Rat striatal monoamine oxidase-B inhibition by l-deprenyl and rasagiline: its relationship to 2-phenylethylamine-induced stereotypy and Parkinson's disease

Parkinsonism Relat Disord. 2002 Mar;8(4):247-53. doi: 10.1016/s1353-8020(01)00011-6.

Abstract

Rats were injected intraperitoneally with varying doses of l-deprenyl (selegiline) followed 2h later by 30 mg kg(-1) 2-phenylethylamine (PEA), administered in the same way, and the stereotypic behavioural response elicited was assessed. l-Deprenyl alone at doses of up to 5 mg kg(-1) caused no significant behavioural response. Administration of PEA without prior l-deprenyl treatment resulted in only a modest increase in stereotypic behaviour and this was not significantly enhanced by the prior administration 1 mg kg(-1) l-deprenyl. When the administered dose of l-deprenyl was increased to 2.5 or 5 mgkg(-1), however, the stereotypic behavioural response to PEA was greatly potentiated and in the latter case persisted for 60 min. A dose of 2.5 mg kg(-1) l-deprenyl and 1 mg kg(-1) rasagiline was shown to result in over 90% inhibition of the monoamine oxidase (MAO)-B from rat liver and striatum, whereas the inhibition of MAO-A was about 60 and 40% in liver and striatum, respectively. The recovery of MAO-B activity in rat striatum and liver following a single i.p. injection of 5 mg kg(-1) l-deprenyl gave first-order rate constants of 1.80 and 7.15 h(-1), respectively, which corresponded to half-lives of 9.23 and 2.33 days. Similar results were obtained with rasagiline. The corresponding indices of stereotypic response to PEA (30 mg kg(-1); i.p.) during recovery from the single dose of l-deprenyl were initially high, but had started to decline by the third day after l-deprenyl treatment and was not significant after day 4. At that time, less than 20% of the striatal monoamine oxidase-B activity had been regained, whereas the recovery of the liver enzyme was about 65%. These data are discussed in terms of the suggested involvement of PEA potentiation in the anti-parkinsonian actions of l-deprenyl and rasagiline and the duration of the 'wash-out' period used in studies on the effects of l-deprenyl on patients with Parkinson's disease. The longer duration of the recovery of brain monoamine oxidase B after its selective inhibition and the corresponding behavioural responses of the animals to PEA at same time points, indicate that PEA may have a major pharmacological role in the mechanism of the antiParkinson action of l-deprenyl and rasagiline. Brain monoamine oxidase B inhibition has previously been shown to significantly increases brain PEA and which is capable of releasing dopamine endogenously or that formed from L-dopa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Corpus Striatum / enzymology*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Indans / administration & dosage
  • Indans / pharmacology*
  • Male
  • Monoamine Oxidase / drug effects*
  • Monoamine Oxidase Inhibitors / administration & dosage
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Parkinson Disease, Secondary / chemically induced
  • Phenethylamines / pharmacology
  • Psychotropic Drugs / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Selegiline / administration & dosage
  • Selegiline / pharmacology*
  • Stereotyped Behavior

Substances

  • Indans
  • Monoamine Oxidase Inhibitors
  • Phenethylamines
  • Psychotropic Drugs
  • rasagiline
  • Selegiline
  • phenethylamine
  • Monoamine Oxidase