Cristiane de Moura Freitas

Neonatal SSRI exposure improves mitochondrial function and antioxidant defense in rat heart

Protein restriction during prenatal, postnatal, or in both periods has a close relationship with subsequent development of cardiovascular disease in adulthood. Elevated brain levels of serotonin and its metabolites have been found in malnourished states. The aim in the present study was to investigate whether treatment with fluoxetine (Fx), a selective serotonin reuptake inhibitor, mimics the detrimental effect of low-protein diet during the perinatal period on the male rat heart. Our hypothesis is that increased circulating serotonin as a result of pharmacologic treatment with Fx leads to cardiac dysfunction similar to that observed in protein-restricted rats. Male Wistar rat pups received daily subcutaneous injection of Fx or vehicle from postnatal day 1 to postnatal day 21. Male rats were euthanized at 60 days of age and the following parameters were evaluated in the cardiac tissue: mitochondrial respiratory capacity, respiratory control ratio, reactive oxygen species (ROS) production, mitochondrial membrane potential, and biomarkers of oxidative stress and antioxidant defense. We found that Fx treatment increased mitochondrial respiratory capacity (123%) and membrane potential (212%) and decreased ROS production (55%). In addition we observed an increase in the antioxidant capacity (elevation in catalase activity (5-fold) and glutathione peroxidase (4.6-fold)). Taken together, our results suggest that Fx treatment in the developmental period positively affects the mitochondrial bioenergetics and antioxidant defense in the cardiac tissue.

Serotonin modulation in neonatal age does not impair cardiovascular physiology in adult female rats: Hemodynamics and oxidative stress analysis.

AIMS The present study investigates the effects of neonatal serotonin modulation in female rats on cardiac parameters related to hemodynamics and oxidative metabolism in the mature animal. MAIN METHODS Female Wistar rat pups were administered daily subcutaneous injections of fluoxetine (Fx-treated group) or vehicle solution (Ct-group) from the 1st to 21st day of life. At 60days of age, animals from both groups were either used for cardiovascular evaluation or sacrificed for tissue collection for biochemical assays. KEY FINDINGS We found that body weight in the Fx-treated group was less than that in the control. When analyzing hemodynamic parameters (i.e., arterial blood pressure, heart rate-HR, sympathetic and vagal tonus, or intrinsic HR), we did not observe significant difference in the Fx-treated group. Evaluating oxidative stress in brainstem and heart by measuring carbonyl content and malondialdehyde-MDA formation, we observe a decrease in carbonyl content only in the Fx-treated group (60.3%, in brainstem; 58.2%, in heart), without difference in the MDA levels. This observation is consonant with an increase in superoxide dismutase-SOD and catalase-CAT activity in brainstem and heart in the Fx-treated group (SOD: 82.7% and CAT: 23.7 in brainstem; SOD: 60.6%, and CAT: 40.7 in heart), with no changes in glutathione S-transferase activity and reduced glutathione levels. With regard to oxidative metabolism markers, citrate synthase activity was higher in brainstem in the Fx-treated group (20%). SIGNIFICANCE Our data suggest that serotonin modulation by Fx-treatment at an early age does not induce hemodynamic alteration, although it modulates oxidative metabolism in cardiac-related tissues.

Oxidative injuries induced by maternal low-protein diet in female brainstem

Many studies have shown that a maternal low-protein diet increases the susceptibility of offspring to cardiovascular disease in later-life. Moreover, a lower incidence of cardiovascular disease in females than in males is understood to be largely due to the protective effect of high levels of estrogens throughout a womans reproductive life. However, to our knowledge, the role of estradiol in moderating the later-life susceptibility of offspring of nutrient-deprived mothers to cardiovascular disease is not fully understood. The present study is aimed at investigating whether oxidative stress in the brainstem caused by a maternal low-protein diet administered during a critical period of fetal/neonatal brain development (i.e during gestation and lactation) is affected by estradiol levels. Female Wistar rat offspring were divided into four groups according to their mothers’ diets and to the serum estradiol levels of the offspring at the time of testing: (1) 22 days of age/control diet: (2) 22 days of age/low-protein diet; (3) 122 days of age/control diet: (4) 122 days of age/low-protein diet. Undernutrition in the context of low serum estradiol compared to undernutrition in a higher estradiol context resulted in increased levels of oxidative stress biomarkers and a reduction in enzymatic and non-enzymatic antioxidant defenses. Total global oxy-score showed oxidative damage in 22-day-old rats whose mothers had received a low-protein diet. In the 122-day-old group, we observed a decrease in oxidative stress biomarkers, increased enzymatic antioxidant activity, and a positive oxy-score when compared to control. We conclude from these results that following a protein deficiency in the maternal diet during early development of the offspring, estrogens present at high levels at reproductive age may confer resistance to the oxidative damage in the brainstem that is very apparent in pre-pubertal rats.

Mitochondrial impairment following neonatal overfeeding: A comparison between normal and ischemic-reperfused hearts: MOURA FREITAS et al.

Overweight and obesity are established factors underpin several metabolic impairments, including the cardiovascular. Although the diversity of factors involved in overweight/obesity‐induced cardiovascular diseases, mitochondria has been highlighted due to its role in cardiac metabolism. As obesity can be originated in early postnatal life, the current study evaluates the effects of neonatal overfeeding on the cardiac mitochondrial bioenergetics and oxidative balance in rats that underwent an ischemia‐reperfusion insult. Seventy‐two hours after delivery, Wistar rat litters were randomly assigned into the control (C; nine pups per mother) and the Overfed (OF; three pups per mother) groups throughout the lactation period. At weaning, male offspring were fed with laboratory chow ad libitum until sacrifice at 30 and 60 days of life. Mitochondrial heart bioenergetics and oxidative balance showed to be deeply affected by neonatal overfeeding at both ages. Interestingly, after ischemia‐reperfusion insult I/R (Langendorff or mineral oil incubation), most parameters evaluated in OF animals were not influenced by additional ischemic‐reperfusion injury. Our findings demonstrated that suckling overfeeding deregulates cardiac mitochondrial alike to ischemia‐reperfusion insult by disengaging electrical mitochondrial coupling and potentiate oxidative stress, wherein the neonatal overfeeding shows to be so detrimental as I/R. Our findings support the concept that nutritional insults in the critical development periods increase the risk for cardiovascular disease and mitochondria impairments throughout life while oxidative damage change between molecular targets.

Serotonin transporter inhibition during neonatal period induces sex-dependent effects on mitochondrial bioenergetics in the rat brainstem

The serotonin reuptake is mainly regulated by the serotonin transporters (SERTs), which are abundantly found in the raphe nuclei, located in the brainstem. Previous studies have shown that dysfunction in the SERT has been associated with several disorders, including depression and cardiovascular diseases. In this manuscript, we aimed to investigate how gender and the treatment with a serotonin selective reuptake inhibitor (SSRI) could affect mitochondrial bioenergetics and oxidative stress in the brainstem of male and female rats. Fluoxetine, our chosen SSRI, was used during the neonatal period (i.e., from postnatal Day 1 to postnatal Day 21—PND1 to PND21) in both male and female animals. Thereafter, experiments were conducted in adult rats (60 days old). Our results demonstrate that, during lactation, fluoxetine treatment modulates the mitochondrial bioenergetics in a sex‐dependent manner, such as improving male mitochondrial function and female antioxidant capacity.