2. Academic Validation
  3. Methamphetamine regulates microglial polarization and glycolytic activity to promote Parkinson's disease through the LIPH/LPA/PI3K/AKT signaling axis

Methamphetamine regulates microglial polarization and glycolytic activity to promote Parkinson's disease through the LIPH/LPA/PI3K/AKT signaling axis

  • Int Immunopharmacol. 2026 Mar 15:173:116306. doi: 10.1016/j.intimp.2026.116306.
Yanghong Zou 1,  Chunhai Zhang 2,  Hui Bian 3,  Hao Fan 4,  Ailan Pang 5,  Yingwang Yuan 1,  Jinghui Li 6,  Xin Geng 7
Affiliations

Affiliations

  • 1 The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China; NHC Key Lab of Drug Addiction Medicine (Kunming Medical University), Kunming 650500, Yunnan, China.
  • 2 Department of Emergency Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China.
  • 3 Department of Physiology, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, Yunnan, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Kunming Medical University, Kunming 650500, Yunnan, China.
  • 5 NHC Key Lab of Drug Addiction Medicine (Kunming Medical University), Kunming 650500, Yunnan, China; Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China.
  • 6 The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China; NHC Key Lab of Drug Addiction Medicine (Kunming Medical University), Kunming 650500, Yunnan, China. Electronic address: [email protected].
  • 7 The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China; NHC Key Lab of Drug Addiction Medicine (Kunming Medical University), Kunming 650500, Yunnan, China. Electronic address: [email protected].
PMID: 41628513 DOI: 10.1016/j.intimp.2026.116306
Abstract

Background: The abuse of methamphetamine (METH) is associated with an increased risk of Parkinson's disease (PD), whereas microglial polarization and glucose metabolism disorders are closely related to the progression of PD. This study aimed to investigate the specific molecular mechanism underlying the promotion of PD progression by METH through the regulation of microglial polarization and glycolysis.

Methods: METH-induced C57BL/6 mice and BV2 cells were used to construct PD-like neurotoxicity animal and cell models for experimental investigation. Behavioral tests, immunohistochemistry and Nissl staining were used to assess the behavioral ability and neuronal damage of the Animals. The levels of related proteins, inflammatory cytokines and glycolysis were detected using immunofluorescence, ELISA, Western blotting, and CCK-8 assays.

Results: METH treatment significantly promoted behavioral disorders in PD mice, reduced the number of TH-positive neurons, and aggravated neuronal damage in the substantia nigra (SN). In addition, METH decreased the M2 marker proteins Arg-1 and CD206 and increased the M1 marker proteins iNOS and CD86; the proinflammatory cytokines TNF-α, IL-β, and IL-6; and glucose uptake, glucose consumption and lactic acid production, thus promoting M1 polarization and glycolytic activity in BV2 cells. In terms of the underlying molecular mechanism, METH treatment significantly increased the level of LPA. METH promotes LPA expression via upregulation of LIPH expression, and activates the PI3K/Akt pathway. Knockdown of LIPH or treatment with BrP-LPA reduces the ability of METH to promote M1 microglial polarization and glycolytic activity. Furthermore, the addition of the PI3K/Akt signaling pathway activator 740 YP weakened the inhibitory effect of BrP-LPA on the above process.

Conclusion: METH may promote M1 polarization and glycolytic activity in microglia by activating LIPH/LPA/PI3K/Akt signaling, thus promoting the progression of PD.

Keywords

Glycolysis; LIPH/LPA/PI3K/AKT signaling pathway; Methamphetamine; Microglial polarization; Parkinson's disease.

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