Ciani E, Baldinotti I, Contestabile A
Department of Biology, University of Bologna, Bologna, Italy.
Brain Res Bull. 2001 Sep 1;56(1):29-35. doi: 10.1016/s0361-9230(01)00589-5.
Brain nitric oxide (NO) can be a mediator of physiological and neuroprotective actions and an effector of neural damage. The effectiveness of acute or chronic inhibition of NO production in in vivo experiments of neurotoxicity/neuroprotection is controversial. We report here on the effects of a chronic, sustained inhibition of nitric oxide synthase (NOS) on the neurodegenerative damage caused by three different excitotoxic lesions. The damage caused by intrastriatal injection of ibotenic or kainic acid was aggravated in rats subjected to chronic NOS inhibition. On the contrary, the drop of cortical cholinergic input consequent to ibotenic acid-mediated degeneration of basal forebrain neurons was not altered by chronic NOS inhibition. The worsening of the damage was not related to any overt differential sensitivity to excitotoxicity of NOS-containing striatal neurons under conditions of NOS inhibition. These results suggest that, contrary to what has been often reported for short-term, mild inhibition of NO production, chronic and sustained NOS inhibition may exacerbate neuropathology. Thus, long-lasting shortage of NO may be detrimental when neuroprotective mechanisms related to the physiological action of this free radical are severely impaired. Although we cannot exclude that inhibition of the endothelial NOS isoform could have contributed to the worsening of neuropathology, differences among the paradigms of neurotoxicity used in the present study suggest a primary involvement of the neuronal NOS isoform. In view of the potential therapeutic use of NOS inhibitors, the effects of a too drastic alteration of the balance between neuroprotective and neurodegenerative actions of NO should be carefully considered.
脑内一氧化氮（NO）可以是生理和神经保护作用的介质，也是神经损伤的效应物。在神经毒性/神经保护的体内实验中，急性或慢性抑制NO生成的有效性存在争议。我们在此报告慢性、持续抑制一氧化氮合酶（NOS）对三种不同兴奋性毒性损伤所致神经退行性损害的影响。在慢性NOS抑制的大鼠中，纹状体内注射鹅膏蕈氨酸或 kainic 酸所造成的损害加重。相反，慢性NOS抑制并未改变鹅膏蕈氨酸介导的基底前脑神经元变性导致的皮质胆碱能输入减少。损害的加重与在NOS抑制条件下含NOS的纹状体神经元对兴奋性毒性的任何明显差异敏感性无关。这些结果表明，与经常报道的短期、轻度抑制NO生成的情况相反，慢性和持续的NOS抑制可能会加剧神经病理学变化。因此，当与这种自由基生理作用相关的神经保护机制严重受损时，NO的长期缺乏可能是有害的。虽然我们不能排除内皮型NOS同工酶的抑制可能导致神经病理学恶化，但本研究中使用的神经毒性范式之间的差异表明神经元型NOS同工酶起主要作用。鉴于NOS抑制剂的潜在治疗用途，应仔细考虑NO的神经保护和神经退行性作用之间平衡的过度剧烈改变所产生的影响。
