Department of Zoology, University of Allahabad, Allahabad, 211002, India.
Department of Zoology, University of Allahabad, Allahabad, 211002, India.
Eur J Pharmacol. 2020 Apr 5;872:172978. doi: 10.1016/j.ejphar.2020.172978. Epub 2020 Jan 31.
Evidences from human and animal studies indicate that exposure to infection during early life act as a stressor to impair the hypothalamic-pituitary-adrenal (HPA) axis and may be one of the contributing factors of mental illness of later life. Several atypical antipsychotic drugs (AAPDs) proved to be effective in alleviating psychiatric illness through normalization of HPA axis. However, AAPD are least tried to evaluate their efficacy in modulation of HPA axis impaired under infection. The present study elucidated that the treatment with AAPD paliperidone (PAL: 0.025 mg/kg/bw and 0.05 mg/kg/bw) during periadolescence period (postnatal day 35- postnatal day 56) dose-dependently normalized the HPA axis of the female mice who were gestationally (gestational day 15 and 17) exposed to bacterial endotoxin lipopolysaccharide (LPS: 800 μg/kg/bw; intraperitoneally). The effectiveness of PAL treatment in counteracting the LPS induced hyperactivity of HPA axis was age-related, better observed at postnatal day 120 than at postnatal day 200. The PAL modulation of HPA axis reflected at different levels: inhibition of hypothalamic CRF expression and reduction in plasma levels of adrenocorticotropin and corticosterone. Histopathological alterations such as hypertrophy and/or hyperplasia in cortical zona fasciculata as well as medullary chromaffin cells of adrenal also normalized on PAL treatment. The comparatively long wash out period after drug treatment (postnatal day 57- postnatal day 200) along with age related hormonal imbalance could be correlated to less effectiveness of PAL on HPA axis at postnatal day 200. PAL modulation of HPA axis might be through maintenance of cytokines and reproductive axis homeostasis.
来自人体和动物研究的证据表明，生命早期接触感染会对下丘脑-垂体-肾上腺 (HPA) 轴造成应激，这可能是晚年精神疾病的一个促成因素。几种非典型抗精神病药物 (AAPD) 通过 HPA 轴的正常化被证明对缓解精神疾病有效。然而，AAPD 很少被尝试用于评估它们在感染下调节受损的 HPA 轴的疗效。本研究阐明，在青春期期间（出生后第 35 天至第 56 天）用 AAPD 帕利哌酮（PAL：0.025mg/kg/bw 和 0.05mg/kg/bw）治疗，可剂量依赖性地使孕中期（妊娠第 15 天和第 17 天）暴露于细菌内毒素脂多糖（LPS：800μg/kg/bw；腹腔内注射）的雌性小鼠的 HPA 轴正常化。PAL 治疗对抗 LPS 诱导的 HPA 轴过度活跃的有效性与年龄有关，在出生后第 120 天比第 200 天观察到更好的效果。PAL 对 HPA 轴的调节反映在不同的水平：抑制下丘脑 CRF 表达和降低血浆促肾上腺皮质激素和皮质酮水平。皮质束状带和肾上腺髓质嗜铬细胞的组织病理学改变，如肥大和/或增生，也在 PAL 治疗后得到正常化。药物治疗后的洗脱期相对较长（出生后第 57 天至第 200 天）以及与年龄相关的激素失衡，可能与 PAL 在出生后第 200 天对 HPA 轴的效果较差有关。PAL 对 HPA 轴的调节可能是通过维持细胞因子和生殖轴的平衡。
