Avaliação dos fatores comportamentais e neuroquimicos associados ao efeito da hesperidina em modelos da doença de Parkinson e de depressão em camundongos

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in the elderly population. Its main neuropathological characteristic is the striatal dopamine (DA) depletion, which leads to the appearance of the motor symptoms of the disease. In addition to motor symptoms, the patients with this disease also present non-motor and neuropsychiatric symptoms where depression stands out. Currently, none of the drugs used is fully effective for PD, in this context, promising therapies still need to be explored. Some studies have shown that consumption of flavonoids may decrease the incidence and symptoms of neurodegenerative diseases and depressive disorders. Our previous study has found that the flavonoid hesperidin (4'-methoxy-7-O-rutinosyl-3 ', 5-dihydroxyflavanone) plays a role in PD and in the depressive behavior via oxidative stress in mice induced by 6-hydroxydopamine (6 -OHDA). Based on the evidence, is interesting to investigate the effect of hesperidin in other parameters of PD in the 6-OHDA model, besides the its antidepressant effect in olfactory bulbulometric (BO) model. To evaluate the PD, hesperidin or vehicle (50 mg / kg) were administered orally (gavage) for 28 days. After this period, the mice were submitted to behavioral tests. To assess depression in the OB model, hesperidin or vehicle (50 mg / kg) were administered orally (gavage) for 13 days. After this period, the mice were submitted to behavioral and neurochemical tests. In the 6-OHDA-induced model, treatment with hesperidin protected against inhibition of mitochondrial enzymes of complexes I, II, IV and V, Na + / K + ATPase enzyme, against the decrease in mitochondrial membrane potential, and against the increase of caspases 3 and 9 activities and inflammatory markers levels. In addition, flavonoid administration culminated in restoration of neurotrophic factors levels, as well as tyrosine hydroxylase (TH) positive neurons, DA and its metabolites levels in the striatum. The treatment with hesperidin also attenuated the behavioral changes of rotation, anxiety, anhedonia, memory and olfactory damage induced by 6-OHDA. In addition, in depression model OB-induced, oral hesperidin treatment was effective in reversing the decline of neurotrophic factors, increase of proinflammatory cytokines levels and acetylcholinesterase (AchE) activity in the hippocampus, as well as increase of locomotor activity, memory impairment, depressive behavior and anhedonia due to removal of bulbs. In DP model induced by 6-OHDA it can be proposed that hesperidin acts in the restoration of dopaminergic neurons through the reestablishment of neurotrophic factors, cytokine control, and modulation of mitochondrial and apoptotic activity in striatum, which reflects in the recovery of damages behavioral. In depression model, it is indicated that hippocampal repair on neurotrophic factors and inflammatory markers are responsible for behavioral reestablishment by hesperidin treatment. These results confirm the potential effect of hesperidin in the treatment of PD and depressive disorders, indicating that this flavonoid can act as a multi-target therapy, associating PD and mental disorders. This is due to the regulation of neurotrophic, inflammatory and apoptotic factors, enzymatic activities (AchE and Na+/K+ ATPase), mitochondrial dysfunction and dopaminergic neuronal recovery.