PGC-1α agonism induces fetal hemoglobin and exerts antisickling effects in sickle cell disease.

Sickle cell disease is a growing health burden afflicting millions around the world. Clinical observation and laboratory studies have shown that the severity of sickle cell disease is ameliorated in individuals who have elevated levels of fetal hemoglobin. Additional pharmacologic agents to induce sufficient fetal hemoglobin to diminish clinical severity is an unmet medical need. We recently found that up-regulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) can induce fetal hemoglobin synthesis in human primary erythroblasts. Here, we report that a small molecule, SR-18292, increases PGC-1α leading to enhanced fetal hemoglobin expression in human erythroid cells, ß-globin yeast artificial chromosome mice, and sickle cell disease mice. In SR-18292-treated sickle mice, sickled red blood cells are significantly reduced, and disease complications are alleviated. SR-18292, or agents in its class, could be a promising additional therapeutic for sickle cell disease.

Roles of Nuclear Orphan Receptors TR2 and TR4 during Hematopoiesis.

TR2 and TR4 (NR2C1 and NR2C2, respectively) are evolutionarily conserved nuclear orphan receptors capable of binding direct repeat sequences in a stage-specific manner. Like other nuclear receptors, TR2 and TR4 possess important roles in transcriptional activation or repression with developmental stage and tissue specificity. TR2 and TR4 bind DNA and possess the ability to complex with available cofactors mediating developmental stage-specific actions in primitive and definitive erythrocytes. In erythropoiesis, TR2 and TR4 are required for erythroid development, maturation, and key erythroid transcription factor regulation. TR2 and TR4 recruit and interact with transcriptional corepressors or coactivators to elicit developmental stage-specific gene regulation during hematopoiesis.

Subchronic Exposure to Mixture of Cadmium, Copper, and Nickel Induces Neurobehavioral Deficits and Hippocampal Oxidative Stress of Wistar Rats.

The present study was aimed at evaluating the influence of the subchronic exposure of cadmium (Cd), copper (Cu), and nickel (Ni) mixtures on affective behaviors, memory impairment, and oxidative stress (OS) in the hippocampus. Thirty male Wistar rats were divided into 5 equal groups. Group 1 (control) received a saline solution (NaCl 0.9%). Groups 2, 3, and 4 received Cd (0.25 mg/kg), Cu (0.5 mg/kg), and Ni (0.25 mg/kg), respectively, while group 5 received a Cd, Cu, and Ni mixture through intraperitoneal injections for 2 months. After the exposure period, all rats were submitted to behavioral tests. Subsequently, OS markers and histological changes in the rats' hippocampi were assessed. Results showed that a 2-month exposure to the mixtures of metals (MM) has led to higher anxiety-like and depression-like behaviors and cognitive deficits in rats when compared to the control group and the individual metals. Furthermore, the MM induced heightened OS, evidenced by the rise in lipid peroxidation and nitric oxide levels. These effects were accompanied by a decrease in superoxide dismutase and catalase activities in the hippocampus. The histopathological analysis also supported that MM caused a neuronal loss in the CA3 sub-region. Overall, this study underscores that subchronic exposure to the Cd, Cu, and Ni mixture induces an OS status and histological changes in the hippocampus, with important affective and cognitive behavior variations in rats.

Neuroprotective effect of melatonin on nickel-induced affective and cognitive disorders and oxidative damage in rats.

