HGSD attenuates neuronal apoptosis through enhancing neuronal autophagy in the brain of diabetic mice: The role of AMP-activated protein kinase

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Abstract

Aims:

Berberine (BBR) holds promising effect for neuronal injury in diabetes because its anti-apoptotic activity and our laboratory developed the Huang-Gui Solid Dispersion (HGSD) to improve oral bioavailability of BBR. However, anti-apoptotic effect and the mechanism of HGSD in the brain of diabetic mice are not clear. We hypothesized that the AMPK/mTOR signaling pathway could exert a protective role in high glucose induced cellular apoptotic death via inducing autophagy and HGSD could inhibit apoptosis by activating AMPK/mTOR pathway.

Main methods:

In vivo, we established C57/BL6 mice diabetic model by STZ and detected apoptosis, autophagy and AMPK/mTOR to explore the effect of HGSD. In vitro, we established high glucose-induced apoptotic death model, treating cells with 3-MA, compound C and AICAR to explore the anti-apoptotic mechanism of BBR.

Key findings:

HGSD significantly inhibited cell apoptosis, enhanced cell autophagy and activated the AMPK/mTOR pathway in the hippocampi of diabetic C57/BL6 mice, and the function of BBR is not obvious at the same dosage. Moreover, BBR significantly attenuated apoptotic death, enhanced autophagy and activated the AMPK/mTOR pathway in high glucose-treated SH-SY5Y cells. Pretreated cells with 3-MA, an inhibitor of autophagy, abolished BBR-inhibited apoptosis. Pretreated cells with Compound C, an AMPK inhibitor, blocked BBR-inhibited apoptotic and BBR-induced cell autophagy. AICAR, an AMPK activator, strengthened the function of BBR.

Significance:

HGSD protected against neurotoxicity induced by high glucose through activating autophagy and eventually inhibiting neuronal apoptosis, which was activated by the AMPK/mTOR signaling pathway.

Graphical abstract

Berberine (BBR) holds promising effect for neuronal injury in diabetes because its anti-apoptotic activity, while the poor oral bioavailability of BBR limits its clinical application as an anti-diabetic drug and our laboratory developed the Huang-Gui Solid Dispersion (HGSD) to improve oral bioavailability of BBR. However, anti-apoptotic effect and the mechanism of HGSD in the brain of diabetic mice are not clear. We hypothesized that the AMPK/mTOR signaling pathway could exert a protective role in high glucose induced cellular apoptotic death via inducing autophagy and HGSD could inhibit apoptosis by activating AMPK/mTOR pathway.

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