BackgroundWestern diet and lifestyle are associated with overweight, obesity, and type 2 diabetes, which, in turn, are correlated with neuroinflammation processes. Exercise and a healthy diet are important in the prevention of these disorders. However, molecules inhibiting neuroinflammation might also be efficacious in the prevention and/or treatment of neurological disorders of inflammatory etiology. The abscisic acid (ABA) is a phytohormone involved in hydric-stress responses. This compound is not only found in plants but also in other organisms, including mammals. In rodents, ABA can play a beneficial role in the regulation of peripheral immune response and insulin action. Thus, we hypothesized that chronic ABA administration might exert a protective effect in a model of neuroinflammation induced by high-fat diet (HFD).MethodsMale Wistar rats were fed with standard diet or HFD with or without ABA in the drinking water for 12 weeks. Glucose tolerance test and behavioral paradigms were performed to evaluate the peripheral and central effects of treatments. One-Way ANOVA was performed analyzed statistical differences between groups.ResultsThe HFD induced insulin resistance peripherally and increased the levels of proinflammatory markers in in the brain. We observed that ABA restored glucose tolerance in HFD-fed rats, as expected. In addition, chronic ABA treatment rescued cognitive performance in these animals, while not affecting control diet fed animals. Moreover, it counteracted the changes induced by HFD in the hypothalamus; microglia activations and TNFα mRNA levels.ConclusionThese results suggest that ABA might become a new therapeutic molecule improving the neuroinflammatory status and insulin resistance.

Alzheimer’s disease (AD), considered the most common type of dementia, is characterized by a progressive loss of memory, visuospatial, language and complex cognitive abilities. In addition, patients often show comorbid depression and aggressiveness. Aging is the major factor contributing to AD; however, the initial cause that triggers the disease is yet unknown. Scientific evidence demonstrates that AD, especially the late onset of AD, is not the result of a single event, but rather it appears because of a combination of risk elements with the lack of protective ones. A major risk factor underlying the disease is neuroinflammation, which can be activated by different situations, including chronic pathogenic infections, prolonged stress and metabolic syndrome. Consequently, many therapeutic strategies against AD have been designed to reduce neuro-inflammation, with very promising results improving cognitive function in preclinical models of the disease. The literature is massive; thus, in this review we will revise the translational evidence of these early strategies focusing in anti-diabetic and anti-inflammatory molecules and discuss their therapeutic application in humans. Furthermore, we review the preclinical and clinical data of nutraceutical application against AD symptoms. Finally, we introduce new players underlying neuroinflammation in AD: the activity of the endocannabinoid system and the intestinal microbiota as neuroprotectors. This review highlights the importance of a broad multimodal approach to treat successfully the neuroinflammation underlying AD.

Accumulated evidence indicates that neuroinflammation induces insulin resistance in the brain. Moreover, both processes are intimately linked to neurodegenerative disorders, including Alzheimer's disease. Potential mechanisms underlying insulin resistance include serine phosphorylation of the insulin receptor substrate (IRS) or insulin receptor (IR) misallocation. However, only a few studies have focused on IRS expression in the brain and its modulation in neuroinflammatory processes. This study used the high-fat diet (HFD) model of neuroinflammation to study the alterations of IR, an insulin-like growth factor receptor (IGF1R) and IRS expressions in the hippocampus. We observed that HFD effectively reduced mRNA and protein IRS2 expression. In contrast, a HFD induced the upregulation of the IRS1 mRNA levels, but did not alter an IR and IGF1R expression. As expected, we observed that a HFD increased hippocampal tumor necrosis factor alpha (TNFα) and amyloid precursor protein (APP) levels while reducing brain-derived neurotrophic factor (BDNF) expression and neurogenesis. Interestingly, we found that TNFα correlated positively with IRS1 and negatively with IRS2, whereas APP levels correlated positively only with IRS1 but not IRS2. These results indicate that IRS1 and IRS2 hippocampal expression can be affected differently by HFD-induced neuroinflammation. In addition, we aimed to establish whether abscisic acid (ABA) can rescue hippocampal IRS1 and IRS2 expression, as we had previously shown that ABA supplementation prevents memory impairments and improves neuroinflammation induced by a HFD. In this study, ABA restored HFD-induced hippocampal alterations, including IRS1 and IRS2 expression, TNFα, APP, and BDNF levels and neurogenesis. In conclusion, this study highlights different regulations of hippocampal IRS1 and IRS2 expression using a HFD, indicating the important differences of these scaffolding proteins, and strongly supports ABA therapeutic effects.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome characterized by dopaminergic dysfunction. In this study, we aimed to demonstrate that there is a link between dopaminergic deficit and neuroinflammation that underlies ADHD symptoms. We used a validated ADHD mice model involving perinatal 6-OHDA lesions. The animals received abscisic acid (ABA), an anti-inflammatory phytohormone, at a concentration of 20 mg/L (drinking water) for one month. We tested a battery of behavior tests, learning and memory, anxiety, social interactions, and pain thresholds in female and male mice (control and lesioned, with or without ABA treatment). Postmortem, we analyzed microglia morphology and Ape1 expression in specific brain areas related to the descending pain inhibitory pathway. In females, the dopaminergic deficit increased pain sensitivity but not hyperactivity. In contrast, males displayed hyperactivity but showed no increased pain sensitivity. In females, pain sensitivity was associated with inflammatory microglia and lower Ape1 levels in the anterior cingulate cortex (ACC) and posterior insula cortex (IC). In addition, ABA treatment alleviated pain sensitivity concomitant with reduced inflammation and normalized APE1. In males, ABA reduced hyperactivity but had no significant effect on inflammation in these areas. This is the first study proving a sex-dependent association between dopamine dysfunction and inflammation in specific brain areas, hence leading to different behavioral outcomes in a mouse model of ADHD. These findings provide new clues for potential treatments for ADHD.