The present work is carried out to explore the neuroprotective potential of Melatonin(Mel), on Ni-induced neurobehavioral, biochemical and histological alterations in male and female rats. The rats were intraperitoneally administered by nickel chloride (NiCl2, 1 mg/kg) and Mel (4 mg/kg) for 60 days. A neurobehavioral assessment was performed. Biochemical determinations of oxidative stress (OS) levels, and histological analysis of hippocampal tissues were also performed. Results showed that Nickel (Ni) treatment increased anxiety-like and depression-like behavior in rats. Besides, cognitive behavior on the Morris water maze was compromised following Ni treatment. Alongside this, Ni elevated hippocampal OS markers like lipid peroxidation and nitric oxide formation with a decrease in superoxide dismutase and catalase activities. Histological observations confirmed these results. Significantly, Mel administration alleviated neurobehavioral changes in Ni-treated rats of both genders. Also, Mel attenuated Ni-induced OS and increased the activities of antioxidant enzymes. The histopathological studies in the hippocampus supported that Mel markedly reduced the Ni-induced neuronal loss. In conclusion, this study suggests that Mel has a neuroprotective effect against Ni-induced neurobehavioral alterations, which may be related to lowering OS in the hippocampus.

Animal Models of Early-Life Adversity.

From the prenatal period throughout the first years of life, the brain undergoes its most rapid development, a period during which it is highly sensitive to external experiences. The timing of brain development differs from one region to another, as it also differs between substrates, neurotransmitter systems, and central endocrine circuitries. These discontinuities are part of the "critical periods of brain development." Early-life adversity (ELA), such as exposure to infection, maternal deprivation, and substance use, disrupts the programmed brain development, yielding a myriad of deviations in brain circuitry, stress responsivity, cognitive function, and general health. This is applicable to both humans and animal models.In our laboratory, several experimental animal designs have been developed that allow investigating the long-lasting consequences of ELA on brain function, cognitive and emotional development, and the risk to develop stress-related psychopathology later in adulthood. This book chapter will provide a review of such animal models, in particular, designs related to infections (LPS-induced), the quality of mother-infant relationship (maternal deprivation and separation), and substance use (ethanol intoxication). The behavior tests, biochemical, and immunohistochemistry assays applied after ELA will be explained. The behavioral tests encompass the open-field, elevated plus maze, forced swim, sucrose preference, Y-maze, object recognition, and Morris water maze tests. These experiments allow the assessment of several outcomes of interest, pertaining to locomotor activity, anxiety-like symptoms, depressive-like symptoms, working memory, recognition memory, spatial memory, and learning performance. The biochemical assays are employed to measure the level of oxidative stress and inflammation in brain areas after application of adversity. Immunohistochemistry puts into perspective the degree of immunoreactivity in the brain subjected to adversity. The findings from our laboratory indicate that the nature and timing of exposure play a critical role in sensitivity to develop neurodevelopmental disorders.

Effects of lipopolysaccharide administration and maternal deprivation on anxiety and depressive symptoms in male and female Wistar rats: Neurobehavioral and biochemical assessments.

INTRODUCTION: Preclinical studies of early-life adversity (ELA1) have highlighted the role of postnatal stress in the emergence and persistence of anxiety and depressive disorders. In this study, we compared anxious and depressive behaviors and oxidation levels in male and female Wistar rats subjected to three ELAs (lipopolysaccharide (LPS) induced, maternal deprivation (MD), or combination of the two stressors). METHODS: Rats were split into four groups: control group which received an intraperitoneal (IP) injection of saline on postnatal day (PND) 1, LPS-treated group which received an IP injection of LPS on PND1, MD group which was exposed to a 24-hour period of isolation on PND9, and LPS-treated/MD group which received an IP injection of LPS on PND1 then was exposed to a 24-hour period of isolation on PND9. Each group consisted of 12 rats and had an equal gender distribution. At three months, rats were subjected to neurobehavioral assessments and biochemical oxidative assays. RESULTS: Compared to controls, rats in the LPS and MD groups scored significantly higher on anxiety and depression-related measures. Gender differences in response were mainly observed in the MD group. Exposure to the combination of stressors led to a characteristic decrease in anxiety and an increase in depressive measures in both genders. All groups exposed to ELA showed a statistically significant increase in their oxidative stress levels. CONCLUSION: Response to ELA is gender-dependent and modulated by the nature, type, and number of stressors. Further investigations are critical to understand the mechanisms underlying combination of stressors and gender's effect.