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Protective role of neuropeptide Y Y2 receptors in cell death and microglial response following methamphetamine injury

Authors

  • Joana Gonçalves,

    1. Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 – Polo 3, Azinhaga de Santa Comba, Celas, 3000-354 Coimbra, Portugal
    2. Institute of Biomedical Research on Light and Image (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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  • Carlos F. Ribeiro,

    1. Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 – Polo 3, Azinhaga de Santa Comba, Celas, 3000-354 Coimbra, Portugal
    2. Institute of Biomedical Research on Light and Image (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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  • João O. Malva,

    1. Laboratory of Biochemistry and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
    2. Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
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  • Ana P. Silva

    1. Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 – Polo 3, Azinhaga de Santa Comba, Celas, 3000-354 Coimbra, Portugal
    2. Institute of Biomedical Research on Light and Image (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Dr A. P. Silva, 1Laboratory of Pharmacology and Experimental Therapeutics, as above.
E-mail: apmartins@fmed.uc.pt

Abstract

It has been reported that the hippocampus is very susceptible to methamphetamine (METH) and that neuropeptide Y (NPY) is an important neuroprotective agent against hippocampal excitotoxicity. However, there is very little information regarding the role of the NPYergic system in this brain region under conditions of METH toxicity. To clarify this issue, we investigated the role of NPY and its receptors against METH-induced neuronal cell death in hippocampal organotypic slice cultures. Our data show that NPY (1 μm) is neuroprotective in DG, CA3 and CA1 subregions via Y2 receptors. Moreover, the selective activation of Y1 receptors (1 μm [Leu31,Pro34]NPY) partially prevented the toxicity induced by METH in DG and CA3 subfields, but completely blocked its toxicity in the CA1 pyramidal cell layer. Regarding Y2 receptors, its activation (300 nm NPY13–36) completely prevented METH-induced toxicity in all subregions analysed, which involved changes in levels of pro- and anti-apoptotic proteins Bcl-2 and Bax, respectively. Besides neuronal cell death, we also showed that METH triggers a microglial response in the mouse hippocampus which was attenuated by Y2 receptor activation. To better clarify the effect of METH and the NPY system on microglial cells, we further used the N9 microglial cell line. We found that both NPY and the Y2 receptor agonist were able to protect microglia against METH-induced cell death. Overall, our data demonstrate that METH is toxic to both neurons and microglial cells, and that NPY, mainly via Y2 receptors, has an important protective role against METH-induced cell death and microgliosis.

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