Aspectos moleculares e comportamentais associados ao potencial neuroprotetor do 7-cloro-4-(fenilselanil) quinolina em um modelo mimético à doença de parkinson em Drosophila melanogaster

Abstract

Parkinson's disease (PD) is associated with multiple factors, including mitochondrial impairment, apoptosis and oxidative stress, culminating in the loss of dopaminergic neurons and consequent dopamine deficiency. Clinically it is characterized by locomotor deficits, however, it is evidenced the presence of psychomotor and non-motor symptoms, whose traditional pharmacological therapy is ineffective and associated with side effects, making it essential to develop new therapeutic strategies for PD. Therefore, we evaluated the molecular and behavioral aspects associated with the neuroprotective potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) in a mitotic model for PD induced by rotenone (ROT) in Drosophila melanogaster. Adult flies were divided into groups: (1) control, (2) 4-PSQ 25μM, (3) ROT 500μM, (4) 4-PSQ 25μM + 500μM ROT, concomitantly exposed to 4-PSQ and ROT for 7 days, according to each group. Survival / mortality and behavioral tests were performed to evaluate the motor alterations related to climbing activity, exploratory capacity and spontaneous locomotor activity; and psychomotor and non-motor alterations, involving learning, memory and anxiety-like behavior. The levels of reactive species (RS), lipid peroxidation (LPO), superoxide dismutase activity (SOD), catalase (CAT), and dopamine levels in the head region were also evaluated; and acetylcholinesterase (AChE) activity and selenium levels in the head and body regions of flies. An increase in mortality of the ROT group flies was observed, while in the group treated concomitantly with the 4-PSQ a better survival. Flies exposed to ROT exhibited similar phenotype to PD, with locomotor impairment, deficits in climbing activity, exploratory capacity, and spontaneous locomotor activity; in addition to psychomotor and non-motor damage, including damage to learning, memory, and anxiety-like behavior; in contrast, 4-PSQ was able to prevent such behavioral deficiencies in flies. Exposure to ROT culminated in an increase in RS and LPO levels, in parallel with a decrease in the activity of antioxidant enzymes (SOD and CAT), while 4-PSQ treatment prevented oxidative damage and improved antioxidant defenses. Also, we observed a reduction in dopamine levels in the head of flies and, unprecedentedly, in selenium levels (head / body) with exposure to ROT; in contrast, 4-PSQ reestablished dopamine and selenium levels, and a positive correlation was observed between these two parameters. In addition, an increase in AChE activity was observed with ROT exposure, whereas 4-PSQ prevented the increase in the activity of this enzyme. Our findings evidence 4-PSQ as a multi-target molecule, acting in the dopaminergic system by different mechanisms, reducing oxidative damages, improving antioxidant defenses and exerting anticholinesterase action, factors that together can protect dopaminergic neurons, and consequently prevent mortality and motor deficits, psychomotor and non-motor in Drosophila melanogaster; actions correlated with the presence of selenium in its structure. Therefore, 4-PSQ was able to prevent molecular and behavioral alterations in this model, due to its multi-target action, and mainly for its effectiveness as antioxidant and AChE inhibitor, characteristics that potentiate its therapeutic effect in PD.