Abstract
We identified a novel neuroprotective compound, 1-methoxyoctadecan-1-ol, from Uncaria sinensis (Oliv.) Havil and investigated its effects and mechanisms in primary cortical neurons and in a photothrombotic ischemic model. In primary rat cortical neurons against glutamate-induced neurotoxicity, pretreatment with 1-methoxyoctadecan-1-ol resulted in significantly reduced neuronal death in a dose-dependent manner. In addition, treatment with 1-methoxyoctadecan-1-ol resulted in decreased neuronal apoptotic death, as assessed by nuclear morphological approaches. To clarify the neuroprotective mechanism of 1-methoxyoctadecan-1-ol, we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation. Treatment with glutamate leads to early activation of NMDAR, which in turn leads to calpain-mediated cleavage of striatal-enriched protein tyrosine phosphatase (STEP) and subsequent activation of p38 mitogen activated protein kinase (MAPK). However, pretreatment with 1-methoxyoctadecan-1-ol resulted in significantly attenuated activation of GluN2B-NMDAR and a decrease in calpain-mediated STEP cleavage, leading to subsequent attenuation of p38 MAPK activation. We confirmed the critical role of p38 MAPK in neuroprotective effects of 1-methoxyoctadecan-1-ol using specific inhibitor SB203580. In the photothrombotic ischemic injury in mice, treatment with 1-methoxyoctadecan-1-ol resulted in significantly reduced infarct volume, edema size, and improved neurological function. 1-methoxyoctadecan-1-ol effectively prevents cerebral ischemic damage through down-regulation of calpain-mediated STEP cleavage and activation of p38 MAPK. These results suggest that 1-methoxyoctadecan-1-ol showed neuroprotective effects through down-regulation of calpain-mediated STEP cleavage with activation of GluN2B-NMDAR, and subsequent alleviation of p38 MAPK activation. In addition, 1-methoxyoctadecan-1-ol might be a useful therapeutic agent for brain disorder such as ischemic stroke.
Highlights
The hooks and stems of dried Uncaria sinensis (Oliv.) Havil have been widely used in traditional Korean medicine as a pharmacological medicine against diverse neurological symptoms
The active molecule isolated from U. sinensis was identified by 1H and 13C distortionless enhancement by polarization transfer (Dept), heteronuclear single quantum coherence (HSQC), and heteronuclear multiple bond correlation (HMBC) nuclear magnetic resonance (NMR) spectra in chloroform D (CDCl3)
Treatment with 1-methoxyoctadecan-1-ol resulted in significantly blocked ischemia-induced phosphorylation of p38 mitogen activated protein kinase (MAPK). These results demonstrated that 1-methoxyoctadecan-1-ol may prevent ischemia-induced neuronal damage through inhibition of calpain-mediated striatal-enriched protein tyrosine phosphatase (STEP) cleavage and p38 MAPK activation
Summary
The hooks and stems of dried Uncaria sinensis (Oliv.) Havil have been widely used in traditional Korean medicine as a pharmacological medicine against diverse neurological symptoms. Rhynchophylline has been studied intensively as a main alkaloid constituent of Uncaria species and exhibits antihypertension and neuroprotection activities linkage with traditional concept and uses [4]. Our previous results demonstrated that a hexane extract from U. sinensis protects against cerebral ischemic damage through regulation of Akt/endothelial nitric oxide synthase signaling [5] and exerts significant anti-apoptotic effects against glutamateinduced neurotoxicity [6]. Because it has not been determined which compounds of U. sinensis are bioactive, we isolated a novel single compound, 1-methoxyoctadecan-1-ol, from specific fractions of hexane extracts using an neuronal cells and ischemic animal model for screening of active constituents.
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