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Published on: June 29, 2011
Role of CXCR1 and Interleukin-8 in Methamphetamine-Induced Neuronal Apoptosis
Si-Hao Du1, Wei Zhang1, Xia Yue1
1School of Forensic Medicine, Southern Medical University, Guangzhou, China.
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.
Insights
Methamphetamine (METH) abuse damages the nervous system. This study shows METH increases chemokine receptor CXCR1 and interleukin-8, leading to neuronal apoptosis, suggesting CXCR1 as a therapeutic target for METH neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Methamphetamine (METH) abuse causes significant neurotoxicity, including dopaminergic neuron apoptosis and neuroinflammation.
- The precise mechanisms linking astrocytes and neurons in METH-induced neurotoxicity remain incompletely understood.
- Chemokines like interleukin-8 (IL-8) and their receptors, such as C-X-C motif chemokine receptor 1 (CXCR1), are implicated in inflammatory and apoptotic processes.
Purpose of the Study:
- To investigate the role of astrocyte-derived IL-8 and neuronal CXCR1 in METH-induced neuronal apoptosis.
- To elucidate the signaling pathways involved, specifically the nuclear factor-kappa B (NF-κB) pathway in IL-8 regulation.
- To evaluate CXCR1 as a potential therapeutic target for mitigating METH neurotoxicity.
Main Methods:
- Examined CXCR1 expression in METH-exposed SH-SY5Y cells and C57BL/6 mouse brains using western blotting and immunolabeling.
- Utilized small interfering ribonucleic acid (siRNA) to knockdown CXCR1 expression in METH-exposed cells.
- Detected IL-8 and NF-κB pathway activation in METH-exposed U87MG cells and co-cultured systems.
- Assessed neuronal apoptosis markers (cleaved caspase-3, cleaved PARP) and the effect of IL-8 stimulation.
Main Results:
- METH exposure significantly upregulated CXCR1 expression in vitro and in vivo, with a dose-dependent effect in cells.
- Knockdown of CXCR1 using siRNA reduced METH-induced expression of apoptosis-related proteins.
- METH increased IL-8 expression and release in astrocytes via the NF-κB pathway.
- Blocking CXCR1 attenuated METH-induced neuronal apoptosis in co-cultures, an effect reversible by adding recombinant IL-8.
Conclusions:
- CXCR1 plays a critical role in mediating METH-induced neuronal apoptosis.
- The IL-8/CXCR1 axis, regulated by the NF-κB pathway in astrocytes, contributes significantly to METH neurotoxicity.
- Targeting CXCR1 presents a promising therapeutic strategy for METH-induced neurotoxicity.
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