Department of Integrative Medical Biology, Umeå University, Umeå, Sweden; Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
Department of Integrative Medical Biology, Umeå University, Umeå, Sweden; Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
Neurochem Int. 2019 Dec;131:104551. doi: 10.1016/j.neuint.2019.104551. Epub 2019 Sep 19.
In Parkinson's disease, degeneration of substantia nigra dopaminergic neurons is accompanied by damage on other neuronal systems. A severe denervation is for example seen in the locus coerulean noradrenergic system. Little is known about the relation between noradrenergic and dopaminergic degeneration, and the effects of noradrenergic denervation on the function of the dopaminergic neurons of substantia nigra are not fully understood. In this study, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) was injected in rats, whereafter behavior, striatal KCl-evoked dopamine and glutamate releases, and immunohistochemistry were monitored at 3 days, 3 months, and 6 months. Quantification of dopamine-beta-hydroxylase-immunoreactive nerve fiber density in the cortex revealed a tendency towards nerve fiber regeneration at 6 months. To sustain a stable noradrenergic denervation throughout the experimental timeline, the animals in the 6-month time point received an additional DSP4 injection (2 months after the first injection). Behavioral examinations utilizing rotarod revealed that DSP4 reduced the time spent on the rotarod at 3 but not at 6 months. KCl-evoked dopamine release was significantly increased at 3 days and 3 months, while the concentrations were normalized at 6 months. DSP4 treatment prolonged both time for onset and reuptake of dopamine release over time. The dopamine degeneration was confirmed by unbiased stereology, demonstrating significant loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra. Furthermore, striatal glutamate release was decreased after DSP4. In regards of neuroinflammation, reactive microglia were found over the substantia nigra after DSP4 treatment. In conclusion, long-term noradrenergic denervation reduces the number of dopaminergic neurons in the substantia nigra and affects the functionality of the nigrostriatal system. Thus, locus coeruleus is important for maintenance of nigral dopaminergic neurons.
在帕金森病中，黑质多巴胺能神经元的退化伴随着其他神经元系统的损伤。例如，蓝斑去甲肾上腺素能系统会出现严重的去神经支配。关于去甲肾上腺素能和多巴胺能退化之间的关系以及去甲肾上腺素能去神经支配对黑质多巴胺能神经元功能的影响知之甚少。在这项研究中，将 N-(2-氯乙基)-N-乙基-2-溴苯甲胺（DSP4）注射到大鼠中，然后在 3 天、3 个月和 6 个月时监测行为、纹状体 KCl 诱发的多巴胺和谷氨酸释放以及免疫组织化学。皮层中多巴胺-β-羟化酶免疫反应性神经纤维密度的定量显示，6 个月时存在神经纤维再生的趋势。为了在整个实验时间内维持稳定的去甲肾上腺素能去神经支配，6 个月时间点的动物接受了额外的 DSP4 注射（第一次注射后 2 个月）。利用转棒进行的行为检查表明，DSP4 在 3 天和 3 个月时减少了在转棒上花费的时间，但在 6 个月时没有减少。KCl 诱发的多巴胺释放在 3 天和 3 个月时显著增加，而在 6 个月时恢复正常。DSP4 处理随着时间的推移延长了多巴胺释放的起始和再摄取时间。通过无偏立体学证实了多巴胺的退化，证明了黑质中酪氨酸羟化酶免疫反应性神经元的显著丧失。此外，DSP4 后纹状体谷氨酸释放减少。关于神经炎症，在 DSP4 处理后发现黑质中有反应性小胶质细胞。总之，长期去甲肾上腺素能去神经支配会减少黑质中多巴胺能神经元的数量，并影响黑质纹状体系统的功能。因此，蓝斑对黑质多巴胺能神经元的维持很重要。
