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Low-dose candesartan prevents schizophrenia-like behavioral alterations in a neurodevelopmental two-hit model of schizophrenia
Progress in Neuro-Psychopharmacology and Biological Psychiatry ( IF 5.3 ) Pub Date : 2021-05-10 , DOI: 10.1016/j.pnpbp.2021.110348
Germana Silva Vasconcelos 1 , Manuel Alves Dos Santos Júnior 1 , Aline Santos Monte 2 , Francisco Eliclécio Rodrigues da Silva 1 , Camila Nayane de Carvalho Lima 1 , Abelardo Barbosa Moreira Lima Neto 3 , Ingridy da Silva Medeiros 1 , Antonio Lucio Teixeira 4 , David Freitas de Lucena 1 , Silvânia Maria Mendes Vasconcelos 1 , Danielle S Macedo 5
Affiliation  

Schizophrenia is a severe mental disorder with complex etiopathogenesis. Based on its neurodevelopmental features, an animal model induced by “two-hit” based on perinatal immune activation followed by peripubertal unpredictable stress was proposed. Sex influences the immune response, and concerning schizophrenia, it impacts the age of onset and symptoms severity. The neurobiological mechanisms underlying the influence of sex in schizophrenia is poorly understood. Our study aimed to evaluate sex influence on proinflammatory and oxidant alterations in male and female mice exposed to the two-hit model of schizophrenia, and its prevention by candesartan, an angiotensin II type 1 receptor (AT1R) blocker with neuroprotective properties. The two-hit model induced schizophrenia-like behavioral changes in animals of both sexes. Hippocampal microglial activation alongside the increased expression of NF-κB, and proinflammatory cytokines, namely interleukin (IL)-1β and TNF-α, were observed in male animals. Conversely, females presented increased hippocampal and plasma levels of nitrite and plasma lipid peroxidation. Peripubertal administration of low-dose candesartan (0.3 mg/kg PO) prevented behavioral, hippocampal, and systemic changes in male and female mice. While these results indicate the influence of sex on inflammatory and oxidative changes induced by the two-hit model, candesartan was effective in both males and females. The present study advances the neurobiological mechanisms underlying sex influence in schizophrenia and opens new avenues to prevent this devasting mental disorder.



中文翻译:

低剂量坎地沙坦可预防精神分裂症神经发育二次打击模型中的精神分裂症样行为改变

精神分裂症是一种病因复杂的严重精神障碍。基于其神经发育特征,提出了一种基于围产期免疫激活和青春期不可预知应激的“二次打击”诱导的动物模型。性别会影响免疫反应,而关于精神分裂症,它会影响发病年龄和症状严重程度。对精神分裂症中性别影响的神经生物学机制知之甚少。我们的研究旨在评估性别对暴露于精神分裂症两次打击模型的雄性和雌性小鼠的促炎和氧化变化的影响,以及坎地沙坦(一种具有神经保护特性的血管紧张素 II 型 1 型受体 (AT1R) 阻滞剂)对其的预防作用。两次打击模型在两性动物中诱导了类似精神分裂症的行为变化。在雄性动物中观察到海马小胶质细胞活化以及 NF-κB 和促炎细胞因子(即白细胞介素 (IL)-1β 和 TNF-α)表达增加。相反,女性海马和血浆亚硝酸盐和血浆脂质过氧化水平升高。围青春期给予低剂量坎地沙坦 (0.3 mg/kg PO) 可防止雄性和雌性小鼠的行为、海马和全身变化。虽然这些结果表明性别对两次打击模型诱导的炎症和氧化变化的影响,但坎地沙坦对男性和女性都有效。本研究推进了精神分裂症中性别影响的神经生物学机制,并开辟了预防这种破坏性精神障碍的新途径。即在雄性动物中观察到白细胞介素 (IL)-1β 和 TNF-α。相反,女性海马和血浆亚硝酸盐和血浆脂质过氧化水平升高。围青春期给予低剂量坎地沙坦 (0.3 mg/kg PO) 可防止雄性和雌性小鼠的行为、海马和全身变化。虽然这些结果表明性别对两次打击模型诱导的炎症和氧化变化的影响,但坎地沙坦对男性和女性都有效。本研究推进了精神分裂症中性别影响的神经生物学机制,并开辟了预防这种破坏性精神障碍的新途径。即在雄性动物中观察到白细胞介素 (IL)-1β 和 TNF-α。相反,女性海马和血浆亚硝酸盐和血浆脂质过氧化水平升高。围青春期给予低剂量坎地沙坦 (0.3 mg/kg PO) 可防止雄性和雌性小鼠的行为、海马和全身变化。虽然这些结果表明性别对两次打击模型诱导的炎症和氧化变化的影响,但坎地沙坦对男性和女性都有效。本研究推进了精神分裂症中性别影响的神经生物学机制,并开辟了预防这种破坏性精神障碍的新途径。围青春期给予低剂量坎地沙坦 (0.3 mg/kg PO) 可防止雄性和雌性小鼠的行为、海马和全身变化。虽然这些结果表明性别对两次打击模型诱导的炎症和氧化变化的影响,但坎地沙坦对男性和女性都有效。本研究推进了精神分裂症中性别影响的神经生物学机制,并开辟了预防这种破坏性精神障碍的新途径。围青春期给予低剂量坎地沙坦 (0.3 mg/kg PO) 可防止雄性和雌性小鼠的行为、海马和全身变化。虽然这些结果表明性别对两次打击模型诱导的炎症和氧化变化的影响,但坎地沙坦对男性和女性都有效。本研究推进了精神分裂症中性别影响的神经生物学机制,并开辟了预防这种破坏性精神障碍的新途径。

更新日期:2021-05-22
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