Table 3.

Therapeutic approaches of kynurenine pathway in in vitro and in vivo of Parkinson's disease.

Therapy	Aim of the study	Model	Dosage	Effects	Results	Ref
Ro- 61-8048	Prolong administration of KMO inhibitor reduces LID	Four MPTP treated monkeys received L-dopa (100 mg) and benserazide (25 mg) for a month to develop LID	50 mg/kg daily before treating with L-Dopa/benserazide for a month	↑serum kynurenine		[119]
				↑KYNA reverted after last treatment	LID was reduced whereas no effects no L-Dopa
			First experiment
	Assess the NMDA receptor in L-DOPA + MPTP treated monkeys	Two experiments were conducted in MPTP treated monkeys	1)MPTP treated group (0.5 mg in saline)			[120]
			2) L-Dopa/benserazide treated (100/25 mg)	Glutamate receptors analyzed by autoradiography using [3H]CGP-39653 (NR1/NR2A antagonist) and [3H]Ro25–6981 (NR1/NR2B antagonist).	Striatal [3H]CGP-39653 was unaltered↓ MPTP lesion [3H]Ro25–6981 binding seen in L-Dopa alone treated MPTP monkeys ↓antidyskinetic drugs treated monkeys
			3) L-Dopa + CI1041 (10 mg/kg)
			4) L-Dopa + cabergoline (0.015 to .035 mg/kg)
			Second experiment
			1) MPTP treated
			2) L-Dopa/benserazide (100/25 mg)
			3) Ro- 61-8048 (50 mg/kg) + L-Dopa
	To examine the biochemical and behavioral effects of systemic Ro 61–8048 administration in MPTP parkinsonian monkeys	Four to six female monkeys	MPTP was administered about 40 ml by oral gavage Prolopa (a mixture of 100 mg L-Dopa and 25 mg benserazide)administered orally	↑ KYNA concentration in serum and CSF when administered Ro 61–8048 alone or with L-Dopa	Ro 61–8048 + L-Dopa administration reduced dyskinesias	[121]
					Elevation of KYNA levels through inhibition of kynurenine 3-hydroxylase constitutes a novel approach for managing LID in PD
KYNA pre-treatment	induced neuronal cell death cause increase mitochondrial dysfunction and caspase9/3 activity	SH-SY5Y and SK-N-SH human neuroblastoma cells	Cell lines treated with KYNA 2 h before MPP+ treatment	↑Bax expression and Δψm ↑ cytochrome c release and caspase9/3 activity	KYNA plays a protective role by declining Bax expression and maintaining mitochondrial dysfunction	[50]
L-Kyn + probenecid	Treatment with L-KYN and probenecid evaluated behavioral, morphological and neurochemical alterations in 6-OHDA rats	Rodents	probenecid (50 mg/kg, i.p.) + L-KYN (75 mg/kg, i.p.) and injected with 6-OHDA (20 μg/2 μl)	↑rotation behavior, ↑striatal reactive gliosis, ↑neurodegeneration, ↓ dopamine levels	Therapy modulated glutamatergic and cholinergic activities by increasing endogenous KYNA levels	[51]
Nicotinylalanine+ L-kynurenine and probenecid	Protection of dopaminergic neurons against QUIN toxicity through endogenous KYNA	Rats	nicotinylalanine (5.6 nmoles), kynurenine (450 mg/kg i.p.) and probenecid (200 mg/kg i.p.) induced	↑ KYNA levels with ↓ QUIN levels in substantia nigra and whole brain	The ↑ KYNA levels prevent the loss of dopaminergic neurons from QUIN infusion	[42]
Synthetic kynurenines	Effects of four synthetic kynurenines on MPTP treated PD model	Mice	Seven doses of MPTP (7 × 15 mg/kg) injected: four doses of 15 mg/kg MPTP injected (sc) on the first day and three additional doses after 24 h. Later, kynurenine (20 mg/kg)injected	↓iNOS/i-mtNOS activity, complex I activity	synthetic kynurenines hasneuroprotective properties against PD	[114]

PD – Parkinson's disease; MPTP - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; L-Dopa – Levodopa; LID – L-Dopa induced dyskinesia; KMO – kynurenine -3-monooxygenase; KYNA – kynurenic acid; NMDA - N-methyl-d-aspartate; [³H] – tritium radioactive; NR1,NR2A,NR2B – subunits of NMDA receptors; MPP+ − 1-methyl-4-phenylpyridinium; Δψ_m– mitochondrial membrane potential; L-Kyn – L-Kynurenine; 6-OHDA - 6-hydroxydopamine; QUIN –quinolinic acid; iNOS – inducible nitric oxide synthase; i-mtNOS – mitochondrial iNOS; AMPA- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.