Ks. Ansari et al., RESCUE OF AXOTOMIZED IMMATURE RAT FACIAL MOTONEURONS BY R(-)-DEPRENYL- STEREOSPECIFICITY AND INDEPENDENCE FROM MONOAMINE-OXIDASE INHIBITION, The Journal of neuroscience, 13(9), 1993, pp. 4042-4053
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.