Bruno Dutra Arbo

Astrocytes as a target for neuroprotection: Modulation by progesterone and dehydroepiandrosterone.

Stroke and traumatic injuries of the brain and spinal cord are major public health issues. In the last few decades, hundreds of clinical trials with patients suffering from these conditions have been done, however, most of them had not succeeded and there is still the need to develop more effective treatments for these conditions. Astrocytes play critical roles in the development, function and survival of neurons in the central nervous system. These cells are implicated in the pathophysiology and in the response to several neuropathological conditions and may represent potential cell targets for neuroprotective strategies. Progesterone and dehydroepiandrosterone (DHEA) are neuroactive steroids that modulate neuronal and astroglial function and have neuroprotective effects in different experimental models, being potential candidates to the development of new therapeutic approaches for brain and spinal cord injuries. The aim of this review is to discuss the role of astrocytes in the pathophysiology of brain and spinal cord injuries and how they could be modulated by progesterone and DHEA for the treatment of these conditions.

Therapeutic actions of translocator protein (18 kDa) ligands in experimental models of psychiatric disorders and neurodegenerative diseases.

Translocator protein (TSPO) is an 18kDa protein located at contact sites between the outer and the inner mitochondrial membrane. Numerous studies have associated TSPO with the translocation of cholesterol across the aqueous mitochondrial intermembrane space and the regulation of steroidogenesis, as well as with the control of some other mitochondrial functions, such as mitochondrial respiration, mitochondrial permeability transition pore opening, apoptosis and cell proliferation. In the brain, changes in TSPO expression occur in several neuropathological conditions including neurodegenerative diseases and psychiatric disorders. Furthermore, TSPO ligands have been shown to promote neuroprotection in animal models of brain pathology. At least in some cases, the mechanisms of neuroprotection are associated with modifications in brain steroidogenesis. In addition, regulation of neuroinflammation seems to be a common mechanism in the neuroprotective actions of TSPO ligands in different animal models of brain pathology.

Effect of progesterone on the expression of GABA A receptor subunits in the prefrontal cortex of rats: implications of sex differences and brain hemisphere

Progesterone is a neuroactive hormone with non‐genomic effects on GABAA receptors (GABAAR). Changes in the expression of GABAAR subunits are related to depressive‐like behaviors in rats. Moreover, sex differences and depressive behaviors have been associated with prefrontal brain asymmetry in rodents and humans. Thus, our objective was to investigate the effect of progesterone on the GABAAR α1 and γ2 subunits mRNA expression in the right and left prefrontal cortex of diestrus female and male rats exposed to the forced swimming test (FST). Male and female rats (n = 8/group) were randomly selected to receive a daily dose of progesterone (0·4 mg·kg–1) or vehicle, during two complete female estrous cycles (8–10 days). On the experiment day, male rats or diestrus female rats were euthanized 30 min after the FST. Our results showed that progesterone significantly increased the α1 subunit mRNA in both hemispheres of male and female rats. Moreover, there was an inverse correlation between depressive‐like behaviors and GABAAR α1 subunit mRNA expression in the right hemisphere in female rats. Progesterone decreased the GABAAR γ2 mRNA expression only in the left hemisphere of male rats. Therefore, we conclude that the GABAA system displays an asymmetric distribution according to sex and that progesterone, at lower doses, presents an antidepressant effect after increasing the GABAAR α1 subunit expression in the right prefrontal cortex of female rats. Copyright

Dehydroepiandrosterone protects male and female hippocampal neurons and neuroblastoma cells from glucose deprivation

Dehydroepiandrosterone (DHEA) modulates neurogenesis, neuronal function, neuronal survival and metabolism, enhancing mitochondrial oxidative capacity. Glucose deprivation and hypometabolism have been implicated in the mechanisms that mediate neuronal damage in neurological disorders, and some studies have shown that these mechanisms are sexually dimorphic. It was also demonstrated that DHEA is able to attenuate the hypometabolism that is related to some neurodegenerative diseases, eliciting neuroprotective effects in different experimental models of neurodegeneration. The aim of this study was to evaluate the effect of DHEA on the viability of male and female hippocampal neurons and SH-SY5Y neuroblastoma cells exposed to glucose deprivation. It was observed that after 12h of pre-treatment, DHEA was able to protect SH-SY5Y cells from glucose deprivation for 6h (DHEA 10(-12), 10(-8) and 10(-6)M) and 8h (DHEA 10(-8)M). In contrast, DHEA was not neuroprotective against glucose deprivation for 12 or 24h. DHEA (10(-8)M) also protected SH-SY5Y cells when added together or even 1h after the beginning of glucose deprivation (6h). Furthermore, DHEA (10(-8)M) also protected primary neurons from both sexes against glucose deprivation. In summary, our findings indicate that DHEA is neuroprotective against glucose deprivation in human neuroblastoma cells and in male and female mouse hippocampal neurons. These results suggest that DHEA could be a promising candidate to be used in clinical studies aiming to reduce neuronal damage in people from both sexes.

