Evaluación del potencial terapéutico del extracto vegetal Zanthoxylum martinicense asociado a la actividad agonista de LXR en el modelo murino de enfermedad de Alzheimer (3xTg-AD)
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Pérez Silva, Ana Milena
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Abstract
Evaluation of the therapeutic potential of plant extract from Zanthoxylum martinicense associated with agonist activity of LXR in the murine model of Alzheimer's disease (3xTg-AD)
Alzheimer's disease is a neurodegenerative disorder characterized by a cognitive impairment pathologically associated by the formation of amyloid plaques and neurofibrillary tangles. The amyloid hypothesis postulates that the origin of the disease begins with the accumulation of Aβ peptides, which trigger processes of neuroinflammation, deregulation of kinases, reactive oxygen species increase, loss of dendritic spines, and neuronal death. Preliminary studies have shown that the plant extract Zanthoxylum martinicense presents LXR agonist activity, and the activation of these receptors is related to the modulation of biomarkers of Alzheimer's disease (such as cholesterol homeostasis, the aggregation of amyloid deposits and neuroinflammation) to prevent the development of the pathology. Therefore, the objective is to evaluate the therapeutic potential of the plant extract Zanthoxylum martinicense with LXR agonist activity in the 3xTg-AD murine model. Method: The plant extract Zanthoxylum martinicense was administered orally for 90 days, with doses of 50mg/kg/day and 100mg/kg/day in 3xTg-AD mice of 15 months of age, in order to evaluate: (1) cognitive changes at the behavioral level using the Morris water maze, (2) its effect on Aβ load and the expression of τ, GFAP and Iba-1 and (3) changes in the level of expression of APOE and ABCA1 protein in the hippocampus and cerebral cortex of 3xTg-AD mice. Results: It was shown that the treatment with the plant extract Zanthoxylum martinicense reduced the immunolabeling of the amyloid pathology in a dose-dependent manner (p = 0.0002), it tended to decrease the area of positive immunoreactivity of τ (p = 0.1619), followed by a reversion in neuroinflammation processes at a morphological and immunohistochemical level for GFAP (p = 0.0857) and Iba-1 (p = 0.0286) and increased the expression level of some LXR transcriptional targets: APOE and ABCA1 (p < 0 0001) in the hippocampus and cerebral cortex of 3xTg-AD mice compared to 3xTg-AD animals treated with the vehicle (3xTg-AD VH), which it is associated with an improvement in the consolidation process of spatial memory and learning of 3xTg-AD mice, resembling this behavior to C57 control group in the Morris water maze, which did not present any type of cognitive damage. For this reason, the LXR agonist activity in the Zanthoxylum martinicense plant extract has shown promising therapeutic potential in murine models with the Alzheimer's disease phenotype, which has been associated with an improvement at a cognitive level as a result of a decrease in the immunolabeling of the main histopathological biomarkers of the disease and an increase in the level of expression of its transcriptional targets: APOE and ABCA1.
Keywords: Alzheimer´s disease, Zanthoxylum martinicense, Aβ, τ, GFAP, Iba-1, APOE, ABCA1
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