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Involvement of PUMA in pericyte migration induced by methamphetamine
Yanhong Zhang1, Yuan Zhang1, Ying Bai1
1Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
Abstract:
Mounting evidence indicates that methamphetamine causes blood-brain barrier damage, with emphasis on endothelial cells. The role of pericytes in methamphetamine-induced BBB damage remains unknown. Our study demonstrated that methamphetamine increased the migration of pericytes from the endothelial basement membrane. However, the detailed mechanisms underlying this process remain poorly understood. Thus, we examined the molecular mechanisms involved in methamphetamine-induced pericyte migration. The results showed that exposure of C3H/10T1/2 cells and HBVPs to methamphetamine increased PUMA expression via activation of the sigma-1 receptor, MAPK and Akt/PI3K pathways. Moreover, methamphetamine treatment resulted in the increased migration of C3H/10T1/2 cells and HBVPs. Knockdown of PUMA in pericytes transduced with PUMA siRNA attenuated the methamphetamine-induced increase in cell migration through attenuation of integrin and tyrosine kinase mechanisms, implicating a role of PUMA in the migration of C3H/10T1/2 cells and HBVPs. This study has demonstrated that methamphetamine-mediated pericytes migration involves PUMA up-regulation. Thus, targeted studies of PUMA could provide insights to facilitate the development of a potential therapeutic approach for alleviation of methamphetamine-induced pericyte migration.
Insights
Methamphetamine exposure increases pericyte migration by up-regulating PUMA, a protein crucial for cell movement. Targeting PUMA may offer therapies for methamphetamine-induced blood-brain barrier damage.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Methamphetamine use is linked to blood-brain barrier (BBB) damage, primarily affecting endothelial cells.
- The specific role of pericytes in methamphetamine-induced BBB dysfunction is not well understood.
- Pericytes are crucial for BBB integrity and function.
Purpose of the Study:
- To investigate the molecular mechanisms underlying methamphetamine-induced pericyte migration.
- To determine the role of PUMA (a pro-apoptotic protein) in pericyte migration.
- To explore potential therapeutic targets for mitigating methamphetamine's effects on the BBB.
Main Methods:
- Exposure of C3H/10T1/2 cells and human brain vascular pericytes (HBVPs) to methamphetamine.
- Analysis of PUMA expression and activation of sigma-1 receptor, MAPK, and Akt/PI3K pathways.
- Assessment of cell migration using in vitro assays and PUMA knockdown via siRNA.
Main Results:
- Methamphetamine exposure increased PUMA expression in pericytes through sigma-1 receptor, MAPK, and Akt/PI3K signaling.
- Methamphetamine treatment significantly enhanced pericyte migration.
- PUMA knockdown attenuated methamphetamine-induced pericyte migration by affecting integrin and tyrosine kinase pathways.
Conclusions:
- Methamphetamine-induced pericyte migration is mediated by PUMA up-regulation.
- PUMA plays a significant role in regulating pericyte migration in response to methamphetamine.
- Targeting PUMA presents a potential therapeutic strategy for addressing methamphetamine-induced BBB damage.