PMID- 30529228 OWN - NLM STAT- MEDLINE DCOM- 20190419 LR - 20190419 IS - 1095-9327 (Electronic) IS - 1044-7431 (Linking) VI - 94 DP - 2019 Jan TI - Melanocortin 4 receptor activation protects striatal neurons and glial cells from 3-nitropropionic acid toxicity. PG - 41-51 LID - S1044-7431(18)30302-6 [pii] LID - 10.1016/j.mcn.2018.12.002 [doi] AB - alpha-Melanocyte stimulating hormone (alpha-MSH) is a melanocortin which exerts potent anti-inflammatory and anti-apoptotic effects. Melanocortin 4 receptors (MC4R) are abundantly expressed in the brain and we previously demonstrated that [Nle(4), D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH), an alpha-MSH analogue, increased expression of brain derived-neurotrophic factor (BDNF), and peroxisome proliferator-activated receptor-gamma (PPAR-gamma). We hypothesized that melanocortins could affect striatal cell survival through BDNF and PPAR-gamma. First, we determined the expression of these factors in the striatum. Acute intraperitoneal administration (0.5 mg/kg) of alpha-MSH increased the levels of BDNF mRNA in rat striatum but not in rat cerebral cortex. Also, protein expression of PPAR-gamma and MC4R was increased by acute treatment with alpha-MSH in striatum but not in cortex. No changes were observed by 48 h treatment. Next, we evaluated melanocortins effect on neuron and glial survival. 3-nitropropionic acid (3-NP), which is known to induce striatal degeneration, was used to induce cell death in the rat striatal cell line ST14A expressing mutant human huntingtin (Q120) or in ST14A cells expressing normal human huntingtin (Q15), in primary cultured astrocytes, and in BV2 cells. NDP-MSH protected Q15 cells, astrocytes and BV2 cells from death by 3-NP whereas it did not fully protect Q120 cells. Protection of Q15 cells and astrocytes was blocked by a MC4R specific inhibitor (JKC-363) and a PPAR-gamma antagonist (GW9662). The BDNF receptor antagonist (ANA-12) abolished NDP-MSH protective effect in astrocytes but not in Q15 cells. We demonstrate for the first time that melanocortins, acting through PPAR-gamma and BDNF, protect neurons and glial cells from 3-NP toxicity. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Saba, Julieta AU - Saba J AD - Instituto de Investigaciones Biomedicas (INBIOMED) UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. FAU - Carniglia, Lila AU - Carniglia L AD - Instituto de Investigaciones Biomedicas (INBIOMED) UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. FAU - Ramirez, Delia AU - Ramirez D AD - Instituto de Investigaciones Biomedicas (INBIOMED) UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. FAU - Turati, Juan AU - Turati J AD - Instituto de Investigaciones Biomedicas (INBIOMED) UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. FAU - Imsen, Mercedes AU - Imsen M AD - Instituto de Investigaciones Biomedicas (INBIOMED) UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. FAU - Durand, Daniela AU - Durand D AD - Instituto de Investigaciones Biomedicas (INBIOMED) UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. FAU - Lasaga, Mercedes AU - Lasaga M AD - Instituto de Investigaciones Biomedicas (INBIOMED) UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. FAU - Caruso, Carla AU - Caruso C AD - Instituto de Investigaciones Biomedicas (INBIOMED) UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: ccaruso@fmed.uba.ar. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181204 PL - United States TA - Mol Cell Neurosci JT - Molecular and cellular neurosciences JID - 9100095 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Nitro Compounds) RN - 0 (Propionates) RN - 0 (Receptor, Melanocortin, Type 4) RN - 9002-79-3 (Melanocyte-Stimulating Hormones) RN - QY4L0FOX0D (3-nitropropionic acid) SB - IM MH - Animals MH - Astrocytes/*drug effects MH - Brain-Derived Neurotrophic Factor/metabolism MH - Melanocyte-Stimulating Hormones/drug effects MH - Neuroglia/*drug effects MH - Neurons/*drug effects MH - Nitro Compounds/*pharmacology MH - Propionates/*pharmacology MH - Rats, Wistar MH - Receptor, Melanocortin, Type 4/*metabolism OTO - NOTNLM OT - 3-NP OT - BDNF OT - Glia OT - MC4R OT - PPAR-gamma OT - ST14A OT - Striatum EDAT- 2018/12/12 06:00 MHDA- 2019/04/20 06:00 CRDT- 2018/12/12 06:00 PHST- 2018/10/22 00:00 [received] PHST- 2018/11/23 00:00 [revised] PHST- 2018/12/02 00:00 [accepted] PHST- 2018/12/12 06:00 [pubmed] PHST- 2019/04/20 06:00 [medline] PHST- 2018/12/12 06:00 [entrez] AID - S1044-7431(18)30302-6 [pii] AID - 10.1016/j.mcn.2018.12.002 [doi] PST - ppublish SO - Mol Cell Neurosci. 2019 Jan;94:41-51. doi: 10.1016/j.mcn.2018.12.002. Epub 2018 Dec 4.