Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemiain the rat

Rasagiline, as the mesylate salt (TVP-1012), is a selective, potent, non-re versible MAO-B inhibitor of the propargylamine type. Current cellular and w hole animal studies suggested a potential for neuroprotection by rasagiline . Rasagiline in repeat ip doses of 1-3mg/kg within 16h, or by sustained iv infusion to maintain a 3-h steady-state at corresponding levels, improved t he outcome of permanent middle cerebral artery occlusion (MCAO) in the rat. In five independent studies using different protocols, rasagiline improved neurological severity score (NSS) with respect to saline from a high of 8. 96 +/- 2.18 (n = 94) at 24h, and 7.64 +/- 2.52 (n +/- 49) at 48h, to a low of 7.13 +/- 2.32 (n = 88) at 24h, and 4.99 +/- 2.31 (n = 68) at 48h. Under the same conditions, there was a decrease in the volume of necrotic brain r egion determined at 48h by triphenyl tetrazolium chloride (TTC), from a hig h of 240 +/- 66 (n = 54) to a low of 176 +/- 77mm(3) (n = 55); and by MRI s can at 48h, from a high of 297 +/- 62 (n = 25), to a low of 209 +/- 63mm(3) (n = 28). Improvement in NSS was more obvious at 48h post MCAO, at the hig her dose, when timing of drug administration was within the interval - 30 m in to 3 h from MCAO. A 3-h iv infusion of rasagiline caused a maximal reduc tion in infarct volume of about 49 % of control. The (S)enantiomer of rasag iline TVP-1022, not a MAO inhibitor, was less effective, but still signific antly different from saline, NSS at 48h 5.6 +/- 2.5 (n = 24) vs. 7.5 +/- 2. 5 (n = 24), infarct volume 200 +/- 64 (n = 24) vs. 240 +/- 55mm(3) (n = 24) . Selegiline (n = 19) at corresponding ip doses was not different from sali ne. Dizocilpine decreased infarct volume from 277 +/- 65 (n = 20) to 203 +/ - 52mm(3) (n = 21) but could not improve NSS at 24 or 48h. In this model, r asagiline could have exerted a neuroprotective effect independent of MAO in hibition.