Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno D'Alcontres n, 31 98166, Messina, Italy.
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Saint Louis, MO, USA.
Mol Neurobiol. 2018 Mar;55(3):2403-2419. doi: 10.1007/s12035-017-0496-4. Epub 2017 Mar 29.
Parkinson's disease (PD) is a disorder caused by degeneration of dopaminergic neurons. At the moment, there is no cure. Recent studies have shown that autophagy may have a protective function against the advance of a number of neurodegenerative diseases. Temsirolimus is an analogue of rapamycin that induces autophagy by inhibiting mammalian target of rapamycin complex 1. For this purpose, in the present study we investigated the neuroprotective effects of temsirolimus (5 mg/kg intraperitoneal) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced (MPTP) neurotoxicity in in vivo model of PD. At the end of the experiment, brain tissues were processed for histological, immunohistochemical, Western blot, and immunofluorescent analysis. Treatment with temsirolimus significantly ameliorated behavioral deficits, increased the expression of specific markers of PD such as tyrosine hydroxylase, dopamine transporter, as well as decreased the upregulation of α-synuclein in the substantia nigra after MPTP induction. Furthermore, Western blot and immunohistochemistry analysis showed that temsirolimus administration significantly increased autophagy process. In fact, treatment with temsirolimus maintained high Beclin-1, p62, and microtubule-associated protein 1A/1B-light chain 3 expression and inhibited the p70S6K expression. In addition, we showed that temsirolimus has also anti-inflammatory properties as assessed by the significant inhibition of the expression of mitogen-activated protein kinases such as p-JNK, p-p38, and p-ERK, and the restored levels of neurotrophic factor expression such as BDNF and NT-3. On the basis of this evidence, we clearly demonstrate that temsirolimus is able to modulate both the autophagic process and the neuroinflammatory pathway involved in PD, actions which may underlie its neuroprotective effect.
帕金森病（PD）是一种由多巴胺能神经元变性引起的疾病。目前尚无治愈方法。最近的研究表明，自噬可能对多种神经退行性疾病的进展具有保护作用。替西罗莫司是雷帕霉素的类似物，通过抑制哺乳动物雷帕霉素靶蛋白复合物 1 诱导自噬。为此，本研究探讨了替西罗莫司（5mg/kg 腹腔注射）对体内 1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的（MPTP）神经毒性的神经保护作用。在实验结束时，对脑组织进行了组织学、免疫组织化学、Western blot 和免疫荧光分析。替西罗莫司治疗显著改善了行为缺陷，增加了酪氨酸羟化酶、多巴胺转运体等特定 PD 标志物的表达，并降低了 MPTP 诱导后黑质中α-突触核蛋白的上调。此外，Western blot 和免疫组织化学分析表明，替西罗莫司给药显著增加了自噬过程。事实上，替西罗莫司治疗维持了高 Beclin-1、p62 和微管相关蛋白 1A/1B-轻链 3 的表达，并抑制了 p70S6K 的表达。此外，我们还表明，替西罗莫司还具有抗炎特性，如丝裂原活化蛋白激酶（如 JNK、p38 和 ERK）表达的显著抑制以及神经营养因子表达（如 BDNF 和 NT-3）的恢复。基于这些证据，我们清楚地表明，替西罗莫司能够调节 PD 中涉及的自噬过程和神经炎症途径，其神经保护作用可能与这些作用有关。
