School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, SA 5000, Australia.
School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, SA 5000, Australia.
J Chem Neuroanat. 2019 Apr;97:23-32. doi: 10.1016/j.jchemneu.2019.01.010. Epub 2019 Jan 25.
Loss of dopaminergic neurons in the substantia nigra (SN) is one of the pathological hallmarks in Parkinson's disease (PD). This neuron loss is accompanied by reduced protein and activity levels of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine synthesis. Reduced nigral brain-derived neurotrophic factor (BDNF) has been postulated to contribute to the loss of nigral dopaminergic neurons in PD by causing a lack of trophic support. Prior to this nigral cell loss many patients develop non-motor symptoms such as hyposmia, constipation and orthostatic hypotension. We investigated how TH, BDNF and BDNF related receptors are altered in the SN, olfactory bulb, adrenal glands and colon (which are known to be affected in PD) using rotenone-treated rats. Rotenone was administered to Sprague-Dawley rats at a dose of 2.75 mg/kg, 5 days/week for 4 weeks, via intraperitoneal injections. Rats underwent behavioural testing, and tissues were collected for western blot and ELISA analysis. This rotenone treatment induced reduced rears and distance travelled in the rearing and open field test, respectively but caused no impairments in forced movement (rotarod test). The SN had changes consistent with a pro-apoptotic state, such as increased proBDNF but no change in TH; whereas, the colon had significantly reduced TH and increased sortilin. Thus, our results indicate further investigation is warranted for this rotenone-dosing paradigm's capacity for reproducing the early stage of PD, as we observed impairments in voluntary movement and pathology in the colon without overt motor symptoms or nigral dopaminergic loss.
黑质（SN）中多巴胺能神经元的丧失是帕金森病（PD）的病理标志之一。这种神经元的丧失伴随着酪氨酸羟化酶（TH）的蛋白和活性水平降低，TH 是儿茶酚胺合成的限速酶。据推测，黑质脑源性神经营养因子（BDNF）的减少通过导致缺乏营养支持而导致黑质多巴胺能神经元的丧失。在这种黑质细胞丧失之前，许多患者会出现嗅觉减退、便秘和直立性低血压等非运动症状。我们使用鱼藤酮处理的大鼠研究了 TH、BDNF 和 BDNF 相关受体在 SN、嗅球、肾上腺和结肠（已知在 PD 中受影响）中的变化，这些大鼠每周接受 5 天、每天 2.75mg/kg 的腹腔注射。大鼠接受行为测试，并收集组织进行 Western blot 和 ELISA 分析。这种鱼藤酮处理导致后肢抬起和开放场测试中行进距离减少，但不会导致强制运动（旋转棒测试）受损。SN 发生了与促凋亡状态一致的变化，例如 proBDNF 增加但 TH 没有变化；而结肠中 TH 明显减少，sortilin 增加。因此，我们的结果表明，对于这种鱼藤酮给药方案再现 PD 早期阶段的能力，需要进一步研究，因为我们观察到自愿运动受损和结肠病理学改变，而没有明显的运动症状或黑质多巴胺能丧失。
