Abstract
Methamphetamine (MA), a psychostimulant drug has been associated with a variety of neurotoxic effects which are thought to be mediated by induction of pro-inflammatory cytokines/chemokines, oxidative stress and damage to blood-brain-barrier. Conversely, the ER stress-mediated apoptosis has been implicated in several neurodegenerative diseases. However, its involvement in MA-mediated neurodegenerative effects remains largely unexplored. The present study was undertaken to assess the effect of MA on ER stress and its possible involvement in apoptosis. For this purpose, SVGA astrocytes were treated with MA, which induced the expressions of BiP and CHOP at both, mRNA and protein levels. This phenomenon was also confirmed in HFA and various regions of mouse brain. Assessment of IRE1α, ATF6 and PERK pathways further elucidated the mechanistic details underlying MA-mediated ER stress. Knockdown of various intermediate molecules in ER stress pathways using siRNA demonstrated reduction in MA-mediated CHOP. Finally, MA-mediated apoptosis was demonstrated via MTT assay and TUNEL staining. The involvement of ER stress in the apoptosis was demonstrated with the help of MTT and TUNEL assays in the presence of siRNA against various ER stress proteins. The apoptosis also involved activation of caspase-3 and caspase-9, which was reversed by knockdown with various siRNAs. Altogether, this is the first report demonstrating mechanistic details responsible for MA-mediated ER stress and its role in apoptosis. This study provides a novel group of targets that can be explored in future for management of MA-mediated cell death and MA-associated neurodegenerative disorders.
Highlights
Methamphetamine (MA) is a potent psychostimulant drug that is widely abused worldwide including United States
The peak level of BiP and C/EBP homologous protein (CHOP) RNA were observed in cells treated with 500 μM MA (4.4 ± 0.2 fold for BiP and 2.6 ± 0.5 fold for CHOP)
The protein levels of BiP and CHOP were assessed at 12 H and 24 H, respectively, which showed peak expressions (2.1 ± 0.1 and 1.9 ± 0.1 fold for BiP and CHOP, respectively) with 500 μM MA (Figure 1G-1H)
Summary
Methamphetamine (MA) is a potent psychostimulant drug that is widely abused worldwide including United States. A 2013 study by National Survey on Drug Use and Health (NSDUH) has shown that over 12 million people (4.7 percent of the population) have tried methamphetamine at least once [1]. MA causes alterations in brain structure including gray matter loss, neuronal damage and microgliosis in various regions of the brain [8,9,10]. These changes in the brain have been attributed to oxidative stress [11], alteration in blood-brain barrier (BBB) integrity [12], mitochondrial dysfunction [13] and increased excitotoxicity [14]. The data from our laboratory have reported increase in proinflammatory cytokines and involvement of cytochrome P450 in MA-mediated oxidative stress as other possible mechanisms for MA-mediated neurotoxicity. [15, 16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
