated to promote autophagy. 11) Autophagy is activated during different stress responses, including starvation, oxidative stress, and hypoxia.12,13) Abnormal autophagy has been linked to many pathophysiological events and is involved in disease development.14) The presence of autophagosomes in dying cells indicates that autophagy may play a role in cell death (i.e., "autophagic cell death").15) Autophagy is a critical regulator of cell death and survival and interacts with necrosis and apoptosis in determining the outcome of injured cells. In recent years, the role of autophagy in the pathogenesis of cerebral ischemia had been clearly demonstrated. [16][17][18] Investigations of autophagy-related cures to alleviate the hardships of spinal I/R injury include interventions that attenuate the secondary injury cascade, enhance endogenous repair mechanisms, and replace lost cells.3-Methyladenine (3-MA) is a pharmacological inhibitor of autophagy. It blocks class III phosphoinositide 3-kinase (PI3K) to inhibit autophagosom...

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Excessive Autophagy Contributes to Neuron Death in Cerebral Ischemia

Cited by 237 publications

References 45 publications

Evidence for the recruitment of autophagic vesicles in human brain after stroke

Evidence for the recruitment of autophagic vesicles in human brain after stroke

Ghrelin protects adult rat hippocampal neural stem cells from excessive autophagy during oxygen-glucose deprivation

Intrathecal Injection of 3-Methyladenine Reduces Neuronal Damage and Promotes Functional Recovery <i>via</i> Autophagy Attenuation after Spinal Cord Ischemia/Reperfusion Injury in Rats

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