Galdino Pablinny Moreira, de Oliveira Danillo Ramos, Florentino Iziara Ferreira, Fajemiroye James Oluwagbamigbe, Valadares Marize Campos, de Moura Soraia Santana, da Rocha Fábio Fagundes, de Lima Thereza Christina Monteiro, Costa Elson Alves, Menegatti Ricardo
Department of Pharmacology, Institute of Biological Sciences, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil; Center of Biological Sciences and Health, Federal University of Western Bahia, Barreiras, BA, Brazil.
Department of Pharmacology, Institute of Biological Sciences, Federal University of Goiás, Campus Samambaia, Goiânia, GO, Brazil.
Life Sci. 2015 Dec 15;143:187-93. doi: 10.1016/j.lfs.2015.11.009. Epub 2015 Nov 10.
Piperazinic derivatives have therapeutic potential by acting as analgesic, antidepressant-like, anticonvulsant and antipsychotic in preclinical studies. In order to develop new drugs to treat mental disorders, we designed and synthesized the 4-(1-phenyl-1H-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester (PPMP), a new piperazine derivative with putative activities on central nervous system that seems to involve serotonergic system.
In order to investigate the antidepressant-like activity of PPMP, mice were treated acutely and tested in the forced swimming test (FST) and tail suspension test. Pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., 4 days), and the non-selective blocker of catecholamine synthesis α-methyl para-tyrosine (AMPT, 100 mg/kg, i.p.) were used to assay the involvement of serotonergic and catecholaminergic systems. “Ex vivo” monoamine oxidase (MAO) enzymatic assay and quantification of hippocampal level of brain derived neurotrophic factor (BDNF) were carried out.
PPMP reduced the immobility time in both tests. PCPA or AMPT (100 mg/kg, i.p.) pretreatment blocked the effects of PPMP, thereby suggesting the involvement of serotonergic and catecholaminergic systems in the antidepressant-like effect of PPMP. PPMP did not inhibit the activity of MAO. Moreover, after 14 days of treatment, PPMP 15 mg/kg/day induced antidepressant-like effect and increased hippocampal level of BDNF. None of the treatments in this study altered the locomotor activity in the open field test.
In conclusion, PPMP demonstrates antidepressant-like effect that involve both serotonergic and catecholaminergic systems without inhibition of MAO activity. PPMP administration increased the hippocampal levels of BDNF.
在临床前研究中，哌嗪类衍生物具有镇痛、抗抑郁样、抗惊厥和抗精神病的治疗潜力。为了开发治疗精神障碍的新药，我们设计并合成了4-(1-苯基-1H-吡唑-4-基甲基)-哌嗪-1-羧酸乙酯（PPMP），这是一种新型哌嗪衍生物，对中枢神经系统具有假定活性，似乎涉及血清素能系统。
为了研究PPMP的抗抑郁样活性，对小鼠进行急性处理，并在强迫游泳试验（FST）和悬尾试验中进行测试。使用5-羟色胺合成抑制剂对氯苯丙氨酸（PCPA，100mg/kg，腹腔注射，4天）和儿茶酚胺合成的非选择性阻断剂α-甲基对酪氨酸（AMPT，100mg/kg，腹腔注射）来测定血清素能和儿茶酚胺能系统的参与情况。进行了“体外”单胺氧化酶（MAO）酶活性测定和海马脑源性神经营养因子（BDNF）水平的定量分析。
PPMP在两项试验中均减少了不动时间。PCPA或AMPT（100mg/kg，腹腔注射）预处理可阻断PPMP的作用，从而表明血清素能和儿茶酚胺能系统参与了PPMP的抗抑郁样作用。PPMP不抑制MAO的活性。此外，在治疗14天后，PPMP 15mg/kg/天可诱导抗抑郁样作用，并提高海马BDNF水平。本研究中的任何处理均未改变旷场试验中的运动活性。
总之，PPMP表现出抗抑郁样作用，涉及血清素能和儿茶酚胺能系统，且不抑制MAO活性。给予PPMP可提高海马BDNF水平。
