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

Abstract

The present study investigated the effect of postischaemic infusion of an irreversible monoamine oxidase B (MAO-B) inhibitor, l-deprenyl, an equipotent dose of a reversible MAO-B inhibitor, lazabemide, or 0.9% NaCl on infarct volumes following focal cerebral ischaemia in rats. The drug doses (0.3 mg/kg) were selected to induce selective MAO-B inhibition (45-55%), but not MAO-A inhibition. The infarct volumes in the cortex or in the striatum did not differ between the experimental groups 72 hr after transient occlusion of the middle cerebral artery, which suggests that during ischaemia/reperfusion, suppressed oxidative stress by partial MAO-B inhibition or MAO-B independent mechanisms such as induction of trophic factors, does not protect against ischaemia/reperfusion damage.l-Deprenyl (selegeline) is an irreversible monoamine oxidase B (MAO-B) inhibitor that is used in the treatment of Parkinson's disease, alone or in combination with l-DOPA. Whether the therapeutic effects are only palliative in nature or due to true neuroprotection is controversial. The neuroprotective influence of l-deprenyl is supported by data from cell culture and numerous in vivo models, including cerebral ischaemia (Salo & Tatton, 1992, Lahtinen et al. 1997.The exact neuroprotective mechanism of l-deprenyl is not known, but it might be related to diminished oxidative stress (Matsui & Kumagae 1991;Wu et al. 1993;Suzuki et al. 1995). One of the early responses to cerebral ischaemia is a massive release of neurotransmitters, including the catecholamines dopamine and noradrenaline (Globus et al. 1988). When reperfusion is introduced, oxidative metabolism of excessively released catecholamines by MAO increases H 2 O 2 production, leading to detrimental consequences (e.g., lipid peroxidation). Thus, MAO-B inhibitors, such as l-deprenyl and lazabemide, are expected to be protective against ischaemic damage. In addition, l-deprenyl might protect neurones from oxidative injury by scavenging ¡ OH free radicals (Wu et al. 1993). 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). MPP π -induced apoptosis in a dopaminergic cell line that does not contain MAO-B (Le et al. 1997). MAO-B independent action of l-deprenyl is also supported by a higher neuroprotective potency of desmethylselegeline, a metabolite of l-deprenyl in vitro (Mytilineou et al. 1997).In the present study, we investigated whether irreversible MAO-B inhibition by postischaemic infusion of l-depreny...

Perseveration in a spatial-discrimination serial reversal learning task is differentially affected by MAO-A and MAO-B inhibition and associated with reduced anxiety and peripheral serotonin levels

“…These negative findings were very unlikely to be due an insufficient dose of lazabemide since much lower doses were reported to inhibit ex vivo MAO-B activity by over 80% while leaving MAO-A activity unaffected (2 mg/kg (Henriot et al 1994); 1 mg/kg (Jolkkonen et al 2000)). Moreover, the selected high dose of lazabemide (10 mg/kg) has been shown to produce robust behavioral effects in other settings (Maki et al 2000).…”

“…Contrasting with the effects of moclobemide, selective MAO-B inhibition with lazabemide produced no significant effects on task performance nor did this compound affect tissue levels and turnover of 5-HT, DA, and NE in a number of cortical and subcortical regions. These negative findings were very unlikely to be due an insufficient dose of lazabemide since much lower doses were reported to inhibit ex vivo MAO-B activity by over 80% while leaving MAO-A activity unaffected (2 mg/kg (Henriot et al 1994 ); 1 mg/kg (Jolkkonen et al 2000 )). Moreover, the selected high dose of lazabemide (10 mg/kg) has been shown to produce robust behavioral effects in other settings (Maki et al 2000 ).…”

“…Given the relatively short washout periods for the drugs (Da Prada et al 1988 ), each animal received four separate treatments across 3-day intervals, starting with a baseline retention session (day 1), a drug administration session (day 2), and a drug-free day. Doses for moclobemide (3 and 16 mg/kg, combination of 10 mg/kg of moclobemide and 10 mg/kg lazabemide) and lazabemide (1 and 10 mg/kg) were selected on the basis of previous literature (Da Prada et al 1988 ; Jolkkonen et al 2000 ; Kitaichi et al 2006 , 2010 ; Maki et al 2000 ) and administered intraperitoneally (1 ml/kg). The dosing regimen followed a randomized modified Latin square design to control for training and crossover effects.…”