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Aim: The present study evaluated whether topiramate (TPM) treatment during the peripubertal period affects vascular parameters of male rats and whether oxidative stress plays a role in these changes., Main Methods: Rats were treated with TPM (41 mg/kg/day, gavage) or vehicle (CTR group) from the postnatal day (PND) 28 to 50. At PND 51 and 120 the rats were evaluated for: thoracic aorta reactivity to phenylephrine, in the presence (Endo+) or absence of endothelium (Endo-), to acetylcholine and to sodium nitroprusside (SNP), aortic thickness and endothelial nitric oxide synthase (eNOS) expression. In serum were analyzed: the antioxidant capacity by ferric reducing antioxidant power assay; endogenous antioxidant reduced glutathione, and superoxide anion. Results were expressed as mean ± s.e.m., differences when p < 0.05., Statistics: Two-way ANOVA (and Tukey's) or Student t-test., Key Findings: At PND 51, the contraction induced by phenylephrine in Endo+ ring was higher in TPM when compared to CTR. At PND 120, the aortic sensitivity to acetylcholine in TPM rats was reduced in comparison with CTR. The aortic eNOs expression and the aortic thickness were similar between the groups. At PND 51 and 120, TPM group presented a decrease in antioxidants when compared to CTR groups and at PND 120, in TPM group the superoxide anion was increased., Significance: Taken together, the treatment of rats with TPM during peripubertal period promoted permanent impairment of endothelial function probably mediated by oxidative stress., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: This study aimed to evaluate the short- and long-term adverse effects of blood pressure (BP), vascular endothelial function, and estrogen receptor (ERα and ERβ) modulation on endothelial function in female Wistar rats treated with topiramate (TPM), an antiepileptic drug, during the peripubertal period., Materials and Methods: Female Wistar rats were treated with TPM (41 mg/kg) or water (CTR group) by gavage from postnatal day (PND) 28 to 50 (peripubertal phase). At the end of the treatment, the TPM and CTR rats were divided into two groups and evaluated after 24 h or from PND 85 (adulthood). The rats were evaluated for: thoracic aorta reactivity to phenylephrine (Phenyl), acetylcholine (ACh), and sodium nitroprusside (SNP); aortic ring reactivity after ERα and ERβ antagonism; and BP., Key Findings: It was observed that vascular response to Phenyl, ACh, and SNP was similar between TPM and CTR rats in the short- and long-term evaluations. In addition, the ER antagonism did not interfere with aortic contraction or relaxation in either TPM or CTR., Significance: Taken together, the results show that TPM treatment during the peripubertal period does not alter aortic endothelial function and its estrogen modulation via classic ER in female Wistar rats, suggesting that TPM treatment in this period is safe for the vascular system., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Protein restriction during early phases of body development, such as intrauterine life can favor the development of vascular disorders. However, it is not known if peripubertal protein restriction can favor vascular dysfunction in adulthood. The present study aimed to evaluated whether a protein restriction diet during peripubertal period favors endothelial dysfunction in adulthood. Male Wistar rats from postnatal day (PND) 30 until 60 received a diet with either 23% protein (CTR group) or with 4% protein (LP group). At PND 120, the thoracic aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in the presence or absence of: endothelium, indomethacin, apocynin and tempol. The maximum response (Rmax) and pD2 (-log of the concentration of the drug that causes 50% of the Rmax) were calculated. The lipid peroxidation and catalase activity were also evaluated in the aorta. The data were analyzed by ANOVA (one or two-ways and Tukey's) or independent t -test; the results were expressed as mean ± S.E.M., p < 0.05. The Rmax to phenylephrine in aortic rings with endothelium were increased in LP rats when compared with the Rmax in CTR rats. Apocynin and tempol reduced Rmax to phenylephrine in LP aortic rings but not in CTR. The aortic response to the vasodilators was similar between the groups. Aortic catalase activity was lower and lipid peroxidation was greater in LP compared to CTR rats. Therefore, protein restriction during the peripubertal period causes endothelial dysfunction in adulthood through a mechanism related to oxidative stress.

