P2X7 receptor contributes to long-term neuroinflammation and cognitive impairment in sepsis-surviving mice.

Introduction: Sepsis is defined as a multifactorial debilitating condition with high risks of death. The intense inflammatory response causes deleterious effects on the brain, a condition called sepsis-associated encephalopathy. Neuroinflammation or pathogen recognition are able to stress cells, resulting in ATP (Adenosine Triphosphate) release and P2X7 receptor activation, which is abundantly expressed in the brain. The P2X7 receptor contributes to chronic neurodegenerative and neuroinflammatory diseases; however, its function in long-term neurological impairment caused by sepsis remains unclear. Therefore, we sought to evaluate the effects of P2X7 receptor activation in neuroinflammatory and behavioral changes in sepsis-surviving mice. Methods: Sepsis was induced in wild-type (WT), P2X7-/-, and BBG (Brilliant Blue G)-treated mice by cecal ligation and perforation (CLP). On the thirteenth day after the surgery, the cognitive function of mice was assessed using the novel recognition object and Water T-maze tests. Acetylcholinesterase (AChE) activity, microglial and astrocytic activation markers, and cytokine production were also evaluated. Results: Initially, we observed that both WT and P2X7-/- sepsis-surviving mice showed memory impairment 13 days after surgery, once they did not differentiate between novel and familiar objects. Both groups of animals presented increased AChE activity in the hippocampus and cerebral cortex. However, the absence of P2X7 prevented partly this increase in the cerebral cortex. Likewise, P2X7 absence decreased ionized calcium-binding protein 1 (Iba-1) and glial fibrillary acidic protein (GFAP) upregulation in the cerebral cortex of sepsis-surviving animals. There was an increase in GFAP protein levels in the cerebral cortex but not in the hippocampus of both WT and P2X7-/- sepsis-surviving animals. Pharmacological inhibition or genetic deletion of P2X7 receptor attenuated the production of Interleukin-1ß (IL-1ß), Tumor necrosis factor-α (TNF-α), and Interleukin-10 (IL-10). Conclusion: The modulation of the P2X7 receptor in sepsis-surviving animals may reduce neuroinflammation and prevent cognitive impairment due to sepsis-associated encephalopathy, being considered an important therapeutic target.

High-protein nutrition during pregnancy increases neuroinflammation and homocysteine levels and impairs behavior in male adolescent rats offspring.

AIMS: Throughout gestation, proteins in the diet are a source of essential amino acids that are crucial for proper healthy fetal growth and development. The present study was proposed to investigate the effect of high-protein diet consumption throughout pregnancy on redox homeostasis, neuroinflammatory status and amino acid levels, including homocysteine, in the male adolescent rats offspring's cerebral cortex. We also performed a battery of behavioral tests to evaluate maternal care, olfactory preference, exploratory capacity, habituation, memory, anxiety- and depression-like behavior motor activity in the offspring. MAIN METHODS: After pregnancy confirmation, the pregnant rats were randomly divided into two groups, according to the diet: group 1, (control) standard diet containing 20 % protein, and group 2, the high-protein diet containing 50 % protein. Throughout the gestational period, the pregnant rats received experimental diets. KEY FINDINGS: Results showed an increase in homocysteine levels and neuroinflammatory mediators in the offspring's cerebral cortex from pregnant rats supplemented with a high-protein diet throughout pregnancy. Besides decreasing histidine levels in offspring's serum. The results also revealed an impairment in memory and motricity and an increase in anxiety-like behavior in the offspring supplemented with a high-protein diet throughout pregnancy. Our findings showed a significant effect of high-protein diet consumption throughout pregnancy on offspring's neurobiochemistry, which can negatively impact behavioral performance. SIGNIFICANCE: Our results reinforce the importance of consuming a balanced diet during the gestational period, especially macronutrients such as proteins since the fetus is sensitive to the mother's diet during pregnancy which may impact the development of the offspring.

Folic acid supplementation during pregnancy alters behavior in male rat offspring: nitrative stress and neuroinflammatory implications.

Pregnancy diet can impact offspring's neurodevelopment, metabolism, redox homeostasis, and inflammatory status. In pregnancy, folate demand is increased due to the requirement for one-carbon transfer reactions. The present study was proposed to investigate the effect of folic acid supplementation throughout pregnancy on a battery of behavior tests (olfactory preference, motor activity, exploratory capacity, habituation, memory, anxiety- and depression-like behavior). Redox homeostasis and neuroinflammatory status in cerebral cortex were also investigated. After pregnancy confirmation, the pregnant rats were randomly divided into two groups, according to the diet: group 1, (control) standard diet (2 mg/kg diet of folic acid) and group 2, supplemented diet with 4 mg/kg diet of folic acid. Throughout the gestational period, the pregnant rats received experimental diets. Results show that the supplemented diet with 4 mg/kg diet of folic acid throughout pregnancy impaired memory and motricity of the offspring when compared with control (standard diet). It was also observed an increase in anxiety- and depression-like behavior in this group. Nitrite levels increased in cerebral cortex of the offspring, when compared to control group. In contrast, iNOS expression and immunocontent were not altered. Moreover, we identify an increase in TNF-α, IL-1ß, IL-6, IL-10, and MCP-1 gene expression in the cerebral cortex. In conclusion, our study showed that the supplemented diet with 4 mg/kg diet of folic acid throughout pregnancy may cause behavioral and biochemical changes in the male offspringGraphical abstract After pregnancy confirmation, the pregnant rats were randomly divided into two groups, according to the diet: group 1, (control) standard diet (2 mg/kg diet of folic acid) and group 2, supplemented diet with 4 mg/kg diet of folic acid. Throughout the gestational period, the pregnant rats received experimental diets. Results show that folic acid supplementation did not impair the mother-pup relationship. We showed that supplemented diet with 4 mg/kg diet of folic acid during pregnancy impairs memory and motricity of the offspring when compared with standard diet. It was also observed an increase in anxiety- and depression-like behavior in this group. Nitrative stress and neuroinflammation parameters were increased in the cerebral cortex of the offspring. ROS, reactive oxygen species.