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 rescue of rat facial motoneurons axotomized at postnatal day 14 (P14) was investigated using the (+)- and (-)-enantiomers of deprenyl [S(+)-deprenyl and R(-)-deprenyl]. Previously, doses of R(-)-deprenyl sufficient to inhibit MAO-B were shown to increase the survival of motoneurons following 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. The 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 microns sections were taken through the length of the facial nuclei ipsilaterally and contralaterally to the facial nerve transections. Every third section was immunoreacted for an antibody against ChAT to identify the motoneuron somata, while every adjacent third section was Nissl stained to assess motoneuronal survival. A second series of P14 rats was treated with similar doses of the two deprenyl enantiomers or saline and the brainstems removed for measurement of MAO-A and MAO-B activity at 4 hr after the treatments. Averages of 24% of the facial motoneurons survived axotomy with either saline treatment or 0.001 mg/kg/2d doses 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 48%, 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 survival, revealing a stereospecificity for the increased survival of at least 2000-fold. The ED50 for MAO-B inhibition in the P14 brainstem was approximately 0.1 mg/kg for the (-)-enantiomer and 2.0 mg/kg for the (+)-enantiomer, revealing a 20-fold higher sensitivity of the enzyme toward the (-)-enantiomer in the P14 rat brainstem. A dose of 10 mg/kg of S(+)-deprenyl inhibited about 65% of brainstem MAO-B activity without increasing motoneuronal survival, whereas 0.005 and 0.01 mg/kg of R(-)-deprenyl increased motoneuronal survival without significant inhibition of brainstem MAO-B activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Ansari
K S
KS
Department of Physiology, University of Toronto, Ontario, Canada.
Yu
P H
PH
Kruck
T P
TP
Tatton
W G
WG
D000375:Aging / Q000502:physiology; D000818:Animals; D001369:Axons / Q000502:physiology*; D001933:Brain Stem / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects*; D002795:Choline O-Acetyltransferase / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005154:Facial Nerve / Q000166:cytology / Q000502:physiology*; D007839:Functional Laterality; D008995:Monoamine Oxidase / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology*; D013237:Stereoisomerism; D013997:Time Factors
D012642:Selegiline; D008995:Monoamine Oxidase; D002795:Choline O-Acetyltransferase