No abstract

Oxygen deprivation in newborns leads to hypoxic-ischemic encephalopathy, whose hallmarks are oxidative/nitrosative stress, energetic metabolism alterations, nutrient deficiency, and motor behavior disability. Zinc and taurine are known to protect against hypoxic-ischemic brain damage in adults and neonates. However, the combined effect of prophylactic zinc administration and therapeutic taurine treatment on intrauterine ischemia- (IUI-) induced cerebral damage remains unknown. The present work evaluated this issue in male pups subjected to transient IUI (10 min) at E17 and whose mothers received zinc from E1 to E16 and taurine from E17 to postnatal day 15 (PND15) via drinking water. We assessed motor alterations, nitrosative stress, lipid peroxidation, and the antioxidant system comprised of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Enzymes of neuronal energetic pathways, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), were also evaluated. The hierarchization score of the protective effect of pharmacological strategies (HSPEPS) was used to select the most effective treatment. Compared with the IUI group, zinc, alone or combined with taurine, improved motor behavior and reduced nitrosative stress by increasing SOD, CAT, and GPx activities and decreasing the GSSG/GSH ratio in the cerebral cortex and hippocampus. Taurine alone increased the AST/ALT, LDH/ALT, and AST/LDH ratios in the cerebral cortex, showing improvement of the neural bioenergetics system. This result suggests that taurine improves pyruvate, lactate, and glutamate metabolism, thus decreasing IUI-caused cerebral damage and relieving motor behavior impairment. Our results showed that taurine alone or in combination with zinc provides neuroprotection in the IUI rat model.

Introduction: The existence of ovarian intrinsic neurons is well established. However, the morphology and chemical phenotype are not completely characterized and are even unknown for some species used in medical research. The purpose of this work was to determine the morphology and chemical phenotype of intrinsic neurons of the guinea pig ovary at two ages: neonates (0 days old) and sexually mature reproductive animals (90 days old). Materials and Methods: For the morphological analysis, we employed the modified Golgi-Cox impregnation technique. For the chemical phenotype, we used immunohistochemistry and the following antibodies; tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), transient receptor potential type 1 (TRPV1), neuron-specific nuclear protein (NeuN) and proto-oncogene product of the cFos gene (cFos). We also used enzyme histochemistry for NADPH-diaphorase detection. Results: The number of intrinsic neurons in the neonate ovary was low in comparison to the adult guinea pig ovary. The intrinsic neurons were located in the cortex and the ovarian medulla; some were isolated or clustered, forming ganglia, and others were interconnected and formed networks. The neurons were small, medium or large. In the cortex of neonate vs adult ovaries, the small and medium neurons comprised 23% vs 36% and 5.2% vs 11.6%, respectively. In the medulla, the percent of the same neurons was 10.1% vs 10.1% and 1.1% vs 2.2% in the neonate and adult, respectively. In both cortex and medulla < 1% were large neurons at two ages. Also, the neurons were rounded, fusiform or multipolar. In the cortex, they were 12.7% vs 20.9%, 14.9% vs 24.2% and 1.1% vs 3.0%, respectively. In the medulla, the percent of small vs medium neurons was 6% vs 7.1% and 4.1% vs 4.8% in the neonate and adult ovary, respectively, and <1% were large neurons at both ages. The chemical phenotypes were in the neonate and adult: TH/NeuN-positive neurons, 16.3% vs 26.5%; CGRP/NeuN, 13.5% vs 35.8%; TRPV1/NeuN, 10.2% vs 38.6%; and cFos/NeuN, 4.6% vs 5.4%, re-* Corresponding author. F. Luna et al. 14 spectively. The percent of NADPHd-positive cells in the cortex was 9.5% vs 25.1% and 3.2% vs 62.2% in the medulla in the neonate and adult, respectively. Conclusion: Altogether, these data showed that the number of ovarian intrinsic neurons was low at birth and increased in the sexually mature reproductive guinea pig. The chemical phenotype was rich and peptidergic, catecholaminergic and nitrergic in nature and positive for cFos immunoreactivity. Therefore, intrinsic neurons can be chemical sensors inside of the gonad and transmit signal to the central nervous system.

Introduction: It has been documented that mammalian ovaries receive sympathetic, parasympathetic and sensory nerve fibers. The aim of this work was to investigate the effects of sensory denervation with capsaicin at the first vaginal opening (FVO) on follicular development and the expression of TRPV1 receptors in ovary cells as well as in the dorsal root ganglia (DRGs) and lumbar dorsal spinal cord neurons of guinea pigs. The DRGs and lumbar dorsal spinal cord neurons serve as a nerve connection from the ovaries to the CNS. Materials and Methods: Female guinea pigs received a subcutaneous injection of capsaicin (30 mM) at 10 days of age (P10), while control animals were injected with vehicle. Using light microscopy, we counted healthy preantral follicles (HPF), healthy antral follicles (HAF), atretic preantral follicles (APF), and atretic antral follicles (AAF) in the ovaries at the FVO, and the numbers of TRPV1-positive cells were counted in the ovarian follicles, DRGs, and lumbar dorsal spinal cord (L2-L4) neurons by immunohistochemistry. Results: Guinea pigs treated with capsaicin showed a significant delay of FVO in comparison with the control animals (36 vs. 44 days). In the ovaries, the number of preantral and antral follicles decreased significantly. Additionally, the number of TRPV1-positive theca-interstitial cells of the antral follicles was reduced significantly, and the number of TRPV1-positive neurons in the DRGs and lumbar dorsal spinal cord (L2-L4) decreased. Thus, we showed that TRPV1 receptors throughout the sensory fibers modulate ovarian follicular development and the onset of puberty in guinea pigs. Conclusion: Sensory denervation decreases ovarian follicular development and delays the onset of puberty of guinea pigs. Our data support the idea that through TRPV1 receptors, ovarian afferent fibers sense local stimuli that are sent to the CNS.

Spirostans (SPs) are chemical products widely distributed in the plant kingdom; currently, they are studied by their medical applications. Cancer has a high incidence in humans; it reaches second place worldwide deaths. In molecular biology, it has been accepted that Mitogen-Activated Protein p38alpha Kinase (MAPK14 (p38α) is implicated in the regulation of cancer. This study aimed to identify SPs as potential MAPK14 (p38α) inhibitors. From a set of 133 modified SPs, SwissTargetPrediction platform, and molecular docking, it was obtained that 129 chemical structures had molecular interaction with the MAPK14 (p38α). From those molecules, 123 were bound to a specific inhibition site of MAPK14 (p38α), and 6 of the structures resulted in inhibitors similarly to minocycline and dasatinib. One SP had binding couple energy (BCE, kcal/mol) as that of fostamatinib. In addition, 115 modified SPs had better BCE than the minocycline but not as that using fostamatinib. The key amino acids (aa) for the protein kinase MAPK14 (p38α) inhibition were Arg 70, Asp 168, Lys 53, His 148, and Ile 145, at a different interaction level. The BCE was enhanced when the H atom was substituted in C-2, C-11, and C-17 SPs positions. Similarly, the αOH group at C-5 and C-6 upgraded BCE. Stereochemistry and substitution at C-3, C-12, and C-25 did not present significant differences (Kruskal-Wallis test, p <0.05). From all this ensemble of results, it is foreseeable that the SPs can be an option for MAPK14 (p38α) inhibition, a key modulator in cancer processes.