Diet-induced obesity alters memory consolidation in female rats

Obesity is a multifactorial disease characterized by the abnormal or excessive fat accumulation, which is caused by an energy imbalance between consumed and expended calories. Obesity leads to an inflammatory response that may result in peripheral and central metabolic changes, including insulin and leptin resistance. Insulin and leptin resistance have been associated with metabolic and cognitive dysfunctions. Obesity and some neurodegenerative diseases that lead to dementia affect mainly women. However, the effects of diet-induced obesity on memory consolidation in female rats are poorly understood. Therefore, the aim of this study was to evaluate the effect of a hypercaloric diet on the object recognition memory of female rats and on possible related metabolic changes. The animals submitted to the hypercaloric diet presented a higher food intake in grams and in calories, resulting in increased weight gain and liposomatic index in comparison with the animals exposed to the control diet. These animals presented a memory deficit in the object recognition test and increased serum levels of glucose and leptin. However, no significant differences were found in the serum levels of insulin, TNF-α and IL-1β, in the index of insulin resistance (HOMA), in the hippocampal levels of insulin, TNF-α and IL-1β, as well as on Akt expression or activation in the hippocampus. Our findings indicate that adult female rats submitted to a hypercaloric diet present memory consolidation impairment, which could be associated with diet-induced weight gain and leptin resistance, even without the development of insulin resistance.

Asymmetric effects of low doses of progesterone on GABA(A) receptor α4 subunit protein expression in the olfactory bulb of female rats.

The aim of this study was to evaluate the effect of progesterone on the protein expression of α4 subunit of GABA(A) receptor, serotonin transporter (SERT), Akt, Erk, and caspase-3 in the olfactory bulb (OB) of female rats exposed to the forced swimming test (FST). Female rats were injected daily with progesterone (0.4 mg/kg body mass) or vehicle during 2 complete oestrous cycles and exposed to the FST, and the protein expression of GABA(A) receptor α4 subunit, SERT, Akt, Erk, and caspase-3 in the OB were evaluated. Progesterone increased the expression of the α4 subunit in the right OB and decreased its expression in the left OB, although it did not change the expression of other proteins. In summary, our findings indicate that progesterone has an asymmetric modulatory effect on the expression of GABA(A) receptor α4 subunit in the OB. This effect could be related to the antidepressant-like effect of progesterone in female rats.

Sex-specific effects of dehydroepiandrosterone (DHEA) on glucose metabolism in the CNS

DHEA is a neuroactive steroid, due to its modulatory actions on the central nervous system (CNS). DHEA is able to regulate neurogenesis, neurotransmitter receptors and neuronal excitability, function, survival and metabolism. The levels of DHEA decrease gradually with advancing age, and this decline has been associated with age related neuronal dysfunction and degeneration, suggesting a neuroprotective effect of endogenous DHEA. There are significant sex differences in the pathophysiology, epidemiology and clinical manifestations of many neurological diseases. The aim of this study was to determine whether DHEA can alter glucose metabolism in different structures of the CNS from male and female rats, and if this effect is sex-specific. The results showed that DHEA decreased glucose uptake in some structures (cerebral cortex and olfactory bulb) in males, but did not affect glucose uptake in females. When compared, glucose uptake in males was higher than females. DHEA enhanced the glucose oxidation in both males (cerebral cortex, olfactory bulb, hippocampus and hypothalamus) and females (cerebral cortex and olfactory bulb), in a sex-dependent manner. In males, DHEA did not affect synthesis of glycogen, however, glycogen content was increased in the cerebral cortex and olfactory bulb. DHEA modulates glucose metabolism in a tissue-, dose- and sex-dependent manner to increase glucose oxidation, which could explain the previously described neuroprotective role of this hormone in some neurodegenerative diseases.

