Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Int J Mol Sci. 2024 Jul 8;25(13):7496. doi: 10.3390/ijms25137496.
The application of intracerebroventricular injection of streptozotocin (ICV-STZ) is considered a useful animal model to mimic the onset and progression of sporadic Alzheimer's disease (sAD). In rodents, on day 7 of the experiment, the animals exhibit depression-like behaviors. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn), is closely related to depression and AD. The present study aimed to investigate the pathophysiological mechanisms of preliminary depression-like behaviors in ICV-STZ rats in two distinct cerebral regions of the medial prefrontal cortex, the prelimbic cortex (PrL) and infralimbic cortex (IL), both presumably involved in AD progression in this model, with a focus on IDO-related Kyn pathways. The results showed an increased Kyn/Trp ratio in both the PrL and IL of ICV-STZ rats, but, intriguingly, abnormalities in downstream metabolic pathways were different, being associated with distinct biological effects. In the PrL, the neuroprotective branch of the Kyn pathway was attenuated, as evidenced by a decrease in the kynurenic acid (KA) level and Kyn aminotransferase II (KAT II) expression, accompanied by astrocyte alterations, such as the decrease in glial fibrillary acidic protein (GFAP)-positive cells and increase in morphological damage. In the IL, the neurotoxicogenic branch of the Kyn pathway was enhanced, as evidenced by an increase in the 3-hydroxy-kynurenine (3-HK) level and kynurenine 3-monooxygenase (KMO) expression paralleled by the overactivation of microglia, reflected by an increase in ionized calcium-binding adaptor molecule 1 (Iba1)-positive cells and cytokines with morphological alterations. Synaptic plasticity was attenuated in both subregions. Additionally, microinjection of the selective IDO inhibitor 1-Methyl-DL-tryptophan (1-MT) in the PrL or IL alleviated depression-like behaviors by reversing these different abnormalities in the PrL and IL. These results suggest that the antidepressant-like effects linked to Trp metabolism changes induced by 1-MT in the PrL and IL occur through different pathways, specifically by enhancing the neuroprotective branch in the PrL and attenuating the neurotoxicogenic branch in the IL, involving distinct glial cells.
侧脑室注射链脲佐菌素（ICV-STZ）被认为是一种有用的动物模型，可模拟散发性阿尔茨海默病（sAD）的发病和进展。在啮齿动物中，实验第 7 天，动物表现出抑郁样行为。色氨酸 2,3-双加氧酶（IDO）是一种限速酶，可催化色氨酸（Trp）转化为犬尿氨酸（Kyn），与抑郁和 AD 密切相关。本研究旨在探讨 ICV-STZ 大鼠两个不同的大脑区域——前额皮质内侧前脑区的背侧（PrL）和腹侧（IL）——中初步抑郁样行为的病理生理机制，这两个区域都可能与该模型中 AD 的进展有关，重点是 IDO 相关的 Kyn 途径。结果显示，ICV-STZ 大鼠的 PrL 和 IL 中 Kyn/Trp 比值均升高，但令人好奇的是，下游代谢途径的异常不同，与不同的生物学效应有关。在 PrL 中，Kyn 途径的神经保护分支减弱，表现为犬尿氨酸酸（KA）水平和 kynurenine aminotransferase II（KAT II）表达降低，同时伴有星形胶质细胞改变，如神经胶质纤维酸性蛋白（GFAP）阳性细胞减少和形态损伤增加。在 IL 中，Kyn 途径的神经毒性分支增强，表现为 3-羟基犬尿氨酸（3-HK）水平升高和 kynurenine 3-单加氧酶（KMO）表达增加，同时小胶质细胞过度激活，反映为离子钙结合接头蛋白 1（Iba1）阳性细胞增加和形态改变的细胞因子增加。两个亚区的突触可塑性均减弱。此外，选择性 IDO 抑制剂 1-甲基-DL-色氨酸（1-MT）在 PrL 或 IL 中的微注射通过逆转 PrL 和 IL 中这些不同的异常，缓解了抑郁样行为。这些结果表明，1-MT 在 PrL 和 IL 中诱导的 Trp 代谢变化与抗抑郁作用相关，是通过不同的途径发生的，具体来说，是通过增强 PrL 中的神经保护分支和减弱 IL 中的神经毒性分支来实现的，涉及不同的神经胶质细胞。
