title: Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin.
abstract: Methamphetamine (METH) causes irreversible damage to brain cells leading to neurological and psychiatric abnormalities. However, the mechanisms underlying life-threatening effects of acute METH intoxication remain unclear. Indeed, most of the hypotheses focused on intra-neuronal events, such as dopamine oxidation, oxidative stress and excitotoxicity. Yet, recent reports suggested that glia may contribute to METH-induced neuropathology. In the present study, we investigated the hippocampal dysfunction induced by an acute high dose of METH (30 mg/kg; intraperitoneal injection), focusing on the inflammatory process and changes in several neuronal structural proteins. For that, 3-month-old male wild-type C57BL/6J mice were killed at different time-points post-METH. We observed that METH caused an inflammatory response characterized by astrocytic and microglia reactivity, and tumor necrosis factor (TNF) system alterations. Indeed, glial fibrillary acidic protein (GFAP) and CD11b immunoreactivity were upregulated, likewise TNF-alpha and TNF receptor 1 protein levels. Furthermore, the effect of METH on hippocampal neurons was also investigated, and we observed a downregulation in beta III tubulin expression. To clarify the possible neuronal dysfunction induced by METH, several neuronal proteins were analysed. Syntaxin-1, calbindin D28k and tau protein levels were downregulated, whereas synaptophysin was upregulated. We also evaluated whether an anti-inflammatory drug could prevent or diminish METH-induced neuroinflammation, and we concluded that indomethacin (10 mg/kg; i.p.) prevented METH-induced glia activation and both TNF system and beta III tubulin alterations. In conclusion, we demonstrated that METH triggers an inflammatory process and leads to neuronal dysfunction in the hippocampus, which can be prevented by an anti-inflammatory treatment.
authors.affiliation: Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Gonçalves
authors.forename: Sofia
authors.initials: S
authors.lastname: Baptista
authors.forename: Tânia
authors.initials: T
authors.lastname: Martins
authors.forename: Nuno
authors.initials: N
authors.lastname: Milhazes
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Ribeiro
authors.forename: João O
authors.initials: JO
authors.lastname: Malva
authors.forename: Ana P
authors.initials: AP
authors.lastname: Silva
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D039481:CD11b Antigen / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D039481:CD11b Antigen; D000697:Central Nervous System Stimulants; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D050765:Qa-SNARE Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D008694:Methamphetamine; D051528:Guanylate Kinases; D007213:Indomethacin