Kynurenine 3-hydroxylase is a component of the kynurenine pathway involved in neuronal injury. Ro 61-8048 is an inhibitor of kynurenine 3-hydroxylase with an IC50 value of 37 ± 3nM. It acts as a competitive inhibitor of kynurenine 3-hydroxylase with a Ki value of 4.8 ± 2.1nM. The ED50 values (μmol/kg, p.o.) of Ro 61-8048 for the ex vivo inhibition of kynurenine 3-hydroxylase activity in rat kidney and liver are 1.2 (0.8 – 1.3) and 4.7 (3.6 – 5.6), respectively. Ro 61-8048 also inhibited kynurenine 3-hydroxylase activity in Gerbils brain, kidney, and liver with ED50 values (μmol/kg, p.o.) of 5.5 (3.3 – 9.2), 0.8 (0.5 – 1.2), and 0.4 (0.3 – 0.5). In rat hippocampus after implantation of a transversal microdialysis probe, Ro 61-8048 at a dose of 50μmol/kg (p.o.) led to a 4-fold increase in kynurenic acid levels.[3]
作用机制
Ro 61-8048 is a competitive inhibitor of kynurenine 3-hydroxylase.[3]
Ro 61-8048 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Trypanosoma brucei brucei (427)
50 μM to 12 pM
48 hours
To evaluate the effect of Ro-61-8048 on trypanosome growth, results showed no significant effect on trypanosome proliferation
Brain. 2009 May;132(Pt 5):1259-67.
Human hippocampal progenitor cells HPC03A/07
10 μM
10 days
Ro 61-8048 partially reversed the IL-1β-induced reduction in neurogenesis. Dcx-positive cells changed from −42% with IL-1β alone to −26% with IL-1β plus inhibitor; MAP2-positive cells changed from −37% with IL-1β alone to −22% with IL-1β plus inhibitor.
Neuropsychopharmacology. 2012 Mar;37(4):939-49.
Ro 61-8048 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Female CD1 mice
Human African trypanosomiasis model
Intraperitoneal injection
100 mg/kg
Every second day from Day 12 until Day 28 post-infection
To assess the effect of Ro-61-8048 on CNS inflammation, results showed a significant reduction in neuroinflammatory response during the late stage of infection
Brain. 2009 May;132(Pt 5):1259-67.
Rats
Freely-moving rats
Intraperitoneal injection
30 and 100 mg/kg
Single administration
Ro 61-8048 significantly increased extracellular KYNA levels in the NAc shell and VTA, and dose-dependently blocked THC-induced elevations of dopamine in these areas.
Nat Neurosci. 2013 Nov;16(11):1652-61
C57BL/6 mice
Experimental autoimmune encephalomyelitis (EAE) model
Intraperitoneal injection
100 mg/kg
Once daily for 7 days
Inhibition of KMO enzyme activity increases the synthesis of neuroprotective metabolite KYNA and reduces the synthesis of neurotoxic metabolite QUIN, thereby ameliorating EAE disease severity.
J Neuroinflammation. 2020 Jun 6;17(1):176
Rats and squirrel monkeys
Nicotine self-administration and relapse models
Intraperitoneal injection (rats) and intramuscular injection (squirrel monkeys)
Administered 40 min before sessions, lasting for 3 days
Ro 61-8048 significantly reduced nicotine self-administration and blocked nicotine-induced dopamine release in the nucleus accumbens shell. In squirrel monkeys, the effects of Ro 61-8048 were reversed by the positive allosteric modulator of α7nAChRs, PNU120596, indicating the involvement of α7nAChRs in its mechanism of action.
Neuropsychopharmacology. 2017 Jul;42(8):1619-1629
C57BL/6J mice
Chronic Intermittent Ethanol (CIE) model
Intraperitoneal injection
50 mg/kg
Single dose, observed for 12 hours
Ro 61-8048 reduces ethanol consumption and preference by inhibiting KMO, an effect that involves α7nAChR and depends on the influx of peripheral kynurenine into the brain.
Br J Pharmacol. 2022 Jul;179(14):3711-3726
Mice
Spared nerve injury (SNI) model
Intracerebroventricular injection
0.4 μg/2 μl/day
Once daily for two days
Ro 61-8048 significantly blocked the increased immobility time in the forced swim test in SNI mice without affecting mechanical allodynia
Brain Behav Immun. 2017 Nov;66:94-102
Sprague-Dawley rats
Freely moving rats
Intraperitoneal injection
30 or 100 mg/kg
Single administration, observed for 180 minutes
To investigate the effect of Ro 61-8048 on THC-induced increases in extracellular glutamate levels in the NAcS, VTA, and mPFC, results showed that Ro 61-8048 dose-dependently blocked the effects of THC
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