Impact of pyriproxyfen on virus behavior: implications for pesticide-induced virulence and mechanism of transmission.

BACKGROUND: More than 3 years since the last Zika virus (ZIKV) outbreak in Brazil, researchers are still deciphering the molecular mechanisms of neurovirulence and vertical transmission, as well as the best way to control spread of ZIKV, a flavivirus. The use of pesticides was the main strategy of mosquito control during the last ZIKV outbreak. METHODS: We used vesicular stomatitis virus (VSV) tagged with green fluorescent protein (GFP) as our prototypical virus to study the impact of insecticide pyriproxyfen (PPF). VZV-GFP infected and uninfected Jurkat, HeLa and trophoblast cells were treated with PPF and compared to untreated cells (control). Cell viability was determined by the MTT assay. Cell morphology, presence of extracellular vesicles (EVs), virus infection/GFP expression as well as active mitochondrial levels/localization were examined by confocal microscopy. RESULTS: PPF, which was used to control mosquito populations in Brazil prior to the ZIKV outbreak, enhances VSV replication and has cell membrane-altering properties in the presence of virus. PPF causes enhanced viral replication and formation of large EVs, loaded with virus as well as mitochondria. Treatment of trophoblasts or HeLa cells with increasing concentrations of PPF does not alter cell viability, however, it proportionately increases Jurkat cell viability. Increasing concentrations of PPF followed by VSV infection does not interfere with HeLa cell viability. Both Jurkats and trophoblasts show proportionately increased cell death with increased concentrations of PPF in the presence of virus. CONCLUSIONS: We hypothesize that PPF disrupts the lipid microenvironment of mammalian cells, thereby interfering with pathways of viral replication. PPF lowers viability of trophoblasts and Jurkats in the presence of VSV, implying that the combination renders immune system impairment in infected individuals as well as enhanced vulnerability of fetuses towards viral vertical transmission. We hypothesize that similar viruses such as ZIKV may be vertically transmitted via EV-to-cell contact when exposed to PPF, thereby bypassing immune detection. The impact of pesticides on viral replication must be fully investigated before large scale use in future outbreaks of mosquito borne viruses.

Exposure of dams to fluoxetine during lactation disturbs maternal behavior but had no effect on the offspring behavior.

Fluoxetine is one of the most commonly prescribed drugs for treatment of depression during pregnancy as well as postpartum. Nevertheless, fluoxetine can cross the placental barrier and/or be secreted through breastmilk and questions remain unanswered regarding safety of the unborn and/or nursing infant. Passive administration of antidepressants to infants can cause neurological developmental delay and/or dysfunction. To date, there are limited studies on neurobehavioral effects due to passive administration of fluoxetine in nursing animals. Thus, the aim of the present study was to evaluate the effects of fluoxetine exposure on the behavior of lactating dams and their offspring. Dams received either 1, 10 or 20 mg/kg fluoxetine via oral gavage (controls received water alone) from lactating day (LD) 1 to 21. Maternal behavioral studies were conducted from LD5 to LD7 and offspring studies were conducted from LD2 to LD60. Results showed dysfunction in maternal behavior, both in direct and indirect behavior, but there were no differences and/or deficiencies observed in offspring behavior. These data suggest that the impairment of dams maternal behavior combined with the amount of fluoxetine that the offspring received through breast milk during lactation did not alter their social behavior in infancy and/or adulthood, suggesting no neurodevelopmental damage associated with maternal use of fluoxetine. This study contributes to the field of human psychiatric diseases by further elucidating the effects of antidepressant medications on the health of mothers as well as children who were passively exposed to drug treatment.

Prolonged exposure of rats to varenicline increases anxiety and alters serotonergic system, but has no effect on memory.

Varenicline is a drug used for smoking addiction cessation treatment and acts as a partial agonist of nicotinic cholinergic receptors. Recent clinical trial data support use of varenicline for treatment of conditions/addictions that are not related to smoking cessation. Considering the importance of this issue and the need for new studies on its effects, especially on behavior, more studies using animal models are necessary. Thus, the aim of this study was to evaluate the effects of prolonged exposure to varenicline in anxiety-like behavior and memory, as well as in cerebral neurochemistry of rats. Male rats received three different doses of varenicline: 0.03 (therapeutic dose for humans), 0.1 and 0.3 mg/kg orally (gavage) for 30 days. Animal behavior was analyzed through open field, elevated plus maze, light/dark box, social interaction, Barnes maze and novel object recognition tests. Neurotransmitter levels and their metabolites in different brain structures (hippocampus, striatum and frontal cortex) were measured. Results showed that prolonged exposure of rats to varenicline: 1) did not interfere in motor activity, but caused an anxiogenic effect on elevated plus maze, light/dark box and social interaction testes; 2) did not alter memory; and 3) promoted alterations on serotoninergic system in the striatum and frontal cortex. In conclusion, compilation of the data indicates that prolonged exposure of rats to varenicline promoted anxiogenic effects and alteration in serotonergic system, which corroborated behavioral findings.