Antonelli T, Tomasini M C, Finetti S, Giardino L, Calzà L, Fuxe K, Soubriè P, Tanganelli S, Ferraro L
Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Ferrara, Italy.
J Neurosci Res. 2002 Dec 15;70(6):766-73. doi: 10.1002/jnr.10415.
The tridecapeptide neurotensin has been demonstrated to increase glutamate release in discrete rat brain regions, leading to the hypothesis of a possible involvement of the peptide in neurodegenerative pathologies. The role of neurotensin in modulating glutamate excitotoxicity and the possible neuroprotective action of the neurotensin receptor antagonist SR48692 were investigated in primary cultures of mesencephalic neurons by measuring [(3)H]dopamine uptake and tyrosine hydroxylase immunocytochemistry 24 hr after glutamate treatment. The exposure to glutamate (30 and 100 microM, 10 min) decreased [(3)H]dopamine uptake into mesencephalic neurons. Neurotensin (10 and 100 nM), added before glutamate (30 microM) exposure, significantly enhanced the glutamate-induced reduction of [(3)H]dopamine uptake. In addition, the peptide (10 nM) also significantly enhanced the effect of 100 microM glutamate. The effects of neurotensin were counteracted by the neurotensin receptor antagonist SR48692 (100 nM) and by the protein kinase C inhibitor calphostin C. The exposure to 100 microM, but not 30 microM, glutamate significantly reduced the number of tyrosine hydroxylase-immunoreactive cells, and neurotensin (10 nM) significantly enhanced this effect. SR48692 (100 nM) prevented the neurotensin-induced action. These findings support the view of a possible pathophysiological role of neurotensin in mesencephalic dopamine neuronal function. Furthermore, selective neurotensin antagonists in combination with conventional drug treatments could provide a novel therapeutic approach for the treatment of neurodegenerative disorders, such as Parkinson's disease.
十三肽神经降压素已被证明可增加大鼠特定脑区的谷氨酸释放，从而引发该肽可能参与神经退行性病变的假说。通过在谷氨酸处理24小时后测量[³H]多巴胺摄取和酪氨酸羟化酶免疫细胞化学，研究了神经降压素在调节谷氨酸兴奋性毒性中的作用以及神经降压素受体拮抗剂SR48692可能的神经保护作用。暴露于谷氨酸（30和100微摩尔，10分钟）会降低[³H]多巴胺向中脑神经元的摄取。在暴露于谷氨酸（30微摩尔）之前添加神经降压素（10和100纳摩尔），可显著增强谷氨酸诱导的[³H]多巴胺摄取减少。此外，该肽（10纳摩尔）也显著增强了100微摩尔谷氨酸的作用。神经降压素受体拮抗剂SR48692（100纳摩尔）和蛋白激酶C抑制剂钙泊三醇可抵消神经降压素的作用。暴露于100微摩尔而非30微摩尔谷氨酸会显著减少酪氨酸羟化酶免疫反应性细胞的数量，而神经降压素（10纳摩尔）可显著增强此效应。SR48692（100纳摩尔）可阻止神经降压素诱导的作用。这些发现支持了神经降压素在中脑多巴胺神经元功能中可能具有病理生理作用的观点。此外，选择性神经降压素拮抗剂与传统药物治疗相结合可为治疗神经退行性疾病（如帕金森病）提供一种新的治疗方法。
