STRUCTURE-ACTIVITY RELATIONSHIPS OF SELECTED FLAVONOIDSAND THEIR NEUROPROTECTIVE PROPERTY IN ROTENONE-INDUCED PARKINSONISM

Abstract

Parkinson’s disease (PD) is a progressive,neurodegenerative disorder that affects nerve cells in the basal ganglia and the substantia nigra of the brain. Rotenone, an active ingredient in many pesticides blocks NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain and induces nigrostriatal degeneration in rodents, thus reproducing the pathological features of PD. Drugs for the treatment of PD that are currently available only treat the symptoms and do not slow or prevent progressive neuronal degeneration in the dopaminergic system. However, there is a growing body of evidence suggesting that flavonoids and flavonoid-rich foods may be capable of counteracting such neuronal injury, thereby delaying the progression of PD. The bioactivities of flavonoids are dependent on their structures. Hence, this study was aimed at assessing the structure-activity relationships of selected flavonoids (catechin, quercetin and taxifolin) and their neuroprotective property in rotenone-induced parkinsonism.Male Wistar albino rats were divided into eleven groups with twelve animals per group. Group 1 served as negative control while group 2 was administered rotenone (1.5 mg/kg body weight) for 10 days. Groups 3-11 were administered rotenone for 10 days followed by treatment with catechin (5, 10 and 20 mg/kg body weight), quercetin (5, 10 and 20 mg/kg body weight) and taxifolin (0.25, 0.5 and 1.0 mg/kg body weight), respectively for 3 days. After the period of treatments, the animals were examined for neurobehavioral abnormalities and then sacrificed. The brains were excised and the cortex, hippocampus and striatum separated for biochemical estimations and histopathological examination. Dopamine and calcium ion (Ca2+) levels were evaluated as well asactivities of complex I, tyrosine hydroxylase (TH), monoamine oxidase (MAO), acetylcholinesterase (AchE), glutamine synthetase (GS),glutamate dehydrogenase (GDH), Na+K+-ATPase, lactate dehydrogenase (LDH) and myeloperoxidase (MPO). Histopathological examination was carried outon the striatum using Haematoxylin and Eosin Staining (H&E).Results indicated that there was significant (p<0.0001) ameliorationof rotenone-induced neurological and motor deficits in parkinsonian ratstreated with the selected flavonoidswhen compared to rotenone intoxicated group as adjudged by their effects on bradykinesia, catalepsy, postural instability, open field, tremor, beam balance, pole and hanging wire tests. There was significant (p<0.0001) correction in dopamine metabolism and other neurotransmitters as adjudged by their effects on TH, AchE and MAO activities,mitochondrial dysfunction was also significantly ameliorated (p<0.0001) in rats with rotenone-induced parkinsonism treated with the selected flavonoids when compared to the rotenone intoxicated group.In addition, the flavonoids significantly (p<0.0001) increasedthe activities of GS, GDH and Na+K+-ATPase and significantly (p<0.0001) decreased the activities LDH and MPO as well as Ca2+ levelin rotenone intoxicated rats. These results were consistent with the histopathological findings which showed significant attenuation of neuronal cell death in rotenoneintoxicated rats treated with the selected flavonoids.Comparatively, based on the result, quercetin appeared to show better protection than catechin. Taxifolin, despite applying the lowest doses appeared to be relatively more effective than quercetin which can be adduced to their structural differences that offers the advantage one had over the other in terms of activities.In Conclusion, this study demonstrates the neuroprotective and anti-inflammatory effects of the selected flavonoids against rotenone-induced parkinsonism.