Modification of Nitric Oxide Synthase Activity and Neuronal Response in Rat Striatum by Melatonin and Kynurenine Derivatives

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Abstract
Tryptophan is mainly metabolized in the brain through methoxyindole and kynurenine pathways. The methoxyindole pathway produces (among other compounds) melatonin, which displays inhibitory effects on human and animal central nervous systems, including a significant attenuation of excitatory, glutamate‐mediated responses. The kynurenine pathway produces kynurenines that interact with brain glutamate‐mediated responses. Nitric oxide (NO) increases glutamate release, and melatonin and kynurenines may act via modification of NO synthesis. In the present study, the effects of melatonin and four synthetic kynurenines were studied on the activity of rat striatal nitric oxide synthase (NOS) and on the response of rat striatal neurons to sensorimotor cortex (SMCx) stimulation, a glutamate‐mediated response. Melatonin inhibited both NOS activity and the striatal glutamate response, and these effects were dose‐related. Compound A (2‐acetamide‐4‐(3‐methoxyphenyl)‐4‐oxobutyric acid) did not inhibit NOS activity but inhibited the striatal response similarly to melatonin. Compound B (2‐acetamide‐4‐(2‐amino‐5‐methoxyphenyl)‐4‐oxobutyric acid) was more potent than melatonin in inhibiting both NOS activity and the striatal response. Compound C (2‐butyramide‐4‐(3‐methoxyphenyl)‐4‐oxobutyric acid) did not change NOS activity, but increased the striatal response. Compound D (2‐butyramide‐4‐(2‐amino‐5‐methoxyphenyl)‐4‐oxobutyric acid) showed potent inhibitory effects on both NOS activity and striatal glutamate‐mediated response. A structure‐related effect of the kynurenine derivatives was observed, and those with an amino group in position 2 of the benzenic ring had more potent effects than melatonin itself in inhibiting striatal NOS activity and the response of striatal neurons to SMCx.

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