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

Chung, Hyun Ju; Choi, Jae-Sung; Park, Seungjoon

doi:10.1507/endocrj.ej17-0281

Cited by 30 publications

(14 citation statements)

References 40 publications

(39 reference statements)

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“…Previous experimental studies from our and other laboratories have documented that the detrimental effect of Hcy after ischemia-induced damage involves the loss of neurons, microglia overactivation, and hypertrophy of astrocytes. For instance, increased neuronal damage by Hcy was detected in in vitro ischemic model of hippocampal slices with OGD 24 . Hcy aggravates cortical neural cell injury through neuronal autophagy overactivation 17 .…”

Section: Discussionmentioning

confidence: 99%

Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

et al. 2019

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The elevated level of the amino acid metabolite homocysteine (Hcy) is known as a risk factor for ischemic stroke. The molecular mechanisms responsible for neurotoxicity of Hcy remain largely unknown in ischemic brains. The previous studies have shown that Hcy decreases the proliferation and viability of neural stem cells (NSCs) in vivo and in vitro. Autophagy is required for the maintenance of NSCs homeostasis. In the current study, we hypothesized that the toxic effect of Hcy on NSCs may involve the changes in autophagy level following cerebral ischemia/reperfusion injury. The results showed that Hcy reduced cell viability, increased LDH release, and induced nonapoptotic cell death in primary NSCs exposed to oxygen–glucose deprivation)/reoxygenation (OGD/R). Treatment with autophagy inhibitor 3-methyladenine (3MA) partly reversed the decrease in the viability and prevented LDH release triggered by Hcy combined with OGD/R. Increased punctate LC3 dots co-localizing with Nestin-stained NSCs were also observed in the subventricular zone of Hcy-treated MCAO animals, which were partially blocked by 3MA. In vitro studies further revealed that Hcy induced the formation of autophagosomes, markedly increased the expression of the autophagic markers and decreased p-ERK, p-PI3K, p-AKT, and p-mTOR levels. In addition, MHY1485, an activator of mTOR, reduced Hcy-induced increase in LC3 and Beclin 1 protein levels, meanwhile ERK and PI3K activators (TPA, curcumin for ERK and IGF-1 for PI3K, respectively) enhanced Hcy-triggered mTOR inhibition in OGD/R NSCs. Our findings suggest that Hcy may cause excessive autophagy by downregulation of both PI3K-AKT- and ERK- dependent mTOR signaling, thereby facilitates the toxicity of Hcy on NSCs in ischemic brains.

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Section: Discussionmentioning

confidence: 99%

Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

et al. 2019

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“…Intriguingly, oxidative stress is known to further activate autophagy and aggravate cell injury . Activation of autophagy is well documented in the phase of reperfusion after ischemia in rodent brain and neurons following OGD/R . Nevertheless, the role of autophagy in brain I/R is controversial.…”

Section: Discussionmentioning

confidence: 99%

Suppression of REDD1 attenuates oxygen glucose deprivation/reoxygenation‐evoked ischemic injury in neuron by suppressing mTOR‐mediated excessive autophagy

Sun

Yue

2019

J of Cellular Biochemistry

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Cerebral ischemia/reperfusion (I/R) typically occurs after mechanical thrombectomy to treat ischemic stroke, generation of reactive oxygen species (ROS) after reperfusion may result in neuronal insult, ultimately leading to disability and death. Regulated in development and DNA damage responses 1 (REDD1) is a conserved stress response protein under various pathogenic conditions. Recent research confirms the controversial role of REDD1 in injury processes. Nevertheless, the role of REDD1 in cerebral I/R remains poorly defined. In the current study, increased expression of REDD1 was observed in neurons exposed to simulated I/R via oxygen glucose deprivation/reoxygenation (OGD/R) treatment. Knockdown of REDD1 enhanced OGD/R‐inhibited cell viability, but suppressed lactate dehydrogenase (LDH) release in neurons upon OGD/R. Simultaneously, suppression of REDD1 also antagonized OGD/R‐evoked cell apoptosis, Bax expression, and caspase‐3 activity. Intriguingly, REDD1 depression abrogated neuronal oxidative stress under OGD/R condition by suppressing ROS, MDA generation, and increasing antioxidant SOD levels. Further mechanism analysis corroborated the excessive activation of autophagy in neurons upon OGD/R with increased expression of autophagy‐related LC3 and Beclin‐1, but decreased autophagy substrate p62 expression. Notably, REDD1 inhibition reversed OGD/R‐triggered excessive neuronal autophagy. More importantly, depression of REDD1 also elevated the expression of p‐mTOR. Preconditioning with mTOR inhibitor rapamycin engendered not only a reduction in mTOR activation, but also a reactivation of autophagy in REDD1 knockdown‐neurons upon OGD/R. In addition, blocking the mTOR pathway muted the protective roles of REDD1 inhibition against OGD/R‐induced neuron injury and oxidative stress. Together these data suggested that REDD1 may regulate I/R‐induced oxidative stress injury in neurons by mediating mTOR‐autophagy signaling, supporting a promising therapeutic strategy against brain ischemic diseases.

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“…Similarly, ghrelin protects adult rat hypothalamic neuronal cells from apoptosis and excessive autophagy due to oxygen-glucose deprivation by inhibiting reactive oxygen species (ROS) generation, and by stabilizing mitochondrial integrity and transmembrane potential. Besides, ghrelin treatment prevents cytochrome c release and inhibits caspase-3 activation [108,109]. Ghrelin also induces the proliferation of neuronal precursor cells in the rat fetal spinal cord [110].…”

Section: E Role Of Ghrelin In Cns Pathologiesmentioning

confidence: 99%

Physiological Effect of Ghrelin on Body Systems

Akalu

Molla

Dessie

et al. 2020

International Journal of Endocrinology

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Ghrelin is a relatively novel multifaceted hormone that has been found to exert a plethora of physiological effects. In this review, we found/confirmed that ghrelin has effect on all body systems. It induces appetite; promotes the use of carbohydrates as a source of fuel while sparing fat; inhibits lipid oxidation and promotes lipogenesis; stimulates the gastric acid secretion and motility; improves cardiac performance; decreases blood pressure; and protects the kidneys, heart, and brain. Ghrelin is important for learning, memory, cognition, reward, sleep, taste sensation, olfaction, and sniffing. It has sympatholytic, analgesic, antimicrobial, antifibrotic, and osteogenic effects. Moreover, ghrelin makes the skeletal muscle more excitable and stimulates its regeneration following injury; delays puberty; promotes fetal lung development; decreases thyroid hormone and testosterone; stimulates release of growth hormone, prolactin, glucagon, adrenocorticotropic hormone, cortisol, vasopressin, and oxytocin; inhibits insulin release; and promotes wound healing. Ghrelin protects the body by different mechanisms including inhibition of unwanted inflammation and induction of autophagy. Having a clear understanding of the ghrelin effect in each system has therapeutic implications. Future studies are necessary to elucidate the molecular mechanisms of ghrelin actions as well as its application as a GHSR agonist to treat most common diseases in each system without any paradoxical outcomes on the other systems.

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

Cited by 30 publications

References 40 publications

Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

Suppression of REDD1 attenuates oxygen glucose deprivation/reoxygenation‐evoked ischemic injury in neuron by suppressing mTOR‐mediated excessive autophagy

Physiological Effect of Ghrelin on Body Systems

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