Abstract
BackgroundStroke is the leading cause of long-term motor disability and cognitive impairment. Recently, neurogenesis has become an attractive strategy for the chronic recovery of stroke. It is important to understand the molecular mechanism that promotes neural stem cell (NSC) neurogenesis for future NSC-based therapies. Our previous study showed that Momordica charantia polysaccharides (MCPs) exerted neuroprotective effects on stroke via their anti-oxidant and anti-inflammation activities. However, it remains unknown whether MCPs promote NSC neurogenesis after cerebral ischemic/reperfusion injury (IRI).MethodsWe investigated MCPs’ function in differentiation of neural stem cells (NSCs) in vivo and in vitro experiments. Based on a middle cerebral artery occlusion (MCAO) rat model, the effect of MCPs on neuronal differentiation after MCAO was analyzed. Primary NSCs and neural stem cell line C17.2 were cultured and subjected to glutamate stimulation to establish the cell model of IRI. We evaluated the effect of MCPs on NSC differentiation in IRI cell model by Western blot and immunofluorescence staining. The SIRT1 activity of NSCs post glutamate stimulation was also evaluated by CELL SIRT1 COLORIMETRY ASSAY KIT. In addition, molecular mechanism was clarified by employing the activator and inhibitor of SIRT1.ResultsMCPs had no effects on the differentiation of neural stem cells under physiological conditions while shifted NSC differentiation potential from the gliogenic to neurogenic lineage under pathological conditions. Activation of SIRT1 with MCPs was responsible for the neuronal differentiation of C17.2-NSCs. The neuronal differentiation effect of MCPs was attributed to upregulation SIRT1-mediated deacetylation of β-catenin. MCP-induced deacetylation via SIRT1 promoted nuclear accumulation of β-catenin in NSCs.ConclusionOur findings indicate that the deacetylation of β-catenin by SIRT1 represents a critical mechanism of action of MCPs in promoting NSC neuronal differentiation. It provides an improved understanding of molecular mechanism underlying neuroprotective effects of MCPs in IRI, indicating its potential role on treating ischemic stroke especially chronic recovery.
Highlights
Stroke is a major disease that affects millions of people annually across the world [1,2,3]
Our findings indicate that the deacetylation of β-catenin by Silent information regulator 1 (SIRT1) represents a critical mechanism of action of Momordica charantia polysaccharides (MCPs) in promoting neural stem cells (NSCs) neuronal differentiation
MCPs enhance neuronal differentiation of the subgranular zone (SGZ) after middle cerebral artery occlusion (MCAO) in rats To further explore the effect of MCPs on neuronal differentiation in vivo, we performed double-labeling at day 14 after MCAO with antibodies against BrdU, a marker for DNA replication in newly formed cells, plus TUJ1, BrdU plus MAP 2, BrdU plus
Summary
Stroke is a major disease that affects millions of people annually across the world [1,2,3]. Pharmacological interventions related to promoting endogenous neurogenesis and prolonging the survival of differentiated neurons after stroke are believed to be a promising strategy for brain repair. Momordica charantia polysaccharides (MCPs) have a protective role on nerve injury after stroke by scavenging free radicals [11]. As naturally compounds found in daily foods, MCPs are well known for their anti-oxidation, anti-inflammation, antitumor, hypoglycemic, and anti-diabetic effects [17]; little is known about its effects from neurogenesis regulation perspective. Our previous study showed that Momordica charantia polysaccharides (MCPs) exerted neuroprotective effects on stroke via their anti-oxidant and anti-inflammation activities. It remains unknown whether MCPs promote NSC neurogenesis after cerebral ischemic/reperfusion injury (IRI)
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