Protective effects of synthetic kynurenines on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice

Mitochondrial complex I inhibition is thought to underlie the neurodegenerative process in Parkinson's disease (PD). Moreover, an overproduction of nitric oxide due to both cytosolic (iNOS) and mitochondrial (i-mtNOS) inducible nitric oxide synthases causes free radicals generation and oxidative/nitrosative stress, contributing to mitochondrial dysfunction and neuronal cell death. Looking for active molecules against mitochondrial dysfunction and inflammatory response in PD, we show here the effects of four synthetic kynurenines in the MPTP model of PD in mice. After MPTP administration, mitochondria from substantia nigra and, in a lesser extent, from striatum showed a significant increase in i-mtNOS activity, nitric oxide production, oxidative stress, and complex I inhibition. The four kynurenines assayed counteracted the effects of MPTP, reducing iNOS/i-mtNOS activity, and restoring the activity of the complex I. Consequently, the cytosolic and mitochondrial oxidative/nitrosative stress returned to control values. The results suggest that the kynurenines here reported represent a family of synthetic compounds with neuroprotective properties against PD, and that they can serve as templates for the design of new drugs able to target the mitochondria.

.Figure optionsDownload as PowerPoint slideHighlights
► We synthetized four kynurenines structurally related to the neurohormone melatonin.
► These molecules were assayed in vivo in the mouse model of PD induced by MPTP.
► The four kynurenines reduced the inflammatory response in the nigrostriatal pathway induced by MPTP.
► These kynurenines also counteracted mitochondria failure and recovered mice from the neurotoxin effects.
► The compounds here tested may represent a new classes of neuroprotective drugs.