Introduction: Available studies have shown the involvement of nitric oxide (NO) in the processes that lead to neurodegeneration in Parkinson's disease (PD). Also, the use of inhibitors of the inducible isoform of NO-synthase (iNOS) promotes neuroprotection and attenuates dopamine (DA) loss in experimental models of Parkinsonism. In addition, NO also appears to be involved in cardiovascular changes in 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. The current study aimed to evaluate the effects of iNOS inhibition on cardiovascular and autonomic function in animals that were subjected to Parkinsonism by the administration of 6-OHDA., Materials and Methods: The animals underwent stereotaxic surgery for bilateral microinfusion of the neurotoxin 6-OHDA (6 mg/mL in 0.2% ascorbic acid in sterile saline solution) or vehicle solution for the Sham group. From the day of stereotaxis until the day of femoral artery catheterization, the animals were treated with the iNOS inhibitor, S-methylisothiourea (SMT; 10 mg/kg; i. p.) or saline solution (0.9%; i. p.) for 7 days. The animals were divided into four groups: Sham-Saline, Sham-SMT, 6-OHDA-Saline, and 6-OHDA-SMT. Subsequent analyses were performed on these four groups. After 6 days, they underwent catheterization of the femoral artery, and 24 h later, mean arterial pressure (MAP) and heart rate (HR) were recorded. Another group of animals (the 6-OHDA and Sham groups) was assessed for aortic vascular reactivity after 7 days of bilateral infusion of 6-OHDA or vehicle, in which cumulative concentration-effect curves (CCEC) were made for phenylephrine (Phenyl), acetylcholine and sodium nitroprusside (NPS). Also, CCEC in the presence of Nw-nitro-arginine-methyl-ester (l-NAME) (10-5 M), SMT (10-6 M), and indomethacin (10-5 M) blockers were made., Results: The effectiveness of the 6-OHDA lesion was confirmed with the reduction of DA in 6-OHDA animals. However, treatment with SMT could not reverse the loss of DA. Concerning the baseline parameters, SBP and MAP values were lower in 6-OHDA animals compared to their Sham control, with no effect of treatment with SMT. In the analysis of SBP variability, a decrease in variance, the VLFabs component, and the LFabs component were observed in the 6-OHDA groups when compared to their controls, regardless of treatment with SMT. It was also observed that intravenous injections of SMT resulted in an increase in BP and a decrease in HR. However, the response was not different between the Sham and 6-OHDA groups. In vascular function, there was a hyporeactivity to Phenyl in the 6-OHDA group, and when investigating the mechanisms of this hyporeactivity, it was seen that the Rmax to Phenyl increased with incubation with SMT, indicating that iNOS could be involved in the vascular hyporeactivity of animals with Parkinsonism., Conclusion: Thus, the set of results presented in this study suggests that part of the cardiovascular dysfunction in animals subjected to 6-OHDA Parkinsonism may be peripheral and involve the participation of endothelial iNOS., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Topiramate (TOP) is a psychotropic drug prescribed for the treatment of epilepsy in children older than 2 years of age and for migraine prophylaxis in adolescents. There is evidence that TOP promotes negative effects on the reproductive system of male rats. This study aimed to evaluate the immediate and late treatment effects of TOP during childhood and adolescence on the male rat reproductive system. Two experimental groups received 41 mg/kg of TOP daily, by gavage, from postnatal day (PND) 16 to 28 (TOPc group) or from PND 28 to 50 (TOPa group). Control groups (CTRc group or CTRa group) received water daily. Half of the anim-als were evaluated 24 h after the end of treatment (PND 29 and PND 51, respectively) and the remainder were evaluated in adulthood (PND120). The following parameters were determined: anogenital distance, sperm evaluation, testis' histomorphometry and plasma testosterone concentration. At PND 120, the volume (CTRc:62.58 ± 2.13; TOPc: 54.54 ± 2.10*%, p = 0.018) and total length (CTRc: 25.48 ± 1.61; TOPc: 18.94 ± 2.41*, p = 0.035) of seminiferous tubules were decreased and the volume of interstitial tissue (CTRc:37.41 ± 2.13; TOPc: 45.45 ± 2.09*%, p = 0.018) and number of Leydig cells/testis (CTRc: 277.00 ± 36.70; TOPc: 400.20 ± 13.23*, p = 0.013) were increased in the TOPc group. The other parameters remained similar between the groups. Therefore, the present study contributes to our understanding that childhood treatment with TOP has an impact on the rat reproductive system in adulthood, suggesting that this period is more sensitive to TOP exposure than adolescence.

The present study determined whether treatment during childhood with topiramate (TPM), a new generation antiepileptic drug, results in altered aortic reactivity in adult male and female rats. We also sought to understand the role of endothelium-derived contractile factors in TPM-induced vascular dysfunction. Male and female Wistar rats were treated with TPM (41 mg/kg/day) or water (TPM vehicle) by gavage during childhood (postnatal day, 16-28). In adulthood, thoracic aorta reactivity to phenylephrine (phenyl), as well as aortic thickness and expression of cyclooxygenases (COX-1 and COX-2), NOX2, and p47 phox were evaluated. The aortic response to phenyl was increased in male and female rats from the TPM group when compared with the control group. In TPM male rats, the hyperreactivity to phenyl was abrogated by the inhibition of NADPH oxidase and COX-2, while in female rats, responses were restored only by inhibition of COX-2. In addition, TPM male rats presented aortic hypertrophy and increased expression of NOX-2 and p47phox, while TPM female rats showed increased COX-2 aortic expression. Taken together, for the first-time, the present study provides evidence that treatment with TPM during childhood causes vascular dysfunction in adulthood, and that the mechanism underlying the vascular effects of TPM is sex-specific., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abstract: Paracetamol (PAR) is the most common over-the-counter drug recommended by physicians for treatment of pain and fever during gestation. This drug is not teratogenic, being considered safe for fetus; however, PAR crosses the blood-placental barrier. Considering that, the present study aimed to evaluate the vascular and metabolic safety of PAR exposure during intrauterine and neonatal development in adult male and female-exposed offspring. Wistar female rats were gavaged, with PAR (350 mg/kg/d), from gestational day 6-21 or from gestational day 6 until postnatal day 21. Control dams received water by gavage at the same periods. The male and female offspring were evaluated at adulthood (80 days of life). The thoracic aorta reactivity to acetylcholine, sodium nitroprusside, and phenylephrine was evaluated in male and female adult offspring. It was observed that aortic relaxation was similar between the PAR and control offspring. In addition, the contraction to phenylephrine was similar between the groups. Further, the insulin sensitivity, adipose tissue deposition and blood pressure were not different between PAR and control adult offspring. These results suggest that the protocol of PAR exposure used in the present study did not program vascular and metabolic alterations that would contribute to the development of cardiometabolic diseases in adult life, being safe for the exposed offspring., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)