The Histamine H3 Receptor Antagonist E159 Reverses Memory Deficits Induced by Dizocilpine in Passive Avoidance and Novel Object Recognition Paradigm in Rats.
The Histamine H3 Receptor Antagonist E159 Reverses Memory Deficits Induced by Dizocilpine in Passive Avoidance and Novel Object Recognition Paradigm in Rats.
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DOI：
10.3389/fphar.2017.00709
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发表时间：
2017
影响因子：
5.6
通讯作者：
Sadek B
中科院分区：
文献类型：
--
作者：
Alachkar A;Łażewska D;Kieć-Kononowicz K;Sadek B
组胺 H3 受体 (H3R) 与记忆的关系是众所周知的，并且 H3R 拮抗剂在治疗神经精神疾病（例如阿尔茨海默病 (AD)）方面的潜力也已得到充分证实。因此，在被动回避范式（PAP）和新物体识别（NOR）中，使用匹托利桑（PIT）和多奈哌齐（DOZ）作为标准药物，研究了组胺 H3 受体（H3R）拮抗剂 E159（2.5-10 mg/kg，腹腔注射）对成年雄性大鼠地佐西平（DIZ）诱导的记忆缺陷的影响。以三种不同剂量（即 2.5、5 和 10 mg/kg，腹腔注射）对 E159 进行急性全身预处理后，2.5 和 5 mg/kg（但不是 10 mg/kg）的 E159 抵消了 DIZ（0.1 mg）诱导的记忆缺陷，并且这种 E159（2.5 mg）在 DIZ 诱导的遗忘模型中引起的记忆改善作用在急性治疗后被适度消除。给动物全身施用东莨菪碱(SCO)、H2R拮抗剂唑兰替丁(ZOL)，但不能与H1R拮抗剂吡拉明一起全身施用。此外，当动物同时服用 SCO 和 ZOL 时，观察到的 E159（2.5 mg/kg，腹腔注射）的记忆增强作用被强烈消除。此外，E159 (2.5 mg) 对 DIZ 诱导的 NOR 短期记忆 (STM) 损伤具有显着的记忆改善作用，与 DOZ 提供的记忆增强作用相当，但当动物注射 CNS 渗透性组胺 H3R 激动剂 R-(α)-甲基组胺 (RAMH) 时，该作用被消除。然而，2.5 mg/kg 剂量的 E159 未能对 NOR 中 DIZ 诱导的长期记忆 (LTM) 表现出预知作用。此外，观察到的结果显示，E159 (2.5 mg/kg) 不会改变初次接触高架十字迷宫 (EPM) 的动物的焦虑水平和运动活动，表明 E159 (2.5 mg/kg) 在 PAP 或 NOR 中的表现改善与情绪反应或自发运动活动的变化无关。这些结果为靶向 H3R 的药物治疗神经精神疾病（例如 AD）的潜力提供了证据。
The involvement of histamine H3 receptors (H3Rs) in memory is well known, and the potential of H3R antagonists in therapeutic management of neuropsychiatric diseases, e.g., Alzheimer disease (AD) is well established. Therefore, the effects of histamine H3 receptor (H3R) antagonist E159 (2.5–10 mg/kg, i.p.) in adult male rats on dizocilpine (DIZ)-induced memory deficits were studied in passive avoidance paradigm (PAP) and in novel object recognition (NOR) using pitolisant (PIT) and donepezil (DOZ) as standard drugs. Upon acute systemic pretreatment of E159 at three different doses, namely 2.5, 5, and 10 mg/kg, i.p., 2.5 and 5 but not 10 mg/kg of E159 counteracted the DIZ (0.1 mg)-induced memory deficits, and this E159 (2.5 mg)-elicited memory-improving effects in DIZ-induced amnesic model were moderately abrogated after acute systemic administration of scopolamine (SCO), H2R antagonist zolantidine (ZOL), but not with H1R antagonist pyrilamine to the animals. Moreover, the observed memory-enhancing effects of E159 (2.5 mg/kg, i.p.) were strongly abrogated when animals were administered with a combination of SCO and ZOL. Furthermore, the E159 (2.5 mg)-provided significant memory-improving effect of in DIZ-induced short-term memory (STM) impairment in NOR was comparable to the DOZ-provided memory-enhancing effect, and was abolished when animals were injected with the CNS-penetrant histamine H3R agonist R-(α)-methylhistamine (RAMH). However, E159 at a dose of 2.5 mg/kg failed to exhibit procognitive effect on DIZ-induced long-term memory (LTM) in NOR. Furthermore, the results observed revealed that E159 (2.5 mg/kg) did not alter anxiety levels and locomotor activity of animals naive to elevated-plus maze (EPM), demonstrating that improved performances with E159 (2.5 mg/kg) in PAP or NOR are unrelated to changes in emotional responding or in spontaneous locomotor activity. These results provide evidence for the potential of drugs targeting H3Rs for the treatment of neuropsychiatric disorders, e.g., AD.
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影响因子：
2.7
作者：
Giovannini, MG;Bartolini, L;Blandina, P
通讯作者：
Blandina, P
影响因子：
2.7
作者：
Brabant, Christian;Charlier, Yana;Tirelli, Ezio
通讯作者：
Tirelli, Ezio
影响因子：
2.7
作者：
de Lima, MNM;Laranja, DC;Schröder, N
通讯作者：
Schröder, N
影响因子：
2.7
作者：
ENNACEUR, A;DELACOUR, J
通讯作者：
DELACOUR, J
DOI：
10.1017/s1461145712001514
发表时间：
2013-08-01
影响因子：
4.8
作者：
Benetti, Fernando;Izquierdo, Ivan
通讯作者：
Izquierdo, Ivan