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

Summary.

Rasagiline, as the mesylate salt (TVP-1012), is a selective, potent, non-reversible MAO-B inhibitor of the propargylamine type. Current cellular and whole animal studies suggested a potential for neuroprotection by rasagiline. Rasagiline in repeat ip doses of 1–3 mg/kg within 16 h, or by sustained iv infusion to maintain a 3-h steady-state at corresponding levels, improved the 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 24 h, and 7.64 ± 2.52 (n ± 49) at 48 h, to a low of 7.13 ± 2.32 (n = 88) at 24 h, and 4.99 ± 2.31 (n = 68) at 48 h. Under the same conditions, there was a decrease in the volume of necrotic brain region determined at 48 h by triphenyl tetrazolium chloride (TTC), from a high of 240 ± 66 (n = 54) to a low of 176 ± 77 mm³ (n = 55); and by MRI scan at 48 h, from a high of 297 ± 62 (n = 25), to a low of 209 ± 63 mm³ (n = 28). Improvement in NSS was more obvious at 48 h post MCAO, at the higher dose, when timing of drug administration was within the interval −30 min to 3 h from MCAO. A 3-h iv infusion of rasagiline caused a maximal reduction in infarct volume of about 49% of control. The (S)enantiomer of rasagiline TVP-1022, not a MAO inhibitor, was less effective, but still significantly different from saline, NSS at 48 h 5.6 ± 2.5 (n = 24) vs. 7.5 ± 2.5 (n = 24), infarct volume 200 ± 64 (n = 24) vs. 240 ± 55 mm³ (n = 24). Selegiline (n = 19) at corresponding ip doses was not different from saline. Dizocilpine decreased infarct volume from 277 ± 65 (n = 20) to 203 ± 52 mm³ (n = 21) but could not improve NSS at 24 or 48 h. In this model, rasagiline could have exerted a neuroprotective effect independent of MAO inhibition.