Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China; Department of Histology and Embryology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China.
Neuropharmacology. 2024 Jul 1;252:109946. doi: 10.1016/j.neuropharm.2024.109946. Epub 2024 Apr 9.
The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9-39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.
黑质多巴胺能神经元的自发放电活动与一些重要作用有关，包括调节多巴胺的释放、酪氨酸羟化酶（TH）的表达以及神经元的存活。帕金森病中黑质多巴胺能神经元的神经活性降低。中枢胰高血糖素样肽-1（GLP-1）作为一种神经递质或神经调质发挥多种脑功能。尽管形态学研究显示 GLP-1 受体（GLP-1Rs）在黑质致密部表达，但 GLP-1 对黑质多巴胺能神经元自发放电活动的可能调节尚不清楚。目前的体外在体单细胞记录显示，GLP-1R 激动剂 exendin-4 显著增加成年雄性 C57BL/6 小鼠部分黑质多巴胺能神经元的自发放电频率，并降低其放电规则性。GLP-1R 的阻断剂 exendin（9-39）降低了黑质多巴胺能神经元的放电频率，表明内源性 GLP-1 参与了放电活动的调节。此外，PKA 和瞬时受体电位经典（TRPC）4/5 通道参与了 GLP-1R 激活诱导的黑质多巴胺能神经元兴奋效应。在帕金森病状态下，外源性和内源性 GLP-1 仍能对存活的黑质多巴胺能神经元产生兴奋作用。由于轻度兴奋刺激对黑质多巴胺能神经元具有神经保护作用，因此 GLP-1 诱导的兴奋效应可能部分有助于其抗帕金森病作用。
