The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism.
The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism.
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DOI：
10.1038/s41598-018-31385-7
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发表时间：
2018-08-30
影响因子：
4.6
通讯作者：
Sadek B
中科院分区：
文献类型：
--
作者：
Eissa N;Jayaprakash P;Azimullah S;Ojha SK;Al-Houqani M;Jalal FY;Łażewska D;Kieć-Kononowicz K;Sadek B
自闭症谱系障碍 (ASD) 是一种神经发育障碍，其特征是社交沟通障碍和受限/重复的行为模式或兴趣。针对组胺 H3 受体 (H3R) 的拮抗剂被认为是治疗不同脑部疾病（例如认知障碍）的潜在治疗剂。因此，使用强效选择性 H3R 拮抗剂 DL77（5、10 或 15mg/kg，腹腔注射）进行亚慢性治疗对雄性 Tuck-Ordinary (TO) 小鼠的社交能力、社交新颖性、焦虑和攻击性/重复行为的影响进行了评估，这些小鼠因产前暴露于丙戊酸（VPA，500mg/kg，腹腔注射）而诱发 ASD 样行为。三室试验（TCT）、大理石埋藏试验（MBT）、巢状撕碎试验（NST）和高架十字迷宫（EPM）试验。结果表明，与经 DL77（10 或 15 mg/kg，腹腔注射）预处理的 VPA 暴露小鼠相比，VPA 暴露小鼠表现出显着较低的社交能力和社交新奇偏好。与对照组相比，暴露于 VPA 的小鼠在 MBT 中的埋弹珠百分比显着更高，在 NST 中的碎燕窝百分比显着更高。然而，暴露于 VPA 的动物用 DL77（10 或 15mg/kg，腹腔注射）进行预处理后，MBT 中埋藏的弹珠百分比降低，并且 NST 中的粉碎行为百分比显着降低。另一方面，DL77（5、10或15mg/kg，腹腔注射）预处理未能恢复在EPM中观察到的VPA暴露小鼠的焦虑水平和多动症，而参考药物多奈哌齐（DOZ，1mg/kg，腹腔注射）显着缓解了VPA暴露小鼠的焦虑并减少了多动症。此外，在暴露于 VPA 的小鼠脑组织中，DL77（10 或 15mg/kg，腹腔注射）预处理通过增加 GSH 和减少 MDA 来调节氧化应激状态，并减弱因脂多糖 (LPS) 攻击而加剧的促炎细胞因子 IL-1β、IL-6 和 TNF-α。总而言之，这些结果提供了证据表明，大脑组胺能神经传递的调节，例如通过亚慢性施用 H3R 拮抗剂 DL77，可以作为有效的药物治疗靶点，以挽救 VPA 暴露动物的 ASD 样行为，尽管需要进一步的研究来证实和扩展这些初始数据。
Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments. Therefore, the effects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15 mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15 mg/kg, i.p.). VPA-exposed mice presented a significantly higher percentage of buried marbles in MBT and shredded nestlet significantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15 mg/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a significantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15 mg/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1 mg/kg, i.p.) significantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15 mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinflammatory cytokines IL-1β, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an effective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data.
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影响因子：
3.7
作者：
Baronio D;Castro K;Gonchoroski T;de Melo GM;Nunes GD;Bambini-Junior V;Gottfried C;Riesgo R
通讯作者：
Riesgo R
影响因子：
9.3
作者：
Ferreira R;Santos T;Gonçalves J;Baltazar G;Ferreira L;Agasse F;Bernardino L
通讯作者：
Bernardino L
影响因子：
5.6
作者：
Alachkar A;Łażewska D;Kieć-Kononowicz K;Sadek B
通讯作者：
Sadek B
DOI：
10.1124/jpet.102.047241
发表时间：
2003-06-01
影响因子：
3.5
作者：
Fox, GB;Pan, JB;Hancock, AA
通讯作者：
Hancock, AA
影响因子：
2.7
作者：
Fox, GB;Pan, JB;Decker, MW
通讯作者：
Decker, MW