Antidyskinetic activity of new derivatives of inydazol-4,5-dicarbonic acid in a parkinsonism experimental model due to administration of 6-hydroxydopapine

Abstract

BACKGROUND: Levodopa therapy currently remains the clinical method of choice for patients with Parkinson’s disease. However, in the late stages of the disease, approximately 80% of patients receiving treatment developed levodopa-induced dyskinesia. The studied substances are derivatives of imidazole-4,5-dicarboxylic acid. Their pharmacological effect is produced due to interaction with the recognition site of NMDA receptor, which, together with their high efficiency, implies that they are safer than previously available drugs in this pharmacological group.

AIM: To study the antidyskinetic effect of IEM2295 and IEM2296 derivatives of imidazole-4,5-dicarboxylic acid.

MATERIALS AND METHODS: The model is based on the toxic effect of 6-hydroxydopamine on rat brain tissue. The first (control) group of rats received injections of only Levodopa and Benserazide, the second group received injections of Levodopa, Benserazide, and the test substance IEM2295, and the third group received injections of Levodopa, Benserazide and the test substance IEM2296. Each group was evaluated based on three criteria: motor function violations, limb dyskinesia, and axial and chewing dyskinesia. The severity of motor functions was graded on a scale of 0 to 4 points at 35, 70, 105, and 140 minutes after injection of the above substances, where 0 and 4 represent the absence and most pronounced degree of pathological movements, respectively.

RESULTS: The result analysis showed that the greatest effect on reducing the severity of limb dyskinesia, axial dyskinesia, and chewing dyskinesia in rats was observed at 105 and 140 minutes after injections of the studied substances. Statistically significant differences between the control group and rats receiving injections of the studied substances were revealed at all the time points for limb dyskinesia; i.e., at 35, 105, and 140 minutes for axial dyskinesia and at 105 and 140 minutes for chewing dyskinesia.

CONCLUSIONS: In the experimental model of parkinsonism, IEM2295 and IEM2296 show antiparkinsonian and antidyskinetic activity because they reduce the severity of motor function disorders in rats with levodopa-induced dyskinesia. The results indicate the prospects for continued development of these substances and further research for effective and safe antiparkinsonian agents among compounds of this class.

Keywords

6-hydroxydopamine / dyskinesia / levodopa-induced complications / NMDA / Parkinson’s disease / parkinsonism

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