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Journal of Neuroimmune Pharmacology

, Volume 13, Issue 3, pp 396–411 | Cite as

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

  • Anna V. Sharikova
  • Elizabeth Quaye
  • Jun Yong Park
  • Maxwell C. Maloney
  • Habben Desta
  • Ramkumar Thiyagarajan
  • Kenneth L. Seldeen
  • Neil U. Parikh
  • Parteet Sandhu
  • Alexander Khmaladze
  • Bruce R. Troen
  • Stanley A. Schwartz
  • Supriya D. Mahajan
ORIGINAL ARTICLE

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.

Keywords

Apoptosis Mitochondria Microglia Methamphetamine Neurotoxicity Neuroinflammatory 

Notes

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.

Compliance with Ethical Standards

Conflict of Interest

Authors declare no conflict of interests.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Anna V. Sharikova
    • 1
  • Elizabeth Quaye
    • 2
  • Jun Yong Park
    • 1
  • Maxwell C. Maloney
    • 1
  • Habben Desta
    • 1
  • Ramkumar Thiyagarajan
    • 3
    • 4
  • Kenneth L. Seldeen
    • 3
    • 4
  • Neil U. Parikh
    • 2
  • Parteet Sandhu
    • 2
  • Alexander Khmaladze
    • 1
  • Bruce R. Troen
    • 3
    • 4
  • Stanley A. Schwartz
    • 2
  • Supriya D. Mahajan
    • 2
  1. 1.Department of PhysicsSUNY University at AlbanyAlbanyUSA
  2. 2.Department of Medicine, Division of Allergy, Immunology & RheumatologySUNY University at BuffaloBuffaloUSA
  3. 3.Division of Geriatrics and Palliative MedicineBuffaloUSA
  4. 4.Research ServiceVeterans Affairs Western New York Healthcare SystemBuffaloUSA

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