Cannabidiol effect on long-term brain alterations in septic rats: Involvement of PPARγ activation.

Sepsis is a life-threatening condition induced by a deregulated host response to infection. Post-sepsis injury includes long-term cognitive impairment, whose neurobiological mechanisms and effective treatment remain unknown. The present study was designed to determine the potential effects of cannabidiol (CBD) in a sepsis-associated encephalopathy (SAE) model and explore if peroxisome proliferator activated receptor gamma (PPARγ) is the putative mechanism underpinning the beneficial effects. SAE was induced in Wistar rats by cecal ligation and puncture (CLP) or sham (control). CLP rats received vehicle, CBD (10 mg/kg), PPARγ inhibitor (GW9662 - 1 mg/kg), or GW9662 (1 mg/kg) + CBD (10 mg/kg) intraperitoneally for ten days. During this period, the survival rate was recorded, and at the end of 10 days, a memory test was performed, and the prefrontal cortex and hippocampus were removed to verify brain-derived neurotrophic factor (BDNF), cytokines (IL-1ß, IL-6 and IL-10), myeloperoxidase activity, nitrite nitrate concentration, and lipid and protein carbonylation and catalase activity. Septic rats presented cognitive decline and an increase in mortality following CLP. Only CBD alone improved the cognitive impairment, which was accompanied by restoration of BDNF, reduced neuroinflammation, and oxidative stress, mainly in the hippocampus. This study shows that CLP induces an increase in brain damage and CBD has neuroprotective effects on memory impairment and neurotrophins, as well as against neuroinflammation and oxidative stress, and is mediated by PPARγ activation.

Vitamin B6 Reduces Neurochemical and Long-Term Cognitive Alterations After Polymicrobial Sepsis: Involvement of the Kynurenine Pathway Modulation.

Neurological dysfunction as a result of neuroinflammation has been reported in sepsis and cause high mortality. High levels of cytokines stimulate the formation of neurotoxic metabolites by kynurenine (KYN) pathway. Vitamin B6 (vit B6) has anti-inflammatory and antioxidant properties and also acts as a cofactor for enzymes of the KYN pathway. Thus, by using a relevant animal model of polymicrobial sepsis, we studied the effect of vit B6 on the KYN pathway, acute neurochemical and neuroinflammatory parameters, and cognitive dysfunction in rats. Male Wistar rats (250-300 g) were submitted to cecal ligation and perforation (CLP) and divided into sham + saline, sham + vit B6, CLP + saline, and CLP + vit B6 (600 mg/kg, s.c.) groups. Twenty-four hours later, the prefrontal cortex and hippocampus were removed for neurochemical and neuroinflammatory analyses. Animals were followed for 10 days to determine survival rate, when cognitive function was assessed by behavioral tests. Vitamin B6 interfered in the activation of kynurenine pathway, which led to an improvement in neurochemical and neuroinflammatory parameters and, consequently, in the cognitive functions of septic animals. Thus, the results indicate that vit B6 exerts neuroprotective effects in acute and late consequences after sepsis.

Effects of ω-3 fatty acids on stereotypical behavior and social interactions in Wistar rats prenatally exposed to lipopolysaccarides.

OBJECTIVE: Supplementation with ω-3 polyunsaturated fatty acids (PUFAs) can positively contribute to neurologic development, modulating inflammatory responses, promoting homeostasis, and having a positive effect on animal behaviors associated with mental disorders. The aim of this study was to evaluate behavioral and biochemical effects of ω-3 fatty acid supplementation in an animal model for mental disorders by prenatal maternal exposure to lipopolysaccardies (LPS) from the maternal immune activation. METHODS: Twelve pregnant Wistar rats were used. Each rat received 100 µg/kg of LPS or saline solution on gestational day (GD) 9.5. The offspring remained with mothers until weaning and from postnatal day (PND) 30 were supplemented with ω-3 PUFA or saline solution by gavage at a dose of 0.8 g/kg orally for 21 d. On PND 52, the animals underwent behavioral tests; then, they were sacrificed, and the brain structures were dissected and analyzed by levels: neuron-specific enolase (NSE), brain-derived neurotrophic factor, and transforming growth factor (TGF)-ß. RESULT: Prenatal exposure to LPS significantly increased the episodes of stereotyped movements and decreased social interaction in the offspring (P = 0.009 and P = 0.001, respectively), after ω-3 PUFA supplementation these parameters reversed (P = 0.005 and P = 0.013, respectively). Significant changes also were identified in the biochemical analysis in NSE and TGF-ß in the brain structures; these conditions were reversed after ω-3 PUFA supplementation. CONCLUSION: Supplementation with ω-3 PUFA reversed animal behaviors that often are observed in autism and other mental disorders in rats prenatally exposed to LPS, and also exerted neuroprotective effects in marker levels of neuronal damage and expression of TGF-ß.