RESCUE OF AXOTOMIZED IMMATURE RAT FACIAL MOTONEURONS BY R(-)-DEPRENYL- STEREOSPECIFICITY AND INDEPENDENCE FROM MONOAMINE-OXIDASE INHIBITION

The role of monoamine oxidase B (MAO-B) in R(-)-deprenyl-mediated resc ue of rat facial motoneurons axotomized at postnatal day 14 (P14) was investigated using the (+)- and (-)-enantiomers of deprenyl [S(+)-depr enyl and R(-)-deprenyl]. Previously, doses of R(-)-deprenyl sufficient to inhibit MAO-B were shown to increase the survival of motoneurons f ollowing an apparent loss of target-derived trophic support caused by axotomy in P14 rats. In the present experiments, motoneuronal survival was measured 21 d after unilateral facial nerve transection at P14. T he animals were treated with saline or doses of R(-)- or S(+)-deprenyl ranging from 0.001 to 10 mg/kg every 2 days (/2d). Frontal serial 10 mum sections were taken through the length of the facial nuclei ipsila terally and contralaterally to the facial nerve transections. Every th ird section was immunoreacted for an antibody against ChAT to identify the motoneuron somata, while every adjacent third section was Nissl s tained to assess motoneuronal survival. A second series of P14 rats wa s treated with similar doses of the two deprenyl enantiomers or saline and the brainstems removed for measurement of MAO-A and MAO-B activit y at 4 hr after the treatments. Averages of 24% of the facial motoneur ons survived axotomy with either saline treatment or 0.001 mg/kg/2d do ses of R(-)-deprenyl. Doses of R(-)-deprenyl of 0.005, 0.01, and 10.0 mg/kg/2d increased the surviving facial motoneuron to 38%, 51 %, and 4 8%, respectively, indicating an ED50 of about 0.005 mg/kg/2d. Doses of S(+)-deprenyl as high as 10 mg/kg/2d did not increase motoneuronal su rvival, revealing a stereospecificity for the increased survival of at least 2000-fold. The ED50 for MAO-B inhibition in the P14 brainstem w as approximately 0.1 mg/kg for the (-)-enantiomer and 2.0 mg/kg for th e (+)-enantiomer, revealing a 20-fold higher sensitivity of the enzyme toward the (-)-enantiomer in the P14 rat brainstem. A dose of 10 mg/k g of S(+)-deprenyl inhibited about 65% of brainstem MAO-B activity wit hout increasing motoneuronal survival, whereas 0.005 and 0.01 mg/kg of R(-)-deprenyl increased motoneuronal survival without significant inh ibition of brainstem MAO-B activity. The dosage relationships for moto neuronal rescue versus MAO-A and MAO-B inhibition and the marked diffe rence in the stereospecificity of MAO-B inhibition versus that of moto neuronal rescue show that the increased survival is unlikely to be dep endent on the interaction of deprenyl with the FAD site of MAO-A or MA O-B, and instead appears to depend on a stereospecific interaction at an as yet unknown site.