Abstract
ABSTRACTBBC3 (BCL2 binding component 3) is a known apoptosis inducer; however, its role in microglial survival remains poorly understood. In addition to the classical transcription factor TRP53, Mir143 is involved in BBC3 expression at the post-transcriptional level. Here, we identify unique roles of Mir143-BBC3 in mediating microglial survival via the regulation of the interplay between apoptosis and autophagy. Autophagy inhibition accelerated methamphetamine-induced apoptosis, whereas autophagy induction attenuated the decrease in microglial survival. Moreover, anti-Mir143-dependent BBC3 upregulation reversed the methamphetamine-induced decrease in microglial survival via the regulation of apoptosis and autophagy. The in vivo relevance of these findings was confirmed in mouse models, which demonstrated that the microinjection of anti-Mir143 into the hippocampus ameliorated the methamphetamine-induced decrease in microglia as well as that observed in heterozygous Mir143+/− mice. These findings provide new insight regarding the specific contributions of Mir143-BBC3 to microglial survival in the context of drug abuse.
Highlights
Methamphetamine abuse is a major social and health concern
BBC3 has been intensively studied for many years, its role in the viability of microglia treated with methamphetamine has remained elusive
Our study provides new insights into the role of Mir[143] in the regulation of microglial survival: Mir[143] modulates BBC3 expression, which regulates the interplay of apoptosis and autophagy
Summary
Methamphetamine abuse is a major social and health concern. Methamphetamine is a popular addictive pharmacological psychostimulant of the central nervous system (CNS), and its use is associated with multiple neuropsychiatric adverse reactions as well as neurotoxicity to the dopaminergic and serotonergic systems of the brain.[1,2] Methamphetamine-induced neurotoxicity is associated with microglial activation that is thought to participate in either pro-toxic or protective mechanisms in the brain. Activated microglia secrete not onlyneurotrophic factors, thereby prolonging neuronal survival, and cytotoxic mediators, such as nitric oxide (NO), and cytokines, such as TNF and IL1B, that induce inflammation and neurotoxicity. Cytotoxic factors such as NO and pro-inflammatory cytokines that are secreted from activated microglia have been shown to mediate AICD through the regulation of apoptotic proteins, including caspases and the BCL2 family of proteins.[11] methamphetamine is known to induce microglial activation, whether methamphetamine induces AICD in microglia and the molecular mechanisms in this process remains elusive
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