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Methamphetamine Induces Apoptosis of Microglia via the Intrinsic Mitochondrial-Dependent Pathway

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Abstract

Methamphetamine (METH) is a drug of abuse, the acute and chronic use of which induces neurotoxic responses in the human brain, ultimately leading to neurocognitive disorders. Our goals were to understand the impact of METH on microglial mitochondrial respiration and to determine whether METH induces the activation of the mitochondrial-dependent intrinsic apoptosis pathway in microglia. We assessed the expression of pro- apoptosis genes using qPCR of RNA extracted from a human microglial cell line (HTHU). We examined the apoptosis-inducing effects of METH on microglial cells using digital holographic microscopy (DHM) to quantify real-time apoptotic volume decrease (AVD) in microglia in a noninvasive manner. METH treatment significantly increased AVD, activated Caspase 3/7, increased the gene expression levels of the pro- apoptosis proteins, APAF-1 and BAX, and decreased mitochondrial DNA content. Using immunofluorescence analysis, we found that METH increased the expression of the mitochondrial proteins cytochrome c and MCL-1, supporting the activation of mitochondrion-dependent (intrinsic) apoptosis pathway. Cellular bio-energetic flux analysis by Agilent Seahorse XF Analyzer revealed that METH treatment increased both oxidative and glycolytic respiration after 3 h, which was sustained for at least 24 h. Several events, such as oxidative stress, neuro-inflammatory responses, and mitochondrial dysfunction, may converge to mediate METH-induced apoptosis of microglia that may contribute to neurotoxicity of the CNS. Our study has important implications for therapeutic strategies aimed at preserving mitochondrial function in METH abusing patients.

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Acknowledgments

The authors acknowledge grant support from the Dr. Louis Sklarow Memorial Trust (SDM) and the Troup Fund of the Kaleida Health Foundations (SAS). The authors are grateful to Dr. Jonathan Karn, Chairman and Reinberger Professor of Molecular Biology, and Director of the CASE Center for AIDS Research, Case Western Reserve University, Cleveland, OH for the generous donation of the HTHU cell line.

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Authors and Affiliations

  1. Department of Physics, SUNY University at Albany, 1400 Washington Avenue, Albany, NY, 12222, USA

    Anna V. Sharikova, Jun Yong Park, Maxwell C. Maloney, Habben Desta & Alexander Khmaladze

  2. Department of Medicine, Division of Allergy, Immunology & Rheumatology, SUNY University at Buffalo, 6074 Clinical and Translational Research Center, 875 Ellicott St, Buffalo, NY, 14203, USA

    Elizabeth Quaye, Neil U. Parikh, Parteet Sandhu, Stanley A. Schwartz & Supriya D. Mahajan

  3. Division of Geriatrics and Palliative Medicine, 875 Ellicott Street, Buffalo, NY, 14203, USA

    Ramkumar Thiyagarajan, Kenneth L. Seldeen & Bruce R. Troen

  4. Research Service, Veterans Affairs Western New York Healthcare System, Buffalo, NY, 14240, USA

    Ramkumar Thiyagarajan, Kenneth L. Seldeen & Bruce R. Troen

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  1. Anna V. Sharikova
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  2. Elizabeth Quaye
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Correspondence to Supriya D. Mahajan.

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Sharikova, A.V., Quaye, E., Park, J.Y. et al. Methamphetamine Induces Apoptosis of Microglia via the Intrinsic Mitochondrial-Dependent Pathway. J Neuroimmune Pharmacol 13, 396–411 (2018). https://doi.org/10.1007/s11481-018-9787-4

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  • DOI: https://doi.org/10.1007/s11481-018-9787-4

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