Kaempferol counteracts toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in D. melanogaster: An implication of its mitoprotective activity

Abstract

The current study aimed to investigate whether kaempferol (KMP), the major bioactive component of green leafy vegetables, could counteract the toxicity elicited by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Drosophila melanogaster or not. First, we performed a dose-response curve, where adult wild-type flies were fed on diet-containing different concentrations of KMP throughout their lifespan. Afterward, flies were fed on a diet containing MPTP (500 μM) and KMP (20 and 40 μM) for 7 days. The MPTP- fed flies presented a higher mortality rate, lower emergence rate, locomotor deficits, and disruption in circadian rhythm when compared to the control. MPTP exposure induced severe oxidative stress, which was marked by reduction in thiol content, overproduction of reactive species, lipid and protein oxidation, and disruption of enzymes of antioxidant and neurotransmission pathways. MPTP also compromised the mitochondrial dynamics and respiration of flies, affecting the electron transport chain, oxidative phosphorylation, and fusion/fission processes. Besides extending per se the lifespan of flies, KMP counteracted the toxic effects of MPTP on the circadian cycle, survival, climbing, and hatching rates. KMP was also effective in restoring the activities of acetylcholinesterase (AChE) and monoamine oxidase (MAO) enzymes, as well as in normalizing the levels of all oxidant/antioxidant markers disrupted in MPTP-fed flies. Indeed, KMP reestablished the mitochondrial functionality in MPTP- fed flies, restoring the electron transport system linked to mitochondrial complex I and II, and rescuing the mRNA transcription of genes associated with mitochondrial fusion and fission, namely OPA-1 (Optic atrophy 1) and DRP-1 (Dynamin related protein 1). Our results showed the efficacy of KMP in hindering the toxicity induced by MPTP in D. melanogaster and suggest that the mitoprotective action of flavonoid may be boosting its anti-parkinsonism activity in the model. Besides, the study showed that wild-type strains of D. melanogaster proved to be reproducible in vivo model to mimic parkinsonian phenotypes through exposure to the neurotoxin MPTP.

Keywords: D. melanogaster; Kaempferol; Oxidative stress, MPTP; Parkinson’s disease.