Smoking fewer than 20 cigarettes per day and remaining abstinent for more than 12 hours reduces carboxyhemoglobin levels in packed red blood cells for transfusion

Background The prevalence of smokers among blood donors and the effect of smoking on the quality of donated blood have not been extensively explored. In the present study, we determined the prevalence of smoker donors in a large blood bank in Southern Brazil and evaluated the quality of packed red blood cells (RBCs) from these donors through recommended quality control tests and measurement of carboxyhemoglobin (COHb) levels. We then assessed the influence of smoking habits and abstinence before donation on these parameters. Material and methods An observational study was conducted to determine the prevalence of smoking donors, while a prospective cohort study compared conventional hematological and serological parameters and COHb levels at 0, 15, and 30 days after donation in RBCs donated by smokers (N = 31) and nonsmokers (N = 31) and their association with smoking habits and abstinence before donation. Results Of 14,428 blood donations received in 1 year, 5.9% were provided by smokers. Storage over time slightly altered some quality parameters, such as hematocrit, hemoglobin, hemolysis, and COHb levels, in RBC packs. COHb levels were higher in RBC packs from smokers (8%) than from non-smokers (2%), and increased as a function of the number of cigarettes smoked daily and time elapsed since the last cigarette smoked before donation. Lower levels were found in RBC packs from donors who smoked fewer than 20 cigarettes per day or remained abstinent for more than 12h before giving blood. Conclusion Although cigarette smoke had no significant effect on blood quality parameters such as hematocrit, hemoglobin, or hemolysis, it quadrupled COHb levels in packed RBCs. Abstinence from smoking for more than 12h or smoking fewer than 20 cigarettes daily helped decrease COHb levels. Implications Given the increasing prevalence of tobacco use worldwide, we suggest blood banks recommend 12h of tobacco abstinence before donation and analyze COHb levels in donated blood as an approach to reduce risk for high-risk recipients.

Astrocyte Neuroprotection and Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the most abundant steroid hormones in the systemic circulation of humans. Due to their abundance and reduced production during aging, these hormones have been suggested to play a role in many aspects of health and have been used as drugs for a multiple range of therapeutic actions, including hormonal replacement and the improvement of aging-related diseases. In addition, several studies have shown that DHEA and DHEAS are neuroprotective under different experimental conditions, including models of ischemia, traumatic brain injury, spinal cord injury, glutamate excitotoxicity, and neurodegenerative diseases. Since astrocytes are responsible for the maintenance of neural tissue homeostasis and the control of neuronal energy supply, changes in astrocytic function have been associated with neuronal damage and the progression of different pathologies. Therefore, the aim of this chapter is to discuss the neuroprotective effects of DHEA against different types of brain and spinal cord injuries and how the modulation of astrocytic function by DHEA could represent an interesting therapeutic approach for the treatment of these conditions.

Aging affects the response of female rats to a hypercaloric diet

Abstract Metabolic syndrome is a major risk factor for the development of cardiovascular diseases and diabetes, among other conditions. Studies have shown that aging and metabolic syndrome share several metabolic alterations, and that aged individuals, in particular females, are at an increased risk of developing metabolic disorders. Although several studies have investigated the effects of hypercaloric diets in the development of obesity and metabolic syndrome in young animals, few studies have investigated these parameters in aged animals, especially in females. Therefore, the aim of this study was to investigate the effects of a hypercaloric diet in metabolic parameters of young and aged female rats, including its effects on lipid and glycemic profile and on liver lipid content. When compared to young animals, the aged rats presented increased serum levels of triglycerides and decreased serum levels of HDL cholesterol and glycemia, as well as increased hepatic levels of triglycerides and total cholesterol. The hypercaloric diet increased food intake, body weight gain and adiposity index, leading both young and aged animals to a dyslipidemia, represented by increased serum levels of triglycerides. The hypercaloric diet increased the glycemia and the HOMA index only in the young animals. On the other hand, the diet increased the frequency of hepatocellular microvacuolar degeneration only in the aged animals. In summary, it was observed that the females from different ages respond differently to hypercaloric diet intake: while the aged animals were more resistant to the changes in the glycemic profile, they were more susceptible to the hepatic damage caused by this diet. HighlightsAged females are at an increased risk of developing metabolic disorders.The effects of a hypercaloric diet in young and aged female rats were investigated.The diet increased the weight and led both young and aged animals to a dyslipidemia.Aged females were more resistant to changes in the glycemic profile caused by the diet.Aged females were more susceptible to the hepatic damage caused by the diet.