Novel therapeutic strategies for stroke: The role of autophagy

Nabavi, Seyed Fazel; Sureda, Antoni; Sanches-Silva, A.; Devi, Kasi Pandima; Ahmed, Touqeer; Shahid, Momina; Sobarzo‐Sánchez, Eduardo; Dacrema, Marco; Daglia, Maria; Braidy, Nady; Vacca, Rosa Anna; Berindan‐Neagoe, Ioana; Gulei, Diana; Barreca, Davide; Banach, Maciej; Nabavi, Seyed Mohammad; Dehpour, Ahmad Reza; Shirooie, Samira

doi:10.1080/10408363.2019.1575333

Cited by 50 publications

(30 citation statements)

References 161 publications

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“…This is consistent with our observations of reduced hippocampal levels of LC3-II, indicating that autophagy was impaired at later time points after global ischemia when microglial activation peaks. This finding supports the beneficial effects of autophagy inducers in ischemic brain injury, although this concept remains controversial [66,67].…”

Section: Effects Of Stress Exposure Prior To Ischemia On Autophagysupporting

confidence: 74%

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Espinosa‐García

Atif

Yousuf

et al. 2020

IJMS

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NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone’s (PROG’s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.

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Section: Effects Of Stress Exposure Prior To Ischemia On Autophagysupporting

confidence: 74%

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Espinosa‐García

Atif

Yousuf

et al. 2020

IJMS

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“…Stroke has a significant global impact; currently, the only Food and Drug Administration (FDA)-approved pharmacotherapy for acute stroke includes intravenous thrombolytic treatment with a recombinant tissue plasminogen activator (rtPA). This strategy has a short therapeutic window and a risk for intracerebral hemorrhage, making it safe and effective only in a subset of patients [2,3,4]. Therefore, cutting-edge research for novel targets and drugs to manage stroke is strongly needed.…”

Section: Introductionmentioning

confidence: 99%

Schizandrin Protects against OGD/R-Induced Neuronal Injury by Suppressing Autophagy: Involvement of the AMPK/mTOR Pathway

Wang

Zhang

et al. 2019

Molecules

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The neuroprotective role of schizandrin (SA) in cerebral ischemia-reperfusion (I/R) was recently highlighted. However, whether SA plays a regulatory role on autophagy in cerebral I/R injury is still unclear. This study aimed to explore whether the neuroprotective mechanisms of SA were linked to its regulation of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/autophagy pathway in vivo and in vitro. The present study confirmed that SA significantly improved oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced PC12 cells injury. The results of immunoblotting and confocal microscope showed that SA decreased autophagy in OGD/R-injured PC12 cells, which was reflected by the decreased Beclin-1 and LC3-II expression, autophagy flux level, and LC3 puncta formation. In addition, the autophagy inducer rapamycin partially prevented the effects of SA on cell viability and autophagy after OGD/R, whereas the autophagy inhibitor 3-methyladenine (3-MA) exerted the opposite effect. The results of Western blotting showed that SA markedly decreased the phosphorylation of AMPK (p-AMPK), whereas the phosphor-mTOR (p-mTOR) levels increased in the presence of OGD/R insult. Furthermore, pretreatment with the AMPK inducer AICAR partially reversed the protective effects and autophagy inhibition of SA. However, AMPK inhibitor Compound C pretreatment further promoted the inhibition of SA on autophagy induction and cell damage induced by OGD/R. Taken together, these findings demonstrate that SA protects against OGD/R insult by inhibiting autophagy through the regulation of the AMPK-mTOR pathway and that SA may have therapeutic value for protecting neurons from cerebral ischemia.

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“…Currently, there are no therapeutic options against stroke that demonstrate efficient neuroprotective abilities. For this reason, more indepth mechanism research is still needed about autophagy and its potential use as a new therapeutic target for stroke [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…Finally, both the Ras-ERK and PI3K-mTORC1 pathways represent key mechanisms for cells to regulate cell survival and proliferation and, in addition to their independent signaling programs that provide compensatory mechanisms, the pathways crosstalk extensively and regulate each other both positively and negatively [ 57 ]. Pathway convergence and AGC kinase promiscuity have been shown, and ERK and the AGC kinases, like AKT, often regulate the same substrates, yielding the same phenotypic effects [ 45 ]. However, because no effects of MAPK inhibitors nor AKT inhibitors have been observed in the effect of phytoestrogens on these pathways, our results seem to support that phytoestrogens activate mTOR by reducing MAPK activation through mechanisms involving the inhibition of Beclin-1 expression and AMPK phosphorylation rather than to a negative interaction between ERK and AGC kinases, like AKT.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms

et al. 2020

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Phytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions. First, we found that autophagy initiation affords neuronal protection upon neuronal damage induced by OGD and OGDR. The mammalian target of rapamycin/ribosomal S6 kinase (mTOR/S6K) pathway is blocked in these conditions, and we provide evidence that this is mediated by modulation of both the 5′ AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. These are dampened up or down, respectively, under OGDR-induced neuronal damage. In contrast, the MAPK-Erk kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is increased under these conditions. Regarding the pathways affected by phytoestrogens, we show that their protective properties require autophagy initiation, but at later stages, they decrease mitogen-activated protein kinase (MAPK) and AMPK activation and increase mTOR/S6K activation. Collectively, our results put forward a novel mode of action where phytoestrogens play a dual role in the regulation of autophagy by acting as autophagy initiation enhancers when autophagy is a neuroprotective and pro-survival mechanism, and as autophagy initiation inhibitors when autophagy is a pro-death mechanism. Finally, our results support the therapeutic potential of phytoestrogens in brain ischemia by modulating autophagy.

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Novel therapeutic strategies for stroke: The role of autophagy

Cited by 50 publications

References 161 publications

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

Schizandrin Protects against OGD/R-Induced Neuronal Injury by Suppressing Autophagy: Involvement of the AMPK/mTOR Pathway

Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms

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