Rescue of axotomized immature rat facial motoneurons by R(-)-deprenyl: stereospecificity and independence from monoamine oxidase inhibition

Abstract

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)

Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease

“…However, post-treatment selegiline reversed the shortening of the stride lengths. Moreover, this was not associated with other neurorescue mechanisms apart from MAO-B inhibition; the dose of selegiline (1.0 mg/kg/day) used in our study was lower than the dose reported to inhibit MAO (37). Furthermore, the delayed start of administration in our experiment ensured that any observed effects were not due to the compound interfering with the conversion of MPTP to its active metabolite, MPP + , a reaction that is mediated by MAO-B (15).…”

Neuroprotective actions of selegiline

“…Ansari et al (1993) showed that selegiline rescued axotomized motoneurons independently of an inhibition of MAO-B. Other results have shown that the neurotrophic factors, such as basic fibroblast growth factor (bFGF; Grothe and Unsicker, 1992), brain-derived neurotrophin factor (BDNF; Yan et al, 1992), and ciliary neurotrophic factor (CNTF; Sendtner et al, 1992), reduce experimental axotomy-induced death of facial or hypoglossal motoneurons in neonatal or immature rats similarly to the reduction produced by selegiline.…”

MAO‐B Inhibition by a Single Dose of l‐Deprenyl or Lazabemide Does Not Prevent Neuronal Damage Following Focal Cerebral Ischaemia in Rats

“…Thomas et al (1997) suggested that peroxyl radical trapping by l-deprenyl rather than ¡ OH trapping activity contributes to the therapeutic efficacy of MAO-B inhibitors. Results of studies using low doses of l-deprenyl (Ͻ0.01 mg/kg) after facial nerve transection suggest that its neuroprotective mechanism is independent of MAO-B inhibition (Ansari et al 1993). This notion is consistent with the finding that l-deprenyl protects against Author for correspondence: J. Jolkkonen, Department of Neuroscience and Neurology, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland (fax π358 17 162048, e-mail jukka.jolkkonen/uku.fi).…”