This study mainly investigated the therapeutic effects of BHDPC on ischemic stroke and its underlying mechanisms. In vivo, the transient middle cerebral artery occlusion (MCAO) was used to induce ischemic model. In vitro, oxygen and glucose deprivation/reperfusion (OGD/R)-induced ischemic stroke in BV-2 microglia and primary neurons, and bEnd.3 mouse cerebral microvascular endothelial cells (ECs) were also used. First, we found that BHDPC exerts considerable neuroprotection against MCAO-induced ischemic injury to mice via alleviating neurological deficits and brain infarcts, inhibiting neuronal cell loss and apoptosis, and attenuating blood-brain barrier disruption and tight junction protein changes. Next, we observed that BHDPC significantly reduced microglial M1 activation but enhanced M2 polarization in MCAO-induced ischemic brain. Further experiments in vitro indicated that BHDPC suppressed microglial activation but promoted M2 microglial polarization in OGD/R-induced BV-2 microglia. In addition, conditioned medium (CM) experiments showed that CM from BHDPC-treated BV-2 microglia provided protections against OGD/R-induced ischemic damage in primary neurons and bEnd.3 ECs. Moreover, we found that BHDPC actions on microglial inflammation were associated with the inactivation of NF-κB signaling. Interestingly, we also found that BHDPC enhanced phosphorylation of protein kinase A (PKA) and cAMP-response element-binding protein (CREB). The pharmacological inhibition or gene knockdown of PKA/CREB signaling diminished BHDPC-promoted microglial M2 polarization. In summary, BHDPC conferred neuroprotection against ischemic injury in experimental stroke models. Modulating microglial activation and polarization contributes to BHDPC-mediated neuroprotective actions, which in part were mediated by nuclear factor kappa B and PKA/CREB signaling pathway.
|Number of pages||16|
|Journal||ACS Chemical Neuroscience|
|Early online date||6 Mar 2019|
|Publication status||Published - 15 May 2019|
Bibliographical noteFunding Information:
This study was supported by grants from The Science and Technology Development Fund (FDCT) of Macao SAR (Grants 134/2014/A3, 017/2015/AMJ, and 069/2015/A2) and Research Committee, University of Macau (Grants MYRG2016-00133-ICMS-QRCM MYRG2015-00182-ICMS-QRCM, and MYRG2016-00129-ICMS-QRCM).
- ischemic stroke