Involvement of Nitric Oxide, Neurotrophins and HPA Axis in Neurobehavioural Alterations Induced by Prenatal Stress.

Several studies suggest that negative emotions during pregnancy generate adverse effects on the cognitive, behavioural and emotional development of the descendants. The psychoneuroendocrine pathways involve the transplacentary passage of maternal glucocorticoids in order to influence directly on fetal growth and brain development.Nitric oxide is a gaseous neurotransmitter that plays an important role in the control of neural activity by diffusing into neurons and participates in learning and memory processes. It has been demonstrated that nitric oxide is involved in the regulation of corticosterone secretion. Thus, it has been found that the neuronal isoform of nitric oxide synthase (nNOS) is an endogenous inhibitor of glucocorticoid receptor (GR) in the hippocampus and that nNOS in the hippocampus may participate in the modulation of hypothalamic-pituitary-adrenal axis activity via GR.Neurotrophins are a family of secreted growth factors consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and NT4. Although initially described in the nervous system, they regulate processes such as cell survival, proliferation and differentiation in several other compartments. It has been demonstrated that the NO-citrulline cycle acts together with BDNF in maintaining the progress of neural differentiation.In the present chapter, we explore the interrelation between nitric oxide, glucocorticoids and neurotrophins in brain areas that are key structures in learning and memory processes. The participation of this interrelation in the behavioural and cognitive alterations induced in the offspring by maternal stress is also addressed.

Prenatal stress induces alterations in cerebellar nitric oxide that are correlated with deficits in spatial memory in rat's offspring.

Prenatal stress (PS) has been linked to abnormal cognitive, behavioral and psychosocial outcomes in both animals and humans. Since PS has been shown to induce a cerebellar cytoarchitectural disarrangement and cerebellar abnormalities that have been linked to an impairment of behavioral functions, the aim of the present work was to investigate whether the exposure to PS in a period in which the cerebellum is still immature can induce behavioral deficits in the adult and whether this alterations are correlated with changes in nitric oxide (NO) and cellular oxidative mechanisms in offspring's cerebellum. Our results show impairments in spatial memory and territory discrimination in PS adult rats. PS offspring also displayed alterations in cerebellar nitric oxide synthase (NOS) expression and activity. Moreover, a correlation between spatial memory deficits and the increase in NOS activity was found. The results found here may point to a role of cerebellar NO in the behavioral alterations induced by stress during early development stages.

Partial neuroprotection by 17-ß-estradiol in neonatal γ-irradiated rat cerebellum.

Acute and long-term complications can occur in patients receiving radiation therapy. It has been suggested that cytoprotection might decrease the incidence and severity of therapy-related toxicity in these patients. Developing cerebellum is highly radiosensitive and for that reason it is a useful structure to test potential neuroprotective substances to prevent radiation induced abnormalities. Recent studies have shown that estrogen can rapidly modulate intracellular signalling pathways involved in cell survival. Thus, it has been demonstrated that estrogens mediate neuroprotection by promoting growth, cell survival and by preventing axonal pruning. The aim of this work was to evaluate the effect of the treatment with 17-ß-estradiol on the motor, structural and biochemical changes induced by neonatal ionizing radiation exposure, and to investigate the participation of nitric oxide and protein kinase C, two important intracellular messengers involved in neuronal activity. Our results show that perinatal chronic 17-ß-estradiol treatment partially protects against radiation-induced cerebellar disorganization and motor abnormalities. PKC and NOS activities could be implicated in its neuroprotective mechanisms. These data provide new evidence about the mechanisms underlying estrogen neuroprotection, which could have therapeutic relevance for patients treated with radiotherapy.