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Synergistic Effect and Mechanism of Apoptosis Induction by Morphine and the HIV-1gp120V3 Loop in Hippocampal Neurons

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Abstract

HIV-associated neurocognitive disorders (HAND) are a collective name for neurological disorders associated with HIV-1 infection. The incidence and severity of HAND are increased by concomitant opioid use disorder, such as heroin and morphine abuse. Our previous study showed that the HIV-1 envelope protein gp120 and morphine synergistically induce apoptosis in rat hippocampal neurons. However, the underlying mechanism remains unclear. We hypothesized that morphine and gp120 activated the neuronal apoptosis signaling pathway via their typical membrane receptors. If they shared key signaling molecules, their induction of neuronal apoptosis could be inhibited by blocking these targets. We found that morphine and gp120V3 loop synergistically induced hippocampal neuron apoptosis, mediated by activating the extracellular signal-regulated kinase (ERK) pathway, increasing the intracellular Ca2 + concentration and expression of caspase-, and reducing the mitochondrial membrane potential. The ERK inhibitor PD98509 and the phosphatidylinositol 3-kinase activator IGF-1 blocked this effect. These results indicate that ERK plays a crucial role in the apoptosis of hippocampal neurons in HAND.

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Funding

This study was supported by a grant from the National Natural Science Foundation of China (No. 81171134, 81471235 and 81974185); Guangdong Provincial Natural Science Foundation of China (2019A1515012024); Programme of Introducing Talents of Discipline to Universities (B14036); National Basic Research Program of China C973 program (2011CB707500); Science and Technology Foundation of Guangdong(2010B030700016); The Medical Group Fund of Jinan University (88016013039).

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  1. Xueqin Yan, Zheng Gong and Rui Pan These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, school of Basic medical science and Public health, Jinan University, Guangzhou, 510632, Guangdong Province, China

    Xueqin Yan, Zheng Gong, Huili Wang, Haijie Tang, Hanyang He, Saixian Wen, Yongmei Fu & Jun Dong

  2. Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, Guangdong Province, China

    Jun Dong

  3. Department of Orthopedics, the First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong Province, China

    Rui Pan

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  1. Xueqin Yan
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Jun Dong designed research; Xueqin Yan, Zheng Gong, Rui Pan performed research; Huili Wang, Haijie Tang, Hanyang he, Saixian Wen, Yongmei Fu analyzed and interpreted the data. Xueqin Yan and Haijie Tang corrected English errors in paper. Xueqin Yan wrote the paper.

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Yan, X., Gong, Z., Pan, R. et al. Synergistic Effect and Mechanism of Apoptosis Induction by Morphine and the HIV-1gp120V3 Loop in Hippocampal Neurons. J Neuroimmune Pharmacol 17, 165–180 (2022). https://doi.org/10.1007/s11481-021-09989-0

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