Neuregulin-1/PI3K signaling effects on oligodendrocyte proliferation, remyelination and behaviors deficit in a male mouse model of ischemic stroke.

In this study, we investigated the effect of neuregulin-1 (NRG1) on demyelination and neurological function in an ischemic stroke model, and further explored its neuroprotective mechanisms. Adult male ICR mice underwent photothrombotic ischemia surgery and were injected with NRG1 beginning 30 min after ischemia. Cylinder and grid walking tests were performed to evaluate the forepaw function. In addition, the effect of NRG1 on neuronal damage/death (Cresyl violet, CV), neuronal nuclei (NeuN), nestin, doublecortin (DCX), myelin basic protein (MBP), non-phosphorylated neurofilaments (SMI-32), adenomatous polyposis coli (APC), erythroblastic leukemia viral oncogene homolog (ErbB) 2, 4 and serine-threonine protein kinase (Akt) in cortex were evaluated using immunohistochemistry, immunofluorescence and western blot. The cylinder and grid walking tests exposed that treatment of NRG1 observably regained the forepaw function. NRG1 treatment reduced cerebral infarction, restored forepaw function, promoted proliferation and differentiation of neuron and increased oligodendrogliogenesis. The neuroprotective effect of NRG1 is involved in its activation of PI3K/Akt signaling pathway via ErbB2, as shown by the suppression of the effect of NRG1 by the PI3K inhibitor LY294002. Our results demonstrate that NRG1 is effective in ameliorating the both acute phase neuroprotection and long-term neurological functions via resumption of neuronal proliferation and differentiation and oligodendrogliogenesis in a male mouse model of ischemic stroke.

A target lipidomics approach to investigate the acute inflammatory irritation induced by indolealkylamines from Chansu water fraction in rats.

Chansu has demonstrated adverse reactions in clinical settings, which is associated with its toxicity and limits its clinical applications. But there are methodological limitations for drug safety evaluation. In the current study, ultra-high performance liquid chromatography, lipidomic profiling, and molecular docking were used to systemically assess Chansu-induced acute inflammatory irritation and further identify the underlying drug targets. Compared with the EtOAc extract, Chansu water fraction containing indolealkylamines caused acute inflammatory irritation in rats, including acute pain (spontaneous raising foot reaction), and inflammation (paw edema). At the molecular level, lipids analysis revealed significantly higher levels of pro-inflammatory mediators of the COX and LOX pathways. However, anti-inflammatory mediators from the CYP 450, ALA, and DHA pathways markedly decreased after exposure to Chansu water fraction. Moreover, four indolealkylamines from Chansu showed a high theoretical affinity to a known irritation target, 5-HT2AR. These results suggest that Chansu-induced inflammatory irritation is related to the distinct dysregulation of inflammatory lipids, and peripheral 5-HT2AR is a potential target for irritation therapy. The strategy used in this study can be a crucial approach in the safety evaluation of natural medicinal substances.