Metabolic Brain Disease

, Volume 34, Issue 1, pp 61–69 | Cite as

Role of PUMA in the methamphetamine-induced migration of microglia

  • Lei Zhao
  • Longfei Du
  • Yanhong Zhang
  • Jie Chao
  • Ming Duan
  • Honghong Yao
  • Chuanlu Shen
  • Yuan ZhangEmail author
Original Article


In this study, we demonstrated that PUMA was involved in the microglial migration induced by methamphetamine. PUMA expression was examined by western blotting and immunofluorescence staining. BV2 and HAPI cells were pretreated with a sigma-1R antagonist and extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), c-Jun N-terminal protein kinase (JNK), and phosphatidylinositol-3 kinase (PI3K)/Akt inhibitors, and PUMA expression was detected by western blotting. The cell migration in BV2 and HAPI cells transfected with a lentivirus encoding red fluorescent protein (LV-RFP) was also examined using a wound-healing assay and nested matrix model and cell migration assay respectively. The molecular mechanisms of PUMA in microglial migration were validated using a siRNA approach. The exposure of BV2 and HAPI cells to methamphetamine increased the expression of PUMA, reactive oxygen species (ROS), the MAPK and PI3K/Akt pathways and the downstream transcription factor signal transducer and activator of transcription 3 (STAT3) pathways. PUMA knockdown in microglia transfected with PUMA siRNA attenuated the increased cell migration induced by methamphetamine, thereby implicating PUMA in the migration of BV2 and HAPI cells. This study demonstrated that methamphetamine-induced microglial migration involved PUMA up-regulation. Targeting PUMA could provide insights into the development of a potential therapeutic approach for the alleviation of microglia migration induced by methamphetamine.


PUMA Methamphetamine Microglia Migration 



This work was supported by grants from the National Natural Science Foundation of China (No. 81322048 and No. 81473190).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.


