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Published on: January 22, 2016
Methamphetamine-Triggered Neurotoxicity in Human Dorsolateral Prefrontal Cortex
Ali Zare1, Alireza Ghanbari1, Mohammad Javad Hoseinpour1
1Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
Background:
Methamphetamine (MA), is an extremely addictive stimulant that adversely affects the central nervous system. Accumulating evidence indicates that molecular mechanisms such as oxidative stress, apoptosis, and autophagy are involved in the toxicity of MA. Considering experimental animal studies exhibiting MA-induced neurotoxicity, the relevance of these findings needs to be evidently elucidated in human MA users. It is generally assumed that multiple chemical substances released in the brain following MA-induced metabolic activation are primary factors underlying damage of neural cells. Hence, this study aimed to investigate the role of autophagy and apoptosis as well as oxidative stress in the brain of postmortem MA-induced toxicity.
Materials And Methods:
In this study, we determine the gene expression of autophagy and apoptosis, including BECN1, MAP1ALC3, CASP8, TP53, and BAX genes in ten healthy controls and ten chronic users of MA postmortem dorsolateral prefrontal cortex (DLPFC) by real-time polymerase chain reaction. Also, we applied immunohistochemistry in formalin-fixed and paraffin-embedded human brain samples to analyze brain-derived neurotrophic factor (BDNF). Also, spectrophotometry was performed to measure glutathione (GSH) content.
Results:
The expression level of apoptotic and autophagic genes (BECN1, MAP1ALC3, CASP8, TP53, and BAX) were significantly elevated, while GSH content and BDNF showed substantial reductions in DLPFC of chronic MA users. Discussion: Our data showed that MA addiction provokes transduction pathways, namely apoptosis and autophagy, along with oxidative mechanisms in DLPFC. Also, MA induces multiple functional and structural perturbations in the brain, determining its toxicity and possibly contributing to neurotoxicity.
Discussion:
Our study showed BDNF-positive cells as well as GSH amount, displayed significant declines in DLPFC of MA user. MA addiction provokes transduction pathways, namely apoptosis and autophagy, along with oxidative mechanisms in DLPFC. However, further investigations are needed to throw light on the cellular and molecular mechanisms that act in the various regions of the addicted brain, especially in DLPFC.
Insights
Methamphetamine (MA) use significantly elevates genes involved in apoptosis and autophagy while decreasing protective factors like BDNF and GSH in the brain. These changes indicate MA addiction triggers neurotoxic pathways, including oxidative stress, in chronic users.
Area of Science:
- Neuroscience
- Molecular Biology
- Toxicology
Background:
- Methamphetamine (MA) is a highly addictive stimulant impacting the central nervous system.
- Evidence suggests MA toxicity involves oxidative stress, apoptosis, and autophagy.
- Translating findings from animal models to human MA users is crucial for understanding neurotoxicity.
Purpose of the Study:
- To investigate the roles of autophagy, apoptosis, and oxidative stress in postmortem brains of human MA users.
- To analyze gene expression of key apoptosis and autophagy markers.
- To assess levels of neuroprotective factors like BDNF and GSH.
Main Methods:
- Real-time PCR to quantify gene expression of BECN1, MAP1ALC3, CASP8, TP53, and BAX in DLPFC samples.
- Immunohistochemistry to analyze Brain-Derived Neurotrophic Factor (BDNF) expression.
- Spectrophotometry to measure Glutathione (GSH) content.
Main Results:
- Significantly elevated expression of apoptotic and autophagic genes (BECN1, MAP1ALC3, CASP8, TP53, BAX) was observed.
- Substantial reductions in GSH content and BDNF were found in chronic MA users.
- MA addiction was linked to activated apoptosis, autophagy, and oxidative stress pathways in the dorsolateral prefrontal cortex (DLPFC).
Conclusions:
- MA addiction induces apoptosis, autophagy, and oxidative stress in the human DLPFC.
- Decreased BDNF and GSH levels suggest impaired neuroprotection in MA users.
- Further research is needed to fully elucidate the molecular mechanisms of MA neurotoxicity in different brain regions.
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