Figure 2.

JM6 is a novel pro-drug inhibitor of KMO that increases brain KYNA by blocking KMO in the blood. (A) Chemical synthesis of JM6. JM6 is a pro-drug of the KMO inhibitor Ro 61-8048. (B) Hypothetical mechanism for the acid-induced release of Ro 61-8048 from JM6. JM6 (C) and Ro 61-8048 released from JM6 (D) accumulate at high levels in plasma but not in brain or other tissues 5 h after JM6 administration (300 mg/kg p.o.) in mice. Absolute concentrations of JM6 were 40 µM (plasma), 119 nM (brain), 1.6 µM (muscle) and 5 µM (liver) (n = 5). Absolute concentrations of Ro 61-8048 were 7 µM (plasma), 18 nM (brain), 149 nM (muscle) and 132 nM (liver) (n = 5). (E) Extracellular KYNA levels in the striatum of rats measured by microdialysis following acute JM6 treatment (100 mg/kg, p.o.; arrow). In addition, in one group of animals, the KAT II inhibitor ESBA (1 mM) was applied by reverse dialysis for the first 2 h, and prevented the JM6-induced increase in KYNA levels (p<0.001, repeated-measures 2-way ANOVA; n = 5 per treatment group). (F) In the same rats, serum KYNA levels rose equally over time in the two groups, i.e. intracerebral ESBA administration did not influence circulating KYNA levels in JM6-treated rats. (G) Extracellular KYNA and glutamate were determined by in vivo microdialysis in the prefrontal cortex of rats treated for 7 days with JM6 (75 mg/kg/day p.o.). Baseline values for control rats were 2.5 ± 0.1 nM (KYNA) and 2.0 ± 0.2 µM (glutamate). (H) Extracellular KYNA correlates negatively with extracellular glutamate in these animals. *p<0.05, **p<0.01 (t-test). (n = 6 per group). Values in (C-G) are means ± s.e.m.