| In Vitro | In vitro activity: Ro 61-8048 is a novel, high-affinity, oral, potent and selective kynurenine hydroxylase inhibitor with IC50 of 37 nM. It can improve dystonia in a genetic model of paroxysmal dyskinesia and has the potential to be used for the treatment of dyskinesias. In addition, Ro 61-8048 may be useful to reduce neuronal loss in brain ischemia. Upon oral administration, |
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| In Vivo | Ro 61-8048 blocked rat and gerbil kynurenine 3-hydroxylase after oral administration, with ED50's in the 3-5 mumol/kg range in gerbil brain. In a microdialysis experiment in rats, 16 dose dependently increased kynurenic acid concentration in the extracellular hippocampal fluid. A dose of 100 mumol/kg po led to a 7.5-fold increase in kynurenic acid outflow. A significant reduction in infarct volumes also was found when the kynurenine hydroxylase inhibitors were given to rats after permanent middle cerebral artery occlusion (from 207+/-111 mm3 in vehicle-treated rats to 82+/-18 and to 62+/-57 mm3 in rats treated with mNBA, 400 mg/kg intraperitoneally, or with Ro 61-8048, 40 mg/kg intraperitoneally, respectively). intrastriatal injections of Ro 61-8048 (60-80 microg/hemisphere) significantly reduced the severity of dystonia in dt(sz) hamsters. |
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