Dexmedetomidine attenuates propofol-induced apoptosis of neonatal hippocampal astrocytes by inhibiting the Bcl2l1 signaling pathway

Apoptosis shapes brain structure and function during early life. However, aberrant apoptosis, including that associated with the general anesthetic propofol, is undesirable. Dexmedetomidine (DEX) provides potential neuroprotection against apoptosis, but the underlying mechanism remains unknown. We exposed neonatal rodent hippocampal astrocytes to propofol alone and in combination with DEX and yohimbine (an α2 -adrenergic receptor antagonist), then evaluated cell viability using the MTT assay. The underlying regulatory mechanism associated with apoptosis-related genes was detected using a combinational strategy including double immunofluorescent staining, real-time RT-PCR, western blot, and flow cytometry. Propofol reduced matrix metallopeptidase 9 (MMP9) in cultured astrocytes, and activated the rno-miR-665/Bcl2-like 1 (Bcl2l1)/cleaved caspase 9 (CC9)/cleaved caspase 3 (CC3) pathway. Combinations incorporating propofol with A-1155463 (a selective Bcl2l1 inhibitor) or MMP9 antagomir reduced Bcl2l1 and promoted apoptosis. Co-culture of propofol with Bcl2l1 or with MMP9 agomir was sufficient to decrease the pro-apoptotic effects of propofol. Interestingly, DEX alone had no significant effect on apoptosis. When combined with propofol, however, the negative effects of propofol on the MMP9 and apoptosis-related genes (Bcl2l1, CC9, and CC3) were reduced. Furthermore, yohimbine pretreatment blocked the neuroprotective effects of DEX. Rno-miR-665 was also found to reduce MMP9 expression in propofol-treated hippocampal astrocytes. Taken together, the results indicate that DEX pretreatment reduces propofol-associated pro-apoptosis in developing astrocytes via downregulation of anti-apoptotic signaling mediated by Bcl2l1.

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S7800 A-1155463 A-1155463, a highly potent and selective BCL-XL inhibitor, shows picomolar binding affinity to BCL-XL, and >1000-fold weaker binding to BCL-2 and related proteins BCL-W(Ki=19 nM) and MCL-1(Ki>440 nM).

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