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

Abstract Background and purpose Mammalian target of rapamycin (mTOR) pathway signaling governs cellular responses to hypoxia and inflammation including induction of autophagy and cell survival. Cerebral palsy (CP) is a neurodevelopmental disorder linked to hypoxic and inflammatory brain injury howev...

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Published in:	Neurobiology of disease Vol. 85; pp. 144 - 154
Main Authors:	Srivastava, Isha N, Shperdheja, Jona, Baybis, Marianna, Ferguson, Tanya, Crino, Peter B
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-01-2016 Elsevier
Subjects:	Animals Animals, Newborn Anti-Inflammatory Agents - pharmacology Autophagy Brain - drug effects Brain - pathology Brain - physiopathology Cell death Cell Death - drug effects Cell Death - physiology Cerebral palsy Cerebral Palsy - drug therapy Cerebral Palsy - pathology Cerebral Palsy - physiopathology Disease Models, Animal Hypoxia-Ischemia, Brain Inflammation Lipopolysaccharides Mice, Inbred C57BL Microglia mTOR Neuroimmunomodulation - drug effects Neuroimmunomodulation - physiology Neurology Neurons - drug effects Neurons - pathology Neurons - physiology Neuroprotective Agents - pharmacology Rapamycin Signal Transduction - drug effects Sirolimus - pharmacology TOR Serine-Threonine Kinases - metabolism chloroquine Cerebral palsy rapa Cell death hypoxia–ischemia-lipopolysaccharide mTOR HIL Inflammation CHQ Autophagy rapamycin Microglia Rapamycin
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Summary:	Abstract Background and purpose Mammalian target of rapamycin (mTOR) pathway signaling governs cellular responses to hypoxia and inflammation including induction of autophagy and cell survival. Cerebral palsy (CP) is a neurodevelopmental disorder linked to hypoxic and inflammatory brain injury however, a role for mTOR modulation in CP has not been investigated. We hypothesized that mTOR pathway inhibition would diminish inflammation and prevent neuronal death in a mouse model of CP. Methods Mouse pups (P6) were subjected to hypoxia–ischemia and lipopolysaccharide-induced inflammation (HIL), a model of CP causing neuronal injury within the hippocampus, periventricular white matter, and neocortex. mTOR pathway inhibition was achieved with rapamycin (an mTOR inhibitor; 5 mg/kg) or PF-4708671 (an inhibitor of the downstream p70S6kinase, S6K, 75 mg/kg) immediately following HIL, and then for 3 subsequent days. Phospho-activation of the mTOR effectors p70S6kinase and ribosomal S6 protein and expression of hypoxia inducible factor 1 (HIF-1α) were assayed. Neuronal cell death was defined with Fluoro-Jade C (FJC) and autophagy was measured using Beclin-1 and LC3II expression. Iba-1 labeled, activated microglia were quantified. Results Neuronal death, enhanced HIF-1α expression, and numerous Iba-1 labeled, activated microglia were evident at 24 and 48 h following HIL. Basal mTOR signaling, as evidenced by phosphorylated-S6 and -S6K levels, was unchanged by HIL. Rapamycin or PF-4,708,671 treatment significantly reduced mTOR signaling, neuronal death, HIF-1α expression, and microglial activation, coincident with enhanced expression of Beclin-1 and LC3II, markers of autophagy induction. Conclusions mTOR pathway inhibition prevented neuronal death and diminished neuroinflammation in this model of CP. Persistent mTOR signaling following HIL suggests a failure of autophagy induction, which may contribute to neuronal death in CP. These results suggest that mTOR signaling may be a novel therapeutic target to reduce neuronal cell death in CP.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0969-9961 1095-953X
DOI:	10.1016/j.nbd.2015.10.001