Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
Int J Mol Sci. 2021 Jun 8;22(12):6171. doi: 10.3390/ijms22126171.
Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(,)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague-Dawley pups during early postnatal development (p5-p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42-p44, p60-p62) and in early adulthood (p90-p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.
越来越多的证据表明，大脑氧化还原状态的失调是精神分裂症发病机制的一个重要因素。我们的研究目的是评估 L-丁硫氨酸-(，)-亚砜胺（BSO），一种谷胱甘肽（GSH）合成抑制剂，和 1-[2-双（4-氟苯基）甲氧基]乙基]-4-（3-苯基丙基）哌嗪二盐酸盐（GBR 12909），一种多巴胺再摄取抑制剂，在早期产后发育（p5-p16）期间单独或联合给予 Sprague-Dawley 幼仔，对类精神分裂症行为的发病时间进程，以及成年期前额叶皮层（PFC）和海马（HIP）中脑源性神经营养因子（BDNF）mRNA 及其蛋白的表达的影响。单独给予 BSO 会降低 PFC 和 HIP 中 BDNF mRNA 和其蛋白的水平。BSO+GBR 12909 联合治疗也降低了 PFC 中 BDNF mRNA 和其蛋白的水平，但在 HIP 中，只有 BDNF 蛋白的水平降低。在三个青春期时间点（p30、p42-p44、p60-p62）和早期成年期（p90-p92），使用社会互动测试、新物体识别测试和旷场测试评估大鼠的类精神分裂症行为。单独给予 BSO 或 BSO+GBR 12909 联合治疗的大鼠，在青春期中期首次出现社会和认知缺陷，并持续到成年期。在青春期中期，仅在给予 BSO+GBR 12909 联合治疗的大鼠中出现与人类阳性症状相对应的行为。仅在后一组中，安非他命在成年期加剧了现有的阳性症状。我们的数据表明，在早期产后生活中接受 BSO+GBR 12909 联合治疗的大鼠几乎重现了所有在精神分裂症患者中观察到的症状，因此可以被认为是这种疾病的一个有价值的神经发育模型。
