The neurochemical and behavioral effects of the novel cholinesterase-monoamine oxidase inhibitor, ladostigil, in response to L-dopa and L-tryptophan, in rats.
The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L-dopa- or L-tryptophan-induced rats. Chronic treatment of rats with ladostigil (52 mg kg(-1) for 21 days) inhibited hippocampal and striatal MAO A and B activities by >90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by approximately 50%. Chronic TV3279 (26 mg kg(-1) for 21 days) similarly inhibited approximately 50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L-dopa (50 mg kg(-1)) or L-tryptophan (100 mg kg(-1)), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg(-1)) and chronic TV3279 abolished the ability of TCP to initiate L-dopa-induced hyperactivity, while scopolamine (0.5 mg kg(-1)) reversed the inhibitory effect of chronic ladostigil on L-dopa-induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors.Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB).
Sagi
Yotam
Y
Eve Topf and U.S.A. National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Technion-Rappaport Faculty of Medicine, Haifa, Israel.
Driguès
Noam
N
Youdim
Moussa B H
MB
D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000201:enzymology; D001522:Behavior, Animal / Q000187:drug effects*; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D006948:Hyperkinesis / Q000139:chemically induced / Q000517:prevention & control*; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects; D020961:Lewy Body Disease / Q000188:drug therapy; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D048448:Phenylcarbamates / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068836:Rivastigmine; D012601:Scopolamine / Q000008:administration & dosage / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors; D014191:Tranylcypromine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D014364:Tryptophan / Q000008:administration & dosage / Q000009:adverse effects
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; C476551:(N-propargyl-(3R) and (3S) aminoindan-5-yl)-ethyl methyl carbamate; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018727:Muscarinic Antagonists; D048448:Phenylcarbamates; D012701:Serotonin; D014191:Tranylcypromine; D007980:Levodopa; D014364:Tryptophan; D012601:Scopolamine; D000068836:Rivastigmine; D004298:Dopamine; D009638:Norepinephrine