Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Despite SNpc being considered the primary affected region in PD, the neuropathological features are confined solely to the nigro-striatal axis. With disease progression other brain regions are also affected, namely the cerebral cortex, although the spreading of the neurologic damage to this region is still not completely unraveled.

Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent in PD.

Here, we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. In parallel, we evaluated the anti-oxidant, neuroprotective and anti-inflammatory effects of TUDCA. The anti-inflammatory mechanisms elicited by TUDCA were further dissected in microglia cells.

Our results show that MPTP leads to a decrease of ATP and activated AMP-activated protein kinase levels in mice cortex, and to a transient increase in the expression of antioxidant downstream targets of nuclear factor erythroid 2 related factor 2 (Nrf-2), and parkin. Notably, MPTP increases pro-inflammatory markers, while down-regulating the expression of the anti-inflammatory protein Annexin-A1 (ANXA1). Importantly, we show that TUDCA treatment prevents the deleterious effects of MPTP, sustains increased levels of antioxidant enzymes and parkin, and most of all negatively modulates neuroinflammation and up-regulates ANXA1 expression. Additionally, results from cellular models using microglia corroborate TUDCA modulation of ANXA1 synthesis, linking inhibition of neuroinflammation and neuroprotection by TUDCA.

帕金森氏病（PD）是一种进行性神经系统疾病，其主要特征是黑质致密部（SNpc）中多巴胺能神经元的进行性丧失以及细胞内包裹体（称为路易体）的存在。尽管SNpc被认为是PD的主要受影响区域，但神经病理学特征仅局限于黑质纹状体轴。随着疾病的进展，其他大脑区域也将受到影响，即大脑皮层，尽管神经损伤对这一区域的扩散仍未完全阐明。

牛磺去氧胆酸（TUDCA）是一种内源性胆汁酸，在PD的1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠模型中已显示具有抗氧化特性并显示出神经保护作用。此外，TUDCA的抗炎特性已在神经胶质细胞中得到报道，使其成为PD中的重要治疗剂。

在这里，我们在亚急性范例中使用了注射了MPTP的C57BL / 6小鼠，旨在研究MPTP的神经毒性作用是否可以扩展到大脑皮层。同时，我们评估了TUDCA的抗氧化，神经保护和抗炎作用。在小胶质细胞中进一步剖析了TUDCA引起的抗炎机制。

我们的结果表明，MPTP导致小鼠皮质中ATP和活化的AMP活化的蛋白激酶水平降低，并导致核因子类红细胞2相关因子2（Nrf-2）的抗氧化剂下游靶标的表达瞬时增加，并且帕金。值得注意的是，MPTP增加了促炎性标志物，同时下调了抗炎蛋白Annexin-A1（ANXA1）的表达。重要的是，我们表明，TUDCA治疗可防止MPTP的有害作用，维持抗氧化酶和帕金酸的水平升高，并且大多数都负面调节神经炎症并上调ANXA1表达。此外，使用小胶质细胞的细胞模型结果证实了ANXA1合成的TUDCA调节，与TUDCA对神经炎症的抑制和神经保护有关。