  1. Chipuk JE, Bouchier-Hayes L, Kuwana T, Newmeyer DD, Green DR (2005) PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science (New York, NY) 309:1732–1735. CrossRefPubMedGoogle Scholar
  2. Cregan SP, Arbour NA, Maclaurin JG, Callaghan SM, Fortin A, Cheung EC, Guberman DS, Park DS, Slack RS (2004) p53 activation domain 1 is essential for PUMA upregulation and p53-mediated neuronal cell death. J Neurosci Off J Soc Neurosci 24:10003–10012. CrossRefGoogle Scholar
  3. Deguchi A (2015) Curcumin targets in inflammation and cancer. Endocr Metab Immune Disord Drug Targets 15:88–96CrossRefGoogle Scholar
  4. Gekker G, Hu S, Sheng WS, Rock RB, Lokensgard JR, Peterson PK (2006) Cocaine-induced HIV-1 expression in microglia involves sigma-1 receptors and transforming growth factor-beta1. Int Immunopharmacol 6:1029–1033. CrossRefPubMedGoogle Scholar
  5. Gonzalez B, Raineri M, Cadet JL, Garcia-Rill E, Urbano FJ, Bisagno V (2014) Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex ERK signaling in mice. Neuropharmacology 87:188–197. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Harro J (2015) Neuropsychiatric adverse effects of amphetamine and methamphetamine. Int Rev Neurobiol 120:179–204. CrossRefPubMedGoogle Scholar
  7. Hickman SE, El Khoury J (2010) Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. CNS Neurol Disord Drug Targets 9:168–173CrossRefGoogle Scholar
  8. Hikisz P, Kilianska ZM (2012) PUMA, a critical mediator of cell death--one decade on from its discovery. Cell Mol Biol Lett 17:646–669. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Krasnova IN, Justinova Z, Cadet JL (2016) Methamphetamine addiction: involvement of CREB and neuroinflammatory signaling pathways. Psychopharmacology 233:1945–1962. CrossRefPubMedPubMedCentralGoogle Scholar
  10. LeComte MD, Shimada IS, Sherwin C, Spees JL (2015) Notch1-STAT3-ETBR signaling axis controls reactive astrocyte proliferation after brain injury. Proc Natl Acad Sci U S A 112:8726–8731. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Li X, Liu S, Luo J, Liu A, Tang S, Liu S, Yu M, Zhang Y (2015) Helicobacter pylori induces IL-1beta and IL-18 production in human monocytic cell line through activation of NLRP3 inflammasome via ROS signaling pathway. Pathog Dis 73.
  12. Liao K, Guo M, Niu F, Yang L, Callen SE, Buch S (2016) Cocaine-mediated induction of microglial activation involves the ER stress-TLR2 axis. J Neuroinflammation 13:33. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Liu S, Mi WL, Li Q, Zhang MT, Han P, Hu S, Mao-Ying QL, Wang YQ (2015) Spinal IL-33/ST2 signaling contributes to neuropathic pain via neuronal CaMKII-CREB and Astroglial JAK2-STAT3 cascades in mice. Anesthesiology 123:1154–1169. CrossRefPubMedGoogle Scholar
  14. Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354–365. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Ma J, Wan J, Meng J, Banerjee S, Ramakrishnan S, Roy S (2014) Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the kappa opioid receptor. Cell Death Dis 5:e1099. CrossRefPubMedPubMedCentralGoogle Scholar
  16. McConnell SE, O'Banion MK, Cory-Slechta DA, Olschowka JA, Opanashuk LA (2015) Characterization of binge-dosed methamphetamine-induced neurotoxicity and neuroinflammation. Neurotoxicology 50:131–141. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Muhl H (2016) STAT3, a key parameter of cytokine-driven tissue protection during sterile inflammation - the case of experimental acetaminophen (paracetamol)-induced liver damage. Front Immunol 7:163. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Peri F, Nusslein-Volhard C (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133:916–927. CrossRefPubMedGoogle Scholar
  19. Riddle EL, Fleckenstein AE, Hanson GR (2006) Mechanisms of methamphetamine-induced dopaminergic neurotoxicity. AAPS J 8:E413–E418CrossRefGoogle Scholar
  20. Robson MJ, Turner RC, Naser ZJ, McCurdy CR, Huber JD, Matsumoto RR (2013) SN79, a sigma receptor ligand, blocks methamphetamine-induced microglial activation and cytokine upregulation. Exp Neurol 247:134–142. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Rostasy KM (2005) Inflammation and neuroaxonal injury in multiple sclerosis and AIDS dementia complex: implications for neuroprotective treatment. Neuropediatrics 36:230–239. CrossRefPubMedGoogle Scholar
