SPARING BY RASAGILINE (TVP-1012) OF CHOLINERGIC FUNCTIONS AND BEHAVIOR IN THE POSTNATAL ANOXIA RAT

Rasagiline (N-propargyl-1(R)aminoindan) is a selective and potent MAO- B inhibitor currently under development as the mesylate salt (TVP-1012 ) for the treatment of various neurologic disorders. Preliminary work in adult and senescent rats, either normal or hypoxia-lesioned, showed that chronic rasagiline treatment improved performance in memory and learning tasks, suggesting some beneficial effect on central cholinerg ic function. We have now used the postnatal anoxia-lesioned rat as a m odel of cholinergic dysfunction. In the neonatal rat, anoxia strongly affects the cholinergic system, which has not yet reached full maturat ion at this state of life. Rasagiline mesylate was administered from d ay 1 to completion of the study (day 60), first through nursing mother milk until weaning (day 21), then in drinking water, at the rate of 0 .5 mg/kg/day. Drug access to the CNS was verified by analysis of MAO a ctivity in brain (at 21 days). Treatment improved the juvenile hyperac tivity syndrome associated with anoxia (at day 28). It improved perfor mance in the passive avoidance test to normal control level (at day 40 ). It improved spatial memory performance in the Morris water maze to normal control level (at day 50). The untreated anoxia group failed in these tasks and was significantly inferior to either the normal contr ol and rasagiline-treated anoxia groups. Determination of ChAT activit y in the caudate and hippocampus of rats from each of these groups gav e the following results (pmol ACh/mg protein/min). Caudate: normal con trol, 588 +/- 56; anoxia, 398 +/- 54; rasagiline-treated anoxia, 536 /- 35. Hippocampus: normal control, 380 +/- 31; anoxia, 275 +/- 47: ra sagiline-treated anoxia, 325 +/- 35. Results are mean +/- SD from each of seven to nine different donors in a group. Thus, improvement in me mory and learning tasks of the rasagiline-treated anoxia group finds c orrespondence in the activity of the cholinergic marker ChAT in two br ain regions that have prominent cholinergic innervation. (C) 1998 Else vier Science Inc.