SummaryMultiple sclerosis (MS) is a neurological disorder that affects more than a million people world-wide. The aetiology of MS is not known and there is no medical treatment available that can cure MS. Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARc, a and d agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPARd agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/ 6 mice by blocking interferon (IFN)-c and interleukin (IL)-17 production by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPARd agonists was also associated with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPARd agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases.

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The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expressed in phagocytes is a multi-subunit enzyme complex that generates superoxide (O2.−). This radical is an important precursor of hydrogen peroxide (H2O2) and other reactive oxygen species needed for microbicidal activity during innate immune responses. Inherited defects in NADPH oxidase give rise to chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent infections and granulomatous inflammation. Interestingly, CGD, CGD carrier status, and oxidase gene polymorphisms have all been associated with autoinflammatory and autoimmune disorders, suggesting a potential role for NADPH oxidase in regulating adaptive immune responses. Here, NADPH oxidase function in antigen processing and presentation is reviewed. NADPH oxidase influences dendritic cell (DC) crosspresentation by major histocompatibility complex class I molecules through regulation of the phagosomal microenvironment, while in B lymphocytes, NADPH oxidase alters epitope selection by major histocompatibility complex class II molecules.

Due to the complexity of the disease, several hypotheses exist to explain the etiology of depression. The monoamine theory of depression suggests that disruptions in the serotonergic and noradrenergic systems result in depressive symptoms. Therefore, the serotonin transporter (SERT) has become a pharmacological target for treating these symptoms. This review will discuss what is known about the molecular interactions of antidepressants with SERT. The effects of antidepressants on SERT regulation and expression in addition to the receptors that may be involved in mediating these effects will be addressed. Specifically, how changes to SERT expression following chronic antidepressant treatment may contribute to the therapeutic benefits of antidepressants will be discussed. Furthermore, the effects of SERT gene polymorphisms on antidepressant efficacy will be examined. Finally, a brief overview of other hypotheses of depression will be addressed as well as factors that must be considered for future antidepressant development.