Manosso Luana M, Moretti Morgana, Ribeiro Camille M, Gonçalves Filipe M, Leal Rodrigo B, Rodrigues Ana Lúcia S
Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis 88040-900, SC, Brazil.
Department of Natural Sciences, Universidade Regional de Blumenau, Blumenau 89012-900, SC, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jun 3;59:59-67. doi: 10.1016/j.pnpbp.2015.01.008. Epub 2015 Jan 17.
Considering that intracellular signaling pathways that modulate brain BDNF are implicated in antidepressant responses, this study investigated whether signaling pathway inhibitors upstream to BDNF might influence the antidepressant-like effect of zinc, a metal that has been shown to display antidepressant properties. To this end, the influence of i.c.v. administration of H-89 (1μg/site, PKA inhibitor), KN-62 (1μg/site, CAMKII inhibitor), chelerythrine (1μg/site, PKC inhibitor), PD98059 (5μg/site, MEK1/2 inhibitor), U0126 (5μg/site, MEK1/2 inhibitor), LY294002 (10nmol/site, PI3K inhibitor) on the reduction of immobility time in the tail suspension test (TST) elicited by ZnCl2 (10mg/kg, p.o.) was investigated. Moreover, the effect of the combination of sub-effective doses of ZnCl2 (1mg/kg, p.o.) and AR-A014418 (0.001μg/site, GSK-3β inhibitor) was evaluated. The occurrence of changes in CREB phosphorylation and BDNF immunocontent in the hippocampus and prefrontal cortex of mice following ZnCl2 treatment was also investigated. The anti-immobility effect of ZnCl2 in the TST was prevented by treatment with PKA, PKC, CAMKII, MEK1/2 or PI3K inhibitors. Furthermore, ZnCl2 in combination with AR-A014418 caused a synergistic anti-immobility effect in the TST. None of the treatments altered locomotor activity of mice. ZnCl2 treatment caused no alteration in CREB phosphorylation and BDNF immunocontent. The results extend literature data regarding the mechanisms underlying the antidepressant-like action of zinc by indicating that its antidepressant-like effect may be dependent on the activation of PKA, CAMKII, PKC, ERK, and PI3K/GSK-3β pathways. However, zinc is not able to acutely increase BDNF in the hippocampus and prefrontal cortex.
鉴于调节脑源性神经营养因子（BDNF）的细胞内信号通路与抗抑郁反应有关，本研究调查了BDNF上游的信号通路抑制剂是否可能影响锌的抗抑郁样作用，锌这种金属已被证明具有抗抑郁特性。为此，研究了脑室内注射H-89（1μg/部位，蛋白激酶A（PKA）抑制剂）、KN-62（1μg/部位，钙/钙调蛋白依赖性蛋白激酶II（CAMKII）抑制剂）、白屈菜红碱（1μg/部位，蛋白激酶C（PKC）抑制剂）、PD98059（5μg/部位，丝裂原活化蛋白激酶/细胞外信号调节激酶1/2（MEK1/2）抑制剂）、U0126（5μg/部位，MEK1/2抑制剂）、LY294002（10nmol/部位，磷脂酰肌醇-3激酶（PI3K）抑制剂）对氯化锌（10mg/kg，口服）引起的悬尾试验（TST）中不动时间减少的影响。此外，还评估了亚有效剂量的氯化锌（1mg/kg，口服）和AR-A014418（0.001μg/部位，糖原合成酶激酶-3β（GSK-3β）抑制剂）联合使用的效果。还研究了氯化锌处理后小鼠海马体和前额叶皮质中cAMP反应元件结合蛋白（CREB）磷酸化和BDNF免疫含量的变化。PKA、PKC、CAMKII、MEK1/2或PI3K抑制剂处理可阻止氯化锌在TST中的抗不动作用。此外，氯化锌与AR-A014418联合使用在TST中产生了协同抗不动作用。所有处理均未改变小鼠的运动活性。氯化锌处理未引起CREB磷酸化和BDNF免疫含量的改变。这些结果扩展了关于锌抗抑郁样作用潜在机制的文献数据，表明其抗抑郁样作用可能依赖于PKA、CAMKII、PKC、细胞外信号调节激酶（ERK）和PI3K/GSK-3β信号通路的激活。然而，锌不能急性增加海马体和前额叶皮质中的BDNF。
