Abstract
Methamphetamine (METH), an extremely and widely abused illicit drug, can cause serious nervous system damage and social problems. Previous research has shown that METH use causes dopaminergic neuron apoptosis and astrocyte-related neuroinflammation. However, the relationship of astrocytes and neurons in METH-induced neurotoxicity remains unclear. We hypothesized that chemokine interleukin (IL) eight released by astrocytes and C-X-C motif chemokine receptor 1 (CXCR1) in neurons are involved in METH-induced neuronal apoptosis. We tested our hypothesis by examining the changes of CXCR1 in SH-SY5Y cells and in the brain of C57BL/6 mice exposed to METH by western blotting and immunolabeling. We also determined the effects of knocking down CXCR1 expression with small interfering ribonucleic acid (siRNA) on METH-exposed SH-SY5Y cells. Furthermore, we detected the expression levels of IL-8 and the nuclear factor-kappa B (NF-κB) pathway in U87MG cells and then co-cultured the two cell types to determine the role of CXCR1 and IL-8 in neuronal apoptosis. Our results indicated that METH exposure increased CXCR1 expression both in vitro and in vivo, with the effects obtained in vitro being dose-dependent. Silencing of CXCR1 expression with siRNAs reduced the expression of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), and other related proteins. In addition, IL-8 expression and release were increased in METH-exposed U87MG cells, which is regulated by NF-κB pathway. Neuronal apoptosis was attenuated by siCXCR1 after METH treatment in the co-cultured cells, which can be reversed after exposure to recombinant IL-8. These results demonstrate that CXCR1 plays an important role in neuronal apoptosis induced by METH and may be a potential target for METH-induced neurotoxicity therapy.Highlights –Methamphetamine exposure upregulated the expression of CXCR1.–Methamphetamine exposure increased the expression of interleukin-8 through nuclear factor-kappa B pathway.–Activation of CXCR1 by interleukin-8 induces an increase in methamphetamine-related neuronal apoptosis.
Highlights
Methamphetamine (METH) is a highly addictive psychoactive drug that can have a significant injurious effect on the central nervous system (CNS)
Our recent study showed that the regulation of chemokines through a nuclear factor-kappa B (NF-κB)/IL-8/C-X-C motif chemokine receptor 1 (CXCR1) pathway may play an important role in METH-induced neuronal apoptosis
In order to determine the role of CXCR1 in METH-triggered neurotoxicity, a mouse model treated with METH was used to detect the expression of CXCR1 in vivo
Summary
Methamphetamine (METH) is a highly addictive psychoactive drug that can have a significant injurious effect on the central nervous system (CNS). Our previous studies and other laboratories’ research found that METH can cause neuronal apoptosis through P53 upregulated modulator of apoptosis (PUMA), insulin-like growth factor-binding protein 5 (IGFBP5), and other pathways (Qiao et al, 2014; Carmena et al, 2015; Chen C. et al, 2016; Mendieta et al, 2016). The treatment of primary astrocytes with METH showed that the nuclear import of nuclear factor-kappa B (NF-κB) could be increased through Toll-like receptor 4, leading increased release of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18 (Du et al, 2017). Our recent study showed that the regulation of chemokines through a NF-κB/IL-8/C-X-C motif chemokine receptor 1 (CXCR1) pathway may play an important role in METH-induced neuronal apoptosis
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