Multitarget neuroprotection by quercetin: Changes in gene expression in two perinatal asphyxia models.

Hypoxic-ischemic encephalopathy (HIE) causes mortality and long-term neurologic morbidities in newborns, affecting pathways related to energy failure, excitotoxicity and oxidative stress that often lead to cell death. The whole process of HIE injury is coupled to changes in the expression of a great array of proteins. A nanoliposomal preparation of the flavonoid quercetin has been shown to exert neuroprotective effects in perinatal asphyxia models. This study aimed to identify neonatal HIE markers and explore the effect of quercetin administration in two perinatal asphyxia models: newborn rats and piglets. In the rat model, nanoliposomal quercetin administration reduced mortality after asphyxia. In the piglet model, quercetin partially overrode the reduction of HIF-1α mRNA levels in the cortex induced by asphyxia. Quercetin administration also reduced increased level of HO-1 mRNA in asphyctic piglets. These results suggest that quercetin neuroprotection might be involved in the regulation of HIF-1α, HO-1 and their targets. A proteomic approach revealed that the glycolytic pathway is strongly regulated by quercetin in both species. We also identified a set of proteins differentially expressed that could be further considered as markers. In piglets, this set includes Acidic Leucine-rich nuclear phosphoprotein 32 (ANP32A), associated with nervous system differentiation, proteins related with death pathways and alpha-enolase which can be converted to neuron-specific enolase, a glycolytic enzyme that may promote neuroprotection. In newborn rats, other promising proteins associated with neurogenesis and neuroprotection emerged, such as dihydropyrimidinase-related proteins, catalytic and regulatory subunits of phosphatases and heterogeneous nuclear ribonucleoprotein K (hnRNPK). Our results show that a nanoliposomal preparation of quercetin, with protective effect in two HIE mammal models, modulates the expression of proteins involved in energy metabolism and other putative neuroprotective signals in the cortex. Identification of these signals could reveal potential molecular pathways involved in disease onset and the novel quercetin neuroprotective strategy.

Maternal condition reduces fear behaviors but not the endocrine response to an emotional threat in virgin female rats.

Lactating dams and maternal virgin females are less fearful in behavioral tests compared with non-maternal animals, suggesting that maternal condition per se reduces the negative value of threatening stimuli. In addition, lactating females exhibit a diminished hypothalamic-pituitary-adrenal response to potential environmental threats. Can the maternal condition, independently of the endocrine profile of lactation, promote a reduction in the behavioral as well as in the endocrine response to an emotional stressor? To answer this question, anxiety-related and fear behaviors as well as the levels of corticosterone were evaluated in response to a bright-lit open field-loud noise model in maternal and non-maternal non-ovariectomized virgin females and lactating dams in the presence of the pups. Maternal animals, both lactating and virgin, presented an increased exploration of the bright-lit open field and a significant reduction of fear behaviors, indicated by the decreased flight and immobility responses to the subsequent activation of a loud noise, in comparison to non-maternal virgins. Interestingly, maternal virgin females, as non-maternal rats, showed high corticosterone plasma levels, in contrast to the lower endocrine response exhibited by lactating dams when confronted to this threat. Present results suggest that maternal condition allows females to take risks when caring for their young, a behavioral strategy that is independent of the reduced hypothalamic-pituitary-adrenal axis response characteristic of lactation. This evidence points towards a clear dissociation in the mechanisms regulating behavioral and endocrine responses to emotional stressors during motherhood.

Motivational aspects of maternal anxiolysis in lactating rats.

RATIONALE AND OBJECTIVE: This study examines the role of maternal motivation on the reduced anxiety-like responses displayed by lactating rats in the plus maze test. RESULTS: Maternal animals, both lactating and sensitized (ovariectomized females behaving maternal after a continuous exposure to pups), displayed anxiolytic-like responses in the plus maze test in contrast to ovariectomized non-maternal rats. However, the levels of experimental anxiety were lower in lactating than in sensitized females. Pups placed in the open arms of the maze further reduced the low levels of anxiety-like behavior of both sensitized and lactating rats. Low doses of haloperidol (0.05 and 0.1 mg/kg), a dopamine antagonist, which interfere with maternal motivation but has neither anxiolytic nor anxiogenic effect in the plus maze test, significantly increased the anxiety-like responses of lactating rats. The presence of the pups in the open arms of the maze overrode the behavioral effect of haloperidol on lactating dams' anxiety-related behavior. CONCLUSIONS: These experiments show that maternity induces changes in the way the animals react to the environment, rendering them less anxious to aversive stimuli. The degree of experimental anxiolysis displayed by maternal animals varies according to their maternal motivation, which is modulated by the female's endocrine state, the pups and/or the dopaminergic system.

Experimental anxiety in the black and white model in cycling, pregnant and lactating rats.

This study demonstrates changes in experimental anxiety assessed in the black and white paradigm during various reproductive states of female rats. Low levels of experimental anxiety were observed during late proestrus and on day 17 of gestation, stages related to high progesterone (P) levels. In estrus, metestrus, diestrus and on day 21 of gestation, stages characterized by low P concentrations, high levels of experimental anxiety, similar to those exhibited by ovariectomized females, were found. No changes in experimental anxiety were observed on day 8 of lactation compared to ovariectomized females. These data are discussed from the standpoint of the putative anxiolytic-like effect of progestins.