Effect of kynurenine 3‐hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in parkinsonian monkeys

Abstract

Homeostatic interactions between dopamine and glutamate are central to the normal physiology of the basal ganglia. This relationship is altered in Parkinsonism and in levodopa-induced dyskinesias (LID), resulting in an upregulation of corticostriatal glutamatergic function. Kynurenic acid (KYNA), a tryptophan metabolite with antagonist activity at ionotropic glutamate receptors and the capability to inhibit glutamate release presynaptically, might therefore be of therapeutic value in LID. To evaluate this hypothesis, we used a pharmacological tool, the kynurenine 3-hydroxylase inhibitor Ro 61-8048, which raises KYNA levels acutely. Ro 61-8048 was tested in MPTP cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias after each dose of levodopa. Serum and CSF concentrations of KYNA and its precursor kynurenine increased dose-dependently after Ro 61-8048 administration, alone or in combination with levodopa. Coadministration of Ro 61-8048 with levodopa produced a moderate but significant reduction in the severity of dyskinesias while maintaining the motor benefit. These results suggest that elevation of KYNA levels through inhibition of kynurenine 3-hydroxylase constitutes a promising novel approach for managing LID in Parkinson's disease.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Antagonizing the glycine-binding site by increasing kynurenic acid levels with Ro-61-8048 also alleviated established LID, although modestly, in the MPTP-lesioned macaque, without affecting L-DOPA antiparkinsonian action (Samadi et al, 2005). Accordingly, the glycine prodrug milacemide had no effect on established LID in a small clinical trial (Giuffra et al, 1993).…”

The kynurenine pathway and neurodegenerative disease

“…Similarly to JM6, the KMO inhibitor Ro-61-8048 does not cross the BBB [83]. Nonetheless, oral administration of Ro-61-8048 has been found to increase brain concentrations of KYNA in extracellular hippocampal fluid in rats [84] and convey neuroprotection in a primate model of PD [85]. Therefore a reduction in 3-HK synthesis in the periphery due to peripherally-acting KMO inhibitors may lead to increased blood concentrations of L-KYN, which is transported across the BBB into the CNS, and preferentially converted into neuroprotective KYNA [82] (Figure 2).…”

Implication of NMDA Receptors in the Antidyskinetic Activity of Cabergoline, CI-1041, and Ro 61-8048 in MPTP Monkeys with Levodopa-induced Dyskinesias

“…A fresh solution was prepared every 2 days and was kept at 4°C under constant agitation. Animals of this experimental group received 20-25 ml of Ro 61-8048 suspension by nasogastric gavage; a dose of 50 mg/kg was given 3 h before L-DOPA administration, based on our previous acute experiment with this drug where a significant anti-dyskinetic response was obtained with 30 and 100 mg/kg of Ro 61-8048 (Samadi et al 2005;. MPTP and L-DOPA were administered as described in the first experiment.…”