Antidepressant phenotype by inhibiting the phospholipase Cβ1 - Protein kinase Cγ pathway in the forced swim
Antidepressant phenotype by inhibiting the phospholipase Cβ1 - Protein kinase Cγ pathway in the forced swim
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DOI：
10.1016/j.neuropharm.2011.01.037
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发表时间：
2011-05-01
影响因子：
4.7
通讯作者：
Ghelardini, Carla
中科院分区：
文献类型：
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作者：
Galeotti, Nicoletta;Ghelardini, Carla
虽然近年来对信号转导的研究取得了很大进展，但情感性精神障碍的发病机制仍不清楚。越来越多的证据表明，磷酸肌醇-蛋白激酶C（PI-PKC）信号转导通路的升高可能是双相情感障碍和抑郁症的一个病理生理特征。本研究的目的是进一步研究磷脂酶C-蛋白激酶C（PLC-PKC）级联反应，通过评估在PLC和PKC水平上急性阻断该细胞内途径所产生的影响。成年雄性小鼠给予PLC或PKC的药理学抑制剂，然后进行强迫游泳试验（FST），这是一种模拟抑郁症行为绝望范式的动物模型。在这项研究中，我们还测试了这一假设，它可能是有可能选择性地调节抑郁症的行为，通过抑制特定的PLC和PKC亚型的表达，通过特定的反义寡核苷酸（aODNs）。PLC抑制剂新霉素和U 73122以及PKC抑制剂calphostin C和白屈菜碱的给药剂量依赖性地减少了FST产生抗抑郁样行为的不动时间。PLC β（1）和PKC γ亚型的选择性敲低也诱导了抗抑郁表型。相反，抑制PLC β（3）的表达不能改变不动时间值。在最高有效剂量下使用的PLC和PKC调节剂既不改变自发活动也不改变运动协调。我们证明，选择性阻断PLC β（1）-PKC γ信号通路在小鼠中产生抗抑郁药样表型。(C)2011爱思唯尔有限公司版权所有。
Although great advances have recently been made in the study of signal transduction, the pathogenesis of affective disorders is still unknown. There is mounting evidence suggesting that elevated phosphoinositide-protein kinase C (PI-PKC) signal transduction pathway may be a pathophysiological feature of bipolar and major depressive disorders. The aim of the present study was to further investigated the phospholipase C-protein kinase C (PLC-PKC) cascade by evaluating the effect produced by an acute blockade of this intracellular pathway at PLC and PKC level. Adult male mice were administered with pharmacological inhibitors of PLC or PKC and then subjected to the forced swim test (FST), an animal model which emulates the behavioural despair paradigm of depression. In this study we also tested the hypothesis that it might be possible to selectively modulate depressive behaviour by inhibiting the expression of specific PLC and PKC isoforms by means of specific antisense oligonucleotides (aODNs). Administration of the PLC inhibitors neomycin and U73122 as well as of the PKC inhibitors calphostin C and chelerytrine dose-dependently reduced the immobility time in the FST producing an antidepressant-like behaviour. Selective knockdown of the PLC beta(1) and PKC gamma isoforms also induced an antidepressant phenotype. Conversely, the inhibition of the expression of PLC beta(3) was unable to modify the immobility time values. The PLC and PKC modulators used, at the highest effective doses, altered neither locomotor activity nor motor coordination. We demonstrate that selective blockade of PLC beta(1)-PKC gamma signalling pathway produces an antidepressant-like phenotype in mice. (C) 2011 Elsevier Ltd. All rights reserved.