01 December 2004
Indolalkylamines derivatives as antioxidant and neuroprotective agents in an experimental model of Parkinson’s diseaseElisenda Sanz, Manuel Romera, Lydia Belyk, J I Marco, Mercedes Unzeta
Med Sci Monit 2004; 10(12): BR477-484 :: ID: 13228
Background:The neuroprotective effect of N-(2-propynyl)2-(5-benzyloxy-indol)methylamine (PF 9601N), a novel MAO B inhibitor, and its metabolite FA 72 on the human neuroblastoma SHSY5Y cell line lesioned with (300 M) dopamine was assessed and compared with that of l-deprenyl assayed at identical experimental conditions.Material/Methods:Using this experimental model, PF 9601N showed a neuroprotective effect in a dose-dependent manner, and at a concentration of 10 μM a 20% recovery of cell viability was observed. However, the metabolite FA72 assayed under the same experimental conditions showed an increase in cell viability of nearly 50%. In the case of l-deprenyl, a concentration of 100 μM was necessary to recover only 10% of cell viability.Using this experimental model, PF 9601N showed a neuroprotective effect in a dose-dependent manner, and at a concentration of 10 μM a 20% recovery of cell viability was observed. However, the metabolite FA72 assayed under the same experimental conditions showed an increase in cell viability of nearly 50%. In the case of l-deprenyl, a concentration of 100 μM was necessary to recover only 10% of cell viability.Results:This neuroprotective effect could be explained in terms of the antioxidant capacity of PF 9601N. In this context, the antioxidant capacities of the novel series of MAO inhibitors, PF 9601N and its analogues, were evaluated by their inhibition of the auto-oxidation of dopamine to melanin and by the dichlorofluorescein and 2-deoxyribose methods.Conclusions:All of these compounds have the basic structure of an indole ring in common, but show different substituents at different positions in it. The corresponding structure-activity relationship studies allowed us to conclude that the presence of a benzyloxy group, or a hydroxy or methoxy group, at position 5 of the indol ring enhanced these antioxidant characteristics, presenting a decreasing order of antioxidant activity of the primary > secondary > tertiary amines. The antioxidant properties of PF 9601 N would explain its neuroprotective effect observed in SHSY5Y cells lesioned with dopamine.
Keywords: Antiparkinson Agents - chemistry, Antiparkinson Agents - pharmacology, Melanins - biosynthesis, Neuroprotective Agents - chemistry, Reactive Oxygen Species - analysis, Tryptamines - pharmacology, Antioxidants - therapeutic use, Antiparkinson Agents - therapeutic use, Brain - metabolism, Brain Chemistry, Dopamine - pharmacology, Dose-Response Relationship, Drug, Indoles - therapeutic use, Melanins - biosynthesis, Monoamine Oxidase Inhibitors - therapeutic use, Neuroblastoma, Neuroprotective Agents - therapeutic use, Oxidative Stress - drug effects, Parkinson Disease - drug therapy, Reactive Oxygen Species - metabolism, Selegiline - pharmacology, Tryptamines - pharmacology
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