A hipóxia-isquemia sistêmica pré-natal aumenta a imunorreatividade da NO sintase neuronal na medula espinhal da prole fêmea adulta

Abstract

Hypoxia-ischemia (HI) is the main cause of perinatal brain injury, potentially resulting in late clinical manifestations, such as alterations in pain perception. In more severe cases, it can lead to permanent neurological damage. Evidence suggests that HI impacts circuits involved in nociception, influencing pain modulation in a sex- dependent manner. This study aimed to evaluate the immunoreactivity of neuronal nitric oxide synthase (nNOS), an enzyme that marks inhibitory interneurons, and tyrosine hydroxylase (TH), associated with catecholaminergic neurons, in the spinal cord of adult rats—both male (M) and female (F)—subjected to a prenatal HI model. For this purpose, pregnant rats on the 18th day of gestation were subjected to bilateral occlusion of the uterine and ovarian arteries for 45 minutes (HI Group), while the control group (SH) underwent only exposure of the uterine horns, without interruption of blood flow. After surgery, gestation continued normally until the birth of the offspring, which were analyzed at 90 days of age using immunohistochemistry to quantify the immunoreactivity of nNOS and TH in the spinal cord. The results showed that nNOS immunolabeling in the lumbar region of the spinal cord was similar to that observed in the cervical region, with a significant increase in the number of immunoreactive cell bodies and in the percentage of the labeled area in the HIF group compared to the other groups. Regarding TH, although no statistically significant difference in immunoreactivity was observed, when compared to SHF group, the HIF group showed a decrease in immunostaining compared to the HIM group. These findings suggest that prenatal systemic HI impairs the distribution of key enzymes involved in the biosynthesis of neurotransmitters related to nociception modulation, which may indicate modifications in this circuitry. Furthermore, the results reinforce the notion that the effects of prenatal HI are sex-dependent, being more evident in females, which may be associated with specific mechanisms of vulnerability and/or compensation. Understanding these changes is essential to elucidate the neurobiological mechanisms underlying sensory dysfunctions resulting from perinatal HI and for developing targeted therapeutic approaches.