Bone strength is reduced in a neonatal androgenized rat model.

Background: Whether polycystic ovary syndrome (PCOS) affects bone health during a woman's lifespan remains controversial. An androgenized rodent model replicated many metabolic and reproductive features of women with PCOS, and we aimed to use it to investigate the impact of androgens on microarchitecture (by micro-CT), bone mechanical strength, bone formation and resorption markers in rats with intact ovaries (SHAM) who underwent oophorectomy. Methods: Wistar rats (Rattus norvegicus albinus) were employed for the experiments in this study. The protocol of androgenization consisted of the application of 1.25 mg s.c. testosterone propionate beteween days 2-5 of life, while the controls received the same amount of corn oil s.c. as previously established. Androgenized SHAM rats exhibited chronic anovulation identified by vaginal cytology and a reduction in the proportion of corpus luteum in the ovary in comparison to control SHAM rats. The realization of the ovariectomy or SHAM procedure occurred on Day 100 of life. All groups (n = 8) were followed-up for 180 days to address the study endpoints. Results: Micro-CT from androgenized female rats (SHAM) showed a divergence between the trabecular and cortical bone profiles. Compared to SHAM controls, these rats had an increase in trabecular bone mass with a diminution in bone resorption C-terminal telopeptide of type 1 collagen (CTX) (p < 0.05), a concomitant decrease in cortical area and thickness in the femur, and a reduction in the strength of the femur on the mechanical test (p < 0.01). Conclusions: Our results suggest that a reduction in the cortical thickness and cortical area observed in PCOS model rats was associated with a reduced strength of the femur, despite increased trabecular formation. Ovariectomy in the androgenized OVX group limited the progression rate of cortical bone loss, resulting in bone resistance and cortical thickness comparable to those observed in the control OVX group.

Ovariectomy Improves Metabolic and Oxidative Stress Marker Disruption in Androgenized Rats: Possible Approach to Postmenopausal Polycystic Ovary Syndrome.

Background: This study aims to evaluate metabolic and oxidative stress markers in a postmenopausal rat model of polycystic ovary syndrome (PCOS). Methods: Wistar rats were divided in four groups: control ovariectomized (OVX; n = 9), control SHAM (n = 9), androgenized OVX (n = 10), and androgenized SHAM (n = 10). Female rats were androgenized during the neonatal period and compared with controls. Surgery (ovariectomy or SHAM procedure) was performed at day 100 and euthanasia at day 180 of life. Bodyweight, lipids, glucose, triglyceride glucose (TyG) index, and oxidative stress markers (total oxidant status [TOS], total antioxidant capacity, nitric oxide, ferric-reducing ability of plasma [FRAP], and advanced oxidation protein product) were addressed. Results: Androgenized SHAM rats exhibited a higher total, low-density lipoprotein cholesterol, triglycerides, TyG index (an insulin resistance marker), and increased TOS, FRAP, and albumin in comparison with control SHAM rats. These abnormalities disappeared after ovariectomy despite the fact that ovariectomized androgenized rats became heavier than the other three groups. Conclusion: Ovariectomy improved metabolic and oxidative stress markers in a rat model of PCOS.

EP2 receptor agonist ONO-AE1-259-01 attenuates pentylenetetrazole- and pilocarpine-induced seizures but causes hippocampal neurotoxicity.

Epilepsy is a common and devastating neurological disease affecting more than 50 million people worldwide. Accumulating experimental and clinical evidence suggests that inflammatory pathways contribute to the development of seizures in various forms of epilepsy. In this context, while the activation of the PGE2 EP2 receptor causes early neuroprotective and late neurotoxic effects, the role of EP2 receptor in seizures remains unclear. We investigated whether the systemic administration of the highly selective EP2 agonist ONO-AE1-259-01 prevented acute pentylenetetrazole (PTZ)- and pilocarpine-induced seizures. The effect of ONO-AE1-259-01 on cell death in the hippocampal formation of adult male mice seven days after pilocarpine-induced status epilepticus (SE) was also evaluated. ONO-AE1-259-01 (10µg/kg, s.c.) attenuated PTZ- and pilocarpine-induced seizures, evidenced by the increased latency to seizures, decreased number and duration of seizures episodes and decreased mean amplitude of electrographic seizures. ONO-AE1-259-01 and pilocarpine alone significantly increased the number of pyknotic cells per se in all hippocampal subfields. The EP2 agonist also additively increased pilocarpine-induced pyknosis in the pyramidal cell layer of CA1 but reduced pilocarpine-induced pyknosis in the granule cell layer of the dentate gyrus (DG). Although the systemic administration of ONO-AE1-259-01 caused a significant anticonvulsant effect in our assays, this EP2 agonist caused extensive cell death. These findings limit the likelihood of EP2 receptor agonists being considered as novel potential anticonvulsant drugs.