Role of nitric oxide synthesis inhibitors in iron-induced nigral neurotoxicity: A mechanistic exploration

In the central nervous system, nitric oxide (NO) has been suggested to be a cell-to-cell signaling molecule that regulates guanylyl cyclase, aconitase, and iron regulatory protein. NO is also one of the substances that is involved in neuronal death. On the other hand, iron overload and enhanced hydroxyl radical formation have been implicated as the causative factors of some neurodegenerative disorders. The present study was performed to clarify whether nitric oxide is involved in iron-induced neuron death. Neurotoxicity was produced by microinjection of iron chloride (200 mM, 2.5 mu L) into the left cerebral ventricle. After the intracerebroventricular (ICV) injection, all animals were kept alive for 10 days. During this period, animals in the iron + L-NAME (N-nitro-L-arginine methyl ester) and iron + aminoguanidine groups received intraperitoneal (IP) L-NAME (30 mg/kg) and aminoguanidine (100 mg/kg) injections once a day, respectively. Rats belonging to the control group also received intraperitoneally the same amount of saline. After 10 days, the rats were perfused intracardially under deep urethane anesthesia. Removed brains were processed using the standard histological techniques. The total numbers of neurons in substantia nigra of all rats were estimated with stereological techniques. It was found that L-NAME significantly decreased nigral cell loss from 43.2% to 14.0%, while aminoguanidine did not affect cell loss. Results of the present study suggest that NOS inhibition by L-NAME seems to have neuroprotective effects on iron-induced nigral neurotoxicity.