Role of neuronal nitric oxide synthase in slowly progressive dopaminergic neurodegeneration in the Zitter rat.

ABSTRACT

Neuronal nitric oxide synthase (nNOS) is involved in nigrostriatal dopaminergic (DA) neurodegeneration. However, little is known about the distribution patterns and functions of nNOS in slowly progressive DA neurodegeneration. Here we describe the spatiotemporal change in nNOS expression over the course of neurodegeneration and the effect of short- or long-term treatment with the nNOS inhibitor, 7-nitroindazole (7-NI), in zitter (zi/zi) rats. In the substantia nigra pars compacta (SNc), nNOS expression was significantly increased with progression of neurodegeneration. nNOS-immunoreactive (ir) cells were in the vicinity of tyrosine hydroxylase-ir (TH-ir) DA neurons, and some of these cells were also positive for calbindin. nNOS in the caudate-putamen (CPu) showed little difference during progression of neurodegeneration. However, immunoelectron microscopic analysis revealed that abundant TH-ir fibers in the CPu were degenerated due to compression by vacuoles that contained swollen neuronal and glial elements. Additionally, lipid peroxidation as a marker of membrane oxidation was significantly increased in zi/zi rats. Short-term 7-NI treatment attenuated the increase in lipid peroxidation and inhibited the vacuolation in the CPu. Moreover, long-term 7-NI treatment significantly protected TH-ir neurons in the SNc, and TH-ir fibers and DA contents in the CPu. These results show that nNOS exacerbates slowly progressive DA neurodegeneration, and the neuroprotective effects of 7-NI may result from suppression of membrane oxidation that causes abnormal membrane structures in zi/zi rats.