Cholecystokinin-8 attenuates methamphetamine-induced inflammatory activation of microglial cells through CCK2
Hongyan Gou1, Donglei Sun2, Lijing Hao3
1Gastrointestinal cancer biology & therapeutics laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, PR China; Department of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Province, Shijiazhuang 050017, PR China.
Abstract:
Methamphetamine (METH) exposure reportedly promotes microglial activation and pro-inflammatory cytokines secretion. Sustained inflammation in abusers of psychostimulant drugs further induces neural damage. Cholecystokinin-8 (CCK-8) is a gut-brain peptide which exerts a wide range of biological activities in the gastrointestinal tract and central nervous system. We previously found that pre-treatment with CCK-8 inhibited behavioural and histologic changes typically induced by repeated exposure to METH. Here, we aimed to estimate the effects of CCK-8 on METH-induced neuro-inflammation, which is markedly characterized by microglia activation and increased pro-inflammatory cytokines production in vivo and in vitro. Moreover, we assessed the subtypes of the CCK receptor mediating the regulatory effects of CCK-8, and the changes in the NF-κB signalling pathway. We found that CCK-8 inhibited METH-induced microglial activation and IL-6 and TNF-α generation in vivo and in vitro in a dose-dependent manner. Furthermore, co-treatment of CCK-8 with METH significantly attenuated the activation of the NF-κB signalling pathway by activating the CCK2 receptor subtype in N9 cells. In conclusion, our findings indicated the inhibitory effect of CCK-8 on METH-induced neuro-inflammation in vivo and in vitro, and suggested the underlying mechanism may involve the activation of the CCK2 receptor, which downregulated the NF-κB signalling pathway induced by METH stimulation.
Insights
Cholecystokinin-8 (CCK-8) peptide reduces methamphetamine-induced neuroinflammation by inhibiting microglial activation and pro-inflammatory cytokine release. This effect is mediated through the CCK2 receptor and the NF-κB pathway.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Methamphetamine (METH) exposure triggers microglial activation and pro-inflammatory cytokine release, leading to neural damage.
- Sustained neuroinflammation is a hallmark of chronic psychostimulant abuse.
- Cholecystokinin-8 (CCK-8), a gut-brain peptide, has demonstrated neuroprotective effects in previous studies.
Purpose of the Study:
- To investigate the effects of CCK-8 on METH-induced neuroinflammation in vivo and in vitro.
- To identify the CCK receptor subtypes involved in CCK-8's regulatory actions.
- To elucidate the impact of CCK-8 on the NF-κB signaling pathway.
Main Methods:
- In vivo and in vitro models were used to assess METH-induced neuroinflammation.
- CCK-8 treatment was administered to evaluate its impact on microglial activation and cytokine production (IL-6, TNF-α).
- N9 cells were utilized to investigate CCK receptor subtypes and NF-κB pathway activation.
Main Results:
- CCK-8 dose-dependently inhibited METH-induced microglial activation and the generation of IL-6 and TNF-α.
- CCK-8 treatment attenuated METH-induced NF-κB signaling pathway activation in N9 cells.
- The CCK2 receptor subtype was identified as mediating the inhibitory effects of CCK-8.
Conclusions:
- CCK-8 exhibits inhibitory effects on METH-induced neuroinflammation, both in vivo and in vitro.
- The mechanism involves the activation of the CCK2 receptor, leading to the downregulation of the METH-induced NF-κB signaling pathway.
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