RESUMEN
A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of ß-amyloid peptides (Aß) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aß and a decrease in brain Aß monomer after 7 d, indicating increased transport of Aß from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aß-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aß levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aß. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aß, indicating that increase in liver LRP and sLRP occurring independent of Aß concentration could result in clearance of Aß. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aß clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/sangre , Hígado/efectos de los fármacos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/biosíntesis , Fitoterapia , Extractos Vegetales/uso terapéutico , Withania/química , Administración Oral , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hígado/metabolismo , Hígado/patología , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/patología , Neprilisina/biosíntesis , Neprilisina/genética , Neprilisina/fisiología , Oligonucleótidos Antisentido/farmacología , Especificidad de Órganos , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas/química , Placa Amiloide/patología , Presenilina-1/genética , Regulación hacia ArribaRESUMEN
Intracerebroventricular (i.c.v.) administration of colchicine, a microtubule-disrupting agent, causes cognitive dysfunction and oxidative stress. The present study was designed to investigate the protective effects of quercetin against colchicine-induced memory impairment and oxidative damage in rats. An i.c.v. cannula was implanted in the lateral ventricle of male Wistar rats. Colchicine was administered at dose of 15 microg/rat. Morris water maze and plus-maze performance tests were used to assess memory tasks. Various biochemical parameters such as lipid peroxidation, reduced glutathione, nitrite level, acetylcholinesterase and proteins were also assessed. Central administration of colchicine (15 microg/rat) showed poor retention of memory. Chronic treatment with quercetin (20 and 40 mg/kg, p.o.) twice daily for a period of 25 days beginning 4 days prior to colchicine injection significantly improved the colchicine-induced cognitive impairment. Biochemical analysis revealed that i.c.v. colchicine injection significantly increased lipid peroxidation, nitrite and depleted reduced glutathione activity in the brains of rats. Chronic administration of quercetin significantly attenuated elevated lipid peroxidation and restored the depleted reduced glutathione, acetylcholinesterase activity and nitrite activity. The results of the present study clearly indicated that quercetin has a neuroprotective effect against colchicine-induced cognitive dysfunctions and oxidative damage. This article was published online on 3 November 2008. An error was subsequently identified. This notice is included in the online and print version to indicate that both have been corrected.