  22. Saika F, Kiguchi N, Kishioka S (2015) The role of CC-chemokine ligand 2 in the development of psychic dependence on methamphetamine. Nihon Arukoru Yakubutsu Igakkai Zasshi 50:189–195PubMedGoogle Scholar
  23. Seminerio MJ, Robson MJ, McCurdy CR, Matsumoto RR (2012) Sigma receptor antagonists attenuate acute methamphetamine-induced hyperthermia by a mechanism independent of IL-1beta mRNA expression in the hypothalamus. Eur J Pharmacol 691:103–109. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Sharma HS, Kiyatkin EA (2009) Rapid morphological brain abnormalities during acute methamphetamine intoxication in the rat: an experimental study using light and electron microscopy. J Chem Neuroanat 37:18–32. CrossRefPubMedGoogle Scholar
  25. Shi JX, Wang QJ, Li H, Huang Q (2016) Silencing of USP22 suppresses high glucose-induced apoptosis, ROS production and inflammation in podocytes. Mol BioSyst 12:1445–1456. CrossRefPubMedGoogle Scholar
  26. Shin EJ, Shin SW, Nguyen TTL, Park DH, Wie MB, Jang CG, Nah SY, Yang BW, Ko SK, Nabeshima T, Kim HC (2014) Ginsenoside re rescues methamphetamine-induced oxidative damage, mitochondrial dysfunction, microglial activation, and dopaminergic degeneration by inhibiting the protein kinase Cdelta gene. Mol Neurobiol 49:1400–1421. CrossRefPubMedGoogle Scholar
  27. Thomas DM, Dowgiert J, Geddes TJ, Francescutti-Verbeem D, Liu X, Kuhn DM (2004) Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines. Neurosci Lett 367:349–354. CrossRefPubMedGoogle Scholar
  28. Vavrova J, Rezacova M (2014) Importance of proapoptotic protein PUMA in cell radioresistance. Folia Biol 60:53–56Google Scholar
  29. Venneti S, Wiley CA, Kofler J (2009) Imaging microglial activation during neuroinflammation and Alzheimer's disease. J Neuroimmune Pharmacol 4:227–243. CrossRefPubMedGoogle Scholar
  30. Vousden KH (2005) Apoptosis. p53 and PUMA: a deadly duo. Science (New York, NY) 309:1685–1686. CrossRefPubMedGoogle Scholar
  31. Wake H, Moorhouse AJ, Miyamoto A, Nabekura J (2013) Microglia: actively surveying and shaping neuronal circuit structure and function. Trends Neurosci 36:209–217. CrossRefPubMedGoogle Scholar
  32. Wang SF, Yen JC, Yin PH, Chi CW, Lee HC (2008) Involvement of oxidative stress-activated JNK signaling in the methamphetamine-induced cell death of human SH-SY5Y cells. Toxicology 246:234–241. CrossRefPubMedGoogle Scholar
  33. Wang W, Liu H, Dai X, Fang S, Wang X, Zhang Y, Yao H, Zhang X, Chao J (2015) p53/PUMA expression in human pulmonary fibroblasts mediates cell activation and migration in silicosis. Sci Rep 5:16900. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Xiong XY, Liu L, Yang QW (2016) Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol 142:23–44. CrossRefPubMedGoogle Scholar
  35. Yao H, Ma R, Yang L, Hu G, Chen X, Duan M, Kook Y, Niu F, Liao K, Fu M, Hu G, Kolattukudy P, Buch S (2014) MiR-9 promotes microglial activation by targeting MCPIP1. Nat Commun 5:4386. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Yao H, Yang Y, Kim KJ, Bethel-Brown C, Gong N, Funa K, Gendelman HE, Su TP, Wang JQ, Buch S (2010) Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: implication for increased monocyte transmigration. Blood 115:4951–4962. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Yuan Y, Fang M, Wu CY, Ling EA (2016) Scutellarin as a potential therapeutic agent for microglia-mediated Neuroinflammation in cerebral ischemia. NeuroMolecular Med 18:264–273. CrossRefPubMedGoogle Scholar
  38. Zhang Y, Lv X, Bai Y, Zhu X, Wu X, Chao J, Duan M, Buch S, Chen L, Yao H (2015) Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression. J Neuroinflammation 12:29. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Lei Zhao
    • 1
  • Longfei Du
    • 1
  • Yanhong Zhang
    • 1
  • Jie Chao
    • 2
  • Ming Duan
    • 3
  • Honghong Yao
    • 1
    • 4
  • Chuanlu Shen
    • 5
  • Yuan Zhang
    • 1
    Email author
  1. 1.Department of PharmacologyMedical School of Southeast University, Southeast UniversityNanjingChina
  2. 2.Department of PhysiologyMedical School of Southeast University, Southeast UniversityNanjingChina
  3. 3.Key Laboratory for Zoonosis Research, Ministry of EducationJilin UniversityChangchunChina
  4. 4.Institute of Life Sciences, Key Laboratory of Developmental Genes and Human DiseaseSoutheast UniversityNanjingChina
  5. 5.Department of PathophysiologyMedical School of Southeast University, Southeast UniversityNanjingChina

Personalised recommendations