Alterations in the gut microbiota affect stroke outcomes via modulation of T cells, suggesting a gut-brain axis linking commensal microbes with the CNS. Commensal gut bacteria impact the host immune system and can influence disease processes in several organs, including the brain. However, it remains unclear whether the microbiota has an impact on the outcome of acute brain injury. Here we show that antibiotic-induced alterations in the intestinal flora reduce ischemic brain injury in mice, an effect transmissible by fecal transplants. Intestinal dysbiosis alters immune homeostasis in the small intestine, leading to an increase in regulatory T cells and a reduction in interleukin (IL)-17–positive γδ T cells through altered dendritic cell activity. Dysbiosis suppresses trafficking of effector T cells from the gut to the leptomeninges after stroke. Additionally, IL-10 and IL-17 are required for the neuroprotection afforded by intestinal dysbiosis. The findings reveal a previously unrecognized gut-brain axis and an impact of the intestinal flora and meningeal IL-17+ γδ T cells on ischemic injury.

Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,β-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activate the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway through a Michael addition reaction with the cysteines of Keap1, which acts as a redox sensor and negative regulator of Nrf2. This modification allows the dissociation of Nrf2 from the cytoplasmic complex with Keap1 and its nuclear translocation. At this level, Nrf2 binds to the antioxidant response element (ARE) and activates the expression of several detoxification, antioxidant and anti-inflammatory genes as well as genes involved in the clearance of damaged proteins. In this regard, the Keap1/Nrf2–ARE pathway is a new potential pharmacological target for the treatment of many chronic diseases. In this review we summarize the current progress in the study of Keap1/Nrf2–ARE pathway activation by natural and synthetic chalcones and their potential pharmacological applications. Among the pharmacological activities highlighted, anti-inflammatory activity was more evident than others, suggesting a multi-target Michael acceptor mechanism for the chalcones involving key regulators of the Nrf2 and nuclear factor- κB (NF-κB) pathways.

ATP‐binding cassette (ABC) transporters, in particular P‐glycoprotein (encoded by ABCB1), are important and selective elements of the blood‐brain barrier (BBB), and they actively contribute to brain homeostasis. Changes in ABCB1 expression and/or function at the BBB may not only alter the expression and function of other molecules at the BBB but also affect brain environment. Over the last decade, a number of reports have shown that ABCB1 actively mediates the transport of beta amyloid (Aβ) peptide. This finding has opened up an entirely new line of research in the field of Alzheimer’s disease (AD). Indeed, despite intense research efforts, AD remains an unsolved pathology and effective therapies are still unavailable. Here, we review the crucial role of ABCB1 in the Aβtransport and how oxidative stress may interfere with this process. A detailed understanding of ABCB1 regulation can provide the basis for improved neuroprotection in AD and also enhanced therapeutic drug delivery to the brain.

Oxidative stress (OS) appears to be an important determinant during the different stages of progression of Alzheimer’s Disease (AD). In particular, impaired antioxidant defense mechanisms, such as the decrease of glutathione (GSH) and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), a master regulator of antioxidant genes, including those for GSH, are associated with OS in the human AD brain. Among the neuropathological hallmarks of AD, the soluble oligomers of amyloid beta (A) peptides seem to promote neuronal death through mitochondrial dysfunction and OS. In this regard, bifunctional antioxidants can exert a dual neuroprotective role by scavenging reactive oxygen species (ROS) directly and concomitant induction of antioxidant genes. In this study, among natural coumarins (esculetin, scopoletin, fraxetin and daphnetin), we demonstrated the ability of esculetin (ESC) to prevent and counteract ROS formation in neuronal SH-SY5Y cells, suggesting its profile as a bifunctional antioxidant. In particular, ESC increased the resistance of the SH-SY5Y cells against OS through the activation of Nrf2 and increase of GSH. In similar experimental conditions, ESC could also protect the SH-SY5Y cells from the OS and neuronal death evoked by oligomers of A_1–42 peptides. Further, the use of the inhibitors PD98059 and LY294002 also showed that Erk1/2 and Akt signaling pathways were involved in the neuroprotection mediated by ESC. These results encourage further research in AD models to explore the efficacy and safety profile of ESC as a novel neuroprotective agent.