mTOR pathway inhibition prevents neuroinflammation and neuronal death in a mouse model of cerebral palsy

Srivastava, Isha N.; Shperdheja, Jona; Baybis, Marianna; Ferguson, Tanya S; Crino, Peter B.

doi:10.1016/j.nbd.2015.10.001

Cited by 69 publications

(48 citation statements)

References 56 publications

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“…More recently, peritoneal injection of rapamycin was proposed to prevent neuroinflammation and neuronal death in a mouse model of cerebral palsy. 45 Further experiments are needed to characterize the involvement of autophagy in brain angiogenesis and the in vivo protective effect of rapamycin after PAE.…”

Section: Discussionmentioning

confidence: 99%

Prenatal alcohol exposure impairs autophagy in neonatal brain cortical microvessels

et al. 2017

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Brain developmental lesions are a devastating consequence of prenatal alcohol exposure (PAE). We recently showed that PAE affects cortical vascular development with major effects on angiogenesis and endothelial cell survival. The underlying molecular mechanisms of these effects remain poorly understood. This study aimed at characterizing the ethanol exposure impact on the autophagic process in brain microvessels in human fetuses with fetal alcohol syndrome (FAS) and in a PAE mouse model. Our results indicate that PAE induces an increase of autophagic vacuole number in human fetal and neonatal mouse brain cortical microvessels. Subsequently, ex vivo studies using green fluorescent protein (GFP)-LC3 mouse microvessel preparations revealed that ethanol treatment alters autophagy in endothelial cells. Primary cultures of mouse brain microvascular endothelial cells were used to characterize the underlying molecular mechanisms. LC3 and p62 protein levels were significantly increased in endothelial cells treated with 50 mM ethanol. The increase of autophagic vacuole number may be due to excessive autophagosome formation associated with the partial inhibition of the mammalian target of rapamycin pathway upon ethanol exposure. In addition, the progression from autophagosomes to autolysosomes, which was monitored using autophagic flux inhibitors and mRFP–EGFP vector, showed a decrease in the autolysosome number. Besides, a decrease in the Rab7 protein level was observed that may underlie the impairment of autophagosome–lysosome fusion. In addition, our results showed that ethanol-induced cell death is likely to be mediated by decreased mitochondrial integrity and release of apoptosis-inducing factor. Interestingly, incubation of cultured cells with rapamycin prevented ethanol effects on autophagic flux, ethanol-induced cell death and vascular plasticity. Taken together, these results are consistent with autophagy dysregulation in cortical microvessels upon ethanol exposure, which could contribute to the defects in angiogenesis observed in patients with FAS. Moreover, our results suggest that rapamycin represents a potential therapeutic strategy to reduce PAE-related brain developmental disorders.

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Section: Discussionmentioning

confidence: 99%

Prenatal alcohol exposure impairs autophagy in neonatal brain cortical microvessels

et al. 2017

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“…A recent study demonstrated that mTOR inhibition might substantially reduce neuronal injury in a mouse model of cerebral palsy, a neurodevelopmental disorder often associ ated with hypoxic-ischaemic and inflammatory brain injury 130 : mouse pups were subjected to hypoxia-ischemia combined with lipopolysaccharideinduced inflammation, a model of cerebral palsy that induces neuronal injury in the periventricular white matter, hippocampus, and neocortex. Rapamycin and S6K1 inhibitor PF-4708671 suppressed aberrant mTOR signalling, restored normal levels of hypoxia-inducible factor 1-alpha (HIF-1α) expression and reduced numbers of activated microglia, thereby limiting neuronal death 130 .…”

Section: Cerebral Palsymentioning

confidence: 99%

“…Rapamycin and S6K1 inhibitor PF-4708671 suppressed aberrant mTOR signalling, restored normal levels of hypoxia-inducible factor 1-alpha (HIF-1α) expression and reduced numbers of activated microglia, thereby limiting neuronal death 130 . These results suggest that mTOR signalling might be a novel therapeutic target to mitigate neuronal death in cerebral palsy.…”

Section: Cerebral Palsymentioning

confidence: 99%

The mTOR signalling cascade: paving new roads to cure neurological disease

2016

Self Cite

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Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.

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“…Thus, PF-4708671 had been used in studies determining the role of S6K1 and mTORC1 in physiological and pathological conditions [25][26][27][28]. The inhibitory effect of PF-4708671 on S6K was confirmed by measuring the phosphorylation of S6, which is a downstream target of S6K, in previous studies [22,[25][26][27][28]. Therefore, we similarly examined effects of PF-4708671 on pS6 levels in retinas.…”

Section: Discussionmentioning

confidence: 93%

Protective effects of PF‐4708671 against N‐methyl‐d‐aspartic acid‐induced retinal damage in rats

Hayashi

Aoki

Ushikubo

et al. 2016

Fundamemntal Clinical Pharma

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We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-d-aspartic acid (NMDA)-induced retinal damage in rats. Rapamycin inhibits mTOR activity, thereby preventing the phosphorylation of ribosomal protein S6, which is a downstream target of S6 kinase. Therefore, we aimed to determine whether PF-4708671, an inhibitor of S6 kinase, protects against NMDA-induced retinal injury. Intravitreal injection of NMDA (200 nmol/eye) caused cell loss in the ganglion cell layer and neuroinflammatory responses, such as an increase in the number of CD45-positive leukocytes and Iba1-positive microglia. Surprisingly, simultaneous injection of PF-4708671 (50 nmol/eye) with NMDA significantly attenuated these responses without affecting phosphorylated S6 levels. These results suggest that PF-4708671 and rapamycin likely protect against NMDA-induced retinal damage via distinct pathways. The neuroprotective effect of PF-4708671 is unlikely to be associated with inhibition of the S6 kinase, even though PF-4708671 is reported to be a S6 kinase inhibitor.

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mTOR pathway inhibition prevents neuroinflammation and neuronal death in a mouse model of cerebral palsy

Cited by 69 publications

References 56 publications

Prenatal alcohol exposure impairs autophagy in neonatal brain cortical microvessels

Prenatal alcohol exposure impairs autophagy in neonatal brain cortical microvessels

The mTOR signalling cascade: paving new roads to cure neurological disease

Protective effects of PF‐4708671 against N‐methyl‐d‐aspartic acid‐induced retinal damage in rats

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