Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets.

The involvement of central and peripheral inflammation in the pathogenesis and prognosis of major depressive disorder (MDD) has been demonstrated. The increase of pro-inflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-18, and TNF-α) in individuals with depression may elicit neuroinflammatory processes and peripheral inflammation, mechanisms that, in turn, can contribute to gut microbiota dysbiosis. Together, neuroinflammation and gut dysbiosis induce alterations in tryptophan metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related mechanisms, and glutamate-mediated excitotoxicity. This review aims to highlight the inflammatory mechanisms (neuroinflammation, peripheral inflammation, and gut dysbiosis) involved in the pathophysiology of MDD and to explore novel anti-inflammatory therapeutic approaches for this psychiatric disturbance. Several lines of evidence have indicated that in addition to antidepressants, physical exercise, probiotics, and nutraceuticals (agmatine, ascorbic acid, and vitamin D) possess anti-inflammatory effects that may contribute to their antidepressant properties. Further studies are necessary to explore the therapeutic benefits of these alternative therapies for MDD.

In Pursuit of Healthy Aging: Effects of Nutrition on Brain Function.

Consuming a balanced, nutritious diet is important for maintaining health, especially as individuals age. Several studies suggest that consuming a diet rich in antioxidants and anti-inflammatory components such as those found in fruits, nuts, vegetables, and fish may reduce age-related cognitive decline and the risk of developing various neurodegenerative diseases. Numerous studies have been published over the last decade focusing on nutrition and how this impacts health. The main objective of the current article is to review the data linking the role of diet and nutrition with aging and age-related cognitive decline. Specifically, we discuss the roles of micronutrients and macronutrients and provide an overview of how the gut microbiota-gut-brain axis and nutrition impact brain function in general and cognitive processes in particular during aging. We propose that dietary interventions designed to optimize the levels of macro and micronutrients and maximize the functioning of the microbiota-gut-brain axis can be of therapeutic value for improving cognitive functioning, particularly during aging.

ISX-9 can potentiate cell proliferation and neuronal commitment in the rat dentate gyrus.

Adult hippocampal neurogenesis can be modulated by various physiological and pathological conditions, including stress, affective disorders, and several neurological conditions. Given the proposed role of this form of structural plasticity in the functioning of the hippocampus (namely learning and memory and affective behaviors), it is believed that alterations in hippocampal neurogenesis might underlie some of the behavioral deficits associated with these psychiatric and neurological conditions. Thus, the search for compounds that can reverse these deficits with minimal side effects has become a recognized priority. In the present study we tested the pro-neurogenic effects of isoxazole 9 (Isx-9), a small synthetic molecule that has been recently identified through the screening of chemical libraries in stem cell-based assays. We found that administration of Isx-9 for 14days was able to potentiate cell proliferation and increase the number of immature neurons in the hippocampal DG of adult rats. In addition, Isx-9 treatment was able to completely reverse the marked reduction in these initial stages of the neurogenic process observed in vehicle-treated animals (which were submitted to repeated handling and exposure to daily intraperitoneal injections). Based on these results, we recommend that future neurogenesis studies that require repeated handling and manipulation of animals should include a naïve (non-manipulated) control to determine the baseline levels of hippocampal cell proliferation and neuronal differentiation. Overall, these findings demonstrate that Isx-9 is a promising synthetic compound for the mitigation of stress-induced deficits in adult hippocampal neurogenesis. Future studies are thus warranted to evaluate the pro-neurogenic properties of Isx-9 in animal models of affective and neurological disorders associated with impaired hippocampal structural plasticity.

Screening of therapeutic strategies for Huntington's disease in YAC128 transgenic mice.

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an unstable expansion of cytosine-adenine-guanine (CAG) repeats in the HD gene. The symptoms include cognitive dysfunction and severe motor impairment with loss of voluntary movement coordination that is later replaced by bradykinesia and rigidity. The neuropathology is characterized by neuronal loss mainly in the striatum and cortex, and the appearance of neuronal intranuclear inclusions of mutant huntingtin. The mechanisms responsible for neurodegeneration are still not fully understood although excitotoxicity and a consequent increase in intracellular calcium concentration as well as the activation of caspases and calapins are known to play a key role. There is currently no satisfactory treatment or cure for this disease. The YAC128 transgenic mice express the full-length human HD gene with 128 CAG repeats and constitute a unique model for the study of HD as they replicate the slow and biphasic progression of behavioral deficits characteristic of the human condition and show striatal neuronal loss. As such, these transgenic mice have been an invaluable model not only for the elucidation of the neurodegenerative pathways in HD, but also for the screening and development of new therapeutic approaches. Here, I will review the unique characteristics of this transgenic HD model and will provide a summary of the therapies that have been tested in these mice, namely: potentiation of the protective roles of wild-type huntingtin and mutant huntingtin aggregation, transglutaminase inhibition, inhibition of glutamate- and dopamine-induced toxicity, apoptosis inhibition, use of essential fatty acids, and the novel approach of intrabody gene therapy. The insights obtained from these and future studies will help identify potential candidates for clinical trials and will ultimately contribute to the discovery of a successful treatment for this devastating neurodegenerative disorder.