RESUMEN
Fatty acids play a critical role in brain function but their specific role in the pathophysiology of Parkinson disease (PD) and levodopa-induced motor complications is still unknown. From a therapeutic standpoint, it is important to determine the relation between brain fatty acids and PD because the brain fatty acid content depends on nutritional intake, a readily manipulable environmental factor. Here, we report a postmortem analysis of fatty acid profile by gas chromatography in the brain cortex of human patients (12 PD patients and nine Controls) as well as in the brain cortex of monkeys (four controls, five drug-naive MPTP monkeys and seven levodopa-treated MPTP monkeys). Brain fatty acid profile of cerebral cortex tissue was similar between PD patients and Controls and was not correlated with age of death, delay to autopsy or brain pH. Levodopa administration in MPTP monkeys increased arachidonic acid content (+7%; P < 0 .05) but decreased docosahexaenoic acid concentration (-15%; P < 0.05) and total n-3:n-6 polyunsaturated fatty acids ratio (-27%; P < 0.01) compared to drug-naive MPTP animals. Interestingly, PD patients who experienced motor complications to levodopa had higher arachidonic acid concentrations in the cortex compared to Controls (+13.6%; P < 0.05) and to levodopa-treated PD patients devoid of motor complications (+14.4%; P < 0.05). Furthermore, PD patients who took an above-median cumulative dose of levodopa had a higher relative amount of saturated fatty acids but lower monounsaturated fatty acids in their brain cortex (P < 0.01). These results suggest that changes in brain fatty acid relative concentrations are associated with levodopa treatment in PD patients and in a non-human primate model of parkinsonism.
Asunto(s)
Corteza Cerebral/metabolismo , Ácidos Grasos/metabolismo , Levodopa/farmacología , Metabolismo de los Lípidos/fisiología , Enfermedad de Parkinson/metabolismo , Trastornos Parkinsonianos/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Ácido Araquidónico/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Cromatografía de Gases , Grasas de la Dieta/metabolismo , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Dopaminérgicos/farmacología , Discinesia Inducida por Medicamentos/metabolismo , Discinesia Inducida por Medicamentos/fisiopatología , Ácidos Grasos Insaturados/metabolismo , Femenino , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Macaca fascicularis , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Enfermedad de Parkinson/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Cambios Post Mortem , Especificidad de la EspecieRESUMEN
The steroid dehydroepiandrosterone (DHEA) is abundant in men and women and decreases rapidly during aging. Parkinson's disease (PD) is the second most common neurodegenerative disorder just behind Alzheimer. l-3,4-Dihydroxyphenylalanine (l-Dopa) therapy remains the most effective treatment but many patients develop motor complications. This study investigated the acute effect of DHEA alone and with l-Dopa in 12 females monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model PD. DHEA administration alone improved the mean parkinsonian score at 1, 5 and 15mg/kg in moderately and severely impaired MPTP monkeys and increased blood DHEA concentrations. DHEA with a low dose of l-Dopa increased the l-Dopa effect in moderately and severely impaired MPTP monkeys. DHEA lengthened duration of the effect of the low dose of l-Dopa by 15-45min. DHEA at 1, 5 and 15mg/kg combined with a high dose of l-Dopa did not increase dyskinesias. DHEA could act by reducing inhibitory GABAergic activity in the striatal output pathways. DHEA could also be metabolized into estradiol in the brain and increase acutely dopamine activity.