α-Melanocyte stimulating hormone (α-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 α-MSH analogue, increased expression of brain derived-neurotrophic factor (BDNF), and peroxisome proliferator-activated receptor-γ (PPAR-γ). We hypothesized that melanocortins could affect striatal cell survival through BDNF and PPAR-γ. First, we determined the expression of these factors in the striatum. Acute intraperitoneal administration (0.5 mg/kg) of α-MSH increased the levels of BDNF mRNA in rat striatum but not in rat cerebral cortex. Also, protein expression of PPAR-γ and MC4R was increased by acute treatment with α-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-γ 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-γ and BDNF, protect neurons and glial cells from 3-NP toxicity.

α-黑素细胞刺激激素（α-MSH）是一种黑皮质素，具有强大的抗炎和抗凋亡作用。黑色素皮质素4受体（MC4R）在大脑中大量表达，我们先前证明了[Nle（4），D-Phe（7）]促黑素细胞激素（NDP-MSH），一种α-MSH类似物，增加了大脑的表达衍生神经营养因子（BDNF）和过氧化物酶体增殖物激活受体-γ（PPAR-γ）。我们假设黑皮质素可能通过BDNF和PPAR-γ影响纹状体细胞的存活。首先，我们确定这些因子在纹状体中的表达。急性腹膜内给予（0.5 mg / kg）的α-MSH可增加大鼠纹状体中BDNF mRNA的水平，但不会增加大鼠大脑皮层中的BDNF mRNA水平。同样，通过α-MSH的急性处理，纹状体中的PPAR-γ和MC4R的蛋白表达增加，而皮层中没有。48小时治疗未观察到变化。接下来，我们评估了黑皮质素对神经元和神经胶质生存的影响。已知会诱导纹状体变性的3-硝基丙酸（3-NP）被用于诱导大鼠纹状体细胞系ST14A表达突变的人类亨廷顿蛋白（Q120）或表达正常人亨廷顿蛋白（Q15）的ST14A细胞死亡，在原代培养的星形胶质细胞和BV2细胞中。NDP-MSH通过3-NP保护Q15细胞，星形胶质细胞和BV2细胞免于死亡，而NDP-MSH不能完全保护Q120细胞。Q15细胞和星形胶质细胞的保护被MC4R特异性抑制剂（JKC-363）和PPAR-γ拮抗剂（GW9662）阻断。BDNF受体拮抗剂（ANA-12）消除了星形胶质细胞中的NDP-MSH保护作用，但没有消除Q15细胞中的NDP-MSH保护作用。我们首次证明了黑皮质素通过PPAR-γ和BDNF发挥作用，