ABSTRACT
Dehydroepiandrosterone (DHEA) is an abundant adrenal steroid in serum of humans, and has been reported to have anti-inflammatory, anti-proliferative, and certain immune-regulating properties. Experimental autoimmune neuritis (EAN) is a Th1 cell-mediated animal model of Guillain-Barré syndrome (GBS) in humans. In the present study, DHEA was administered subcutaneously to Lewis rats immunized with bovine peripheral myelin (BPM) in Freund's complete adjuvant. Rats treated with DHEA displayed significant delay in onset, decreased inflammatory cell infiltration in the PNS. Benefit was associated with significant decreases in numbers of IFN-gamma and TNF-alpha expressing cells in the PNS, BPM-stimulated T cell proliferation and IFN-gamma, TNF-alpha-secretion in the spleen cells. Only 2 mg DHEA-treated EAN rats decreased peak clinical score. No significant difference of supernatant IL-10 was found among the treatment and control groups. These results suggest that DHEA can ameliorate the severity of EAN by suppressing the proliferation of autoreactive T cell and expression of pro-inflammatory cytokines.
Subject(s)
Adjuvants, Immunologic/administration & dosage , Dehydroepiandrosterone/administration & dosage , Neuritis, Autoimmune, Experimental/drug therapy , Analysis of Variance , Animals , Cattle , Cell Proliferation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay/methods , Female , Freund's Adjuvant , Interferon-alpha/metabolism , Interferon-gamma/metabolism , Myelin Sheath/immunology , Neuritis, Autoimmune, Experimental/etiology , Neuritis, Autoimmune, Experimental/immunology , Neuritis, Autoimmune, Experimental/pathology , Peripheral Nervous System Neoplasms/metabolism , Rats , Rats, Inbred Lew , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
Substantial development in the pharmacological treatment for attention-deficit hyperactivity disorder (ADHD) has been made recently including approval of new non-stimulant agents targeting noradrenergic, histaminergic and dopaminergic systems. Among such, atomoxetine has been widely used, although its mechanism of action is poorly understood. It is known that central nervous system histamine is closely associated with cognition and it was recently shown that both atomoxetine and methylphenidate enhance cortical histamine release in rats. To that end, the aim of our study was to investigate the effect of atomoxetine (2 mg/kg, intraperitoneally) on histamine release using the microdialysis technique in the spontaneously hypertensive rat (SHR), a suitable genetic model for ADHD. Our data confirmed that atomoxetine increases extracellular levels of histamine in the prefrontal cortex, a brain region that is implicated in the pathophysiology of ADHD. Given the tie between histamine neurotransmission and treatment of cognitive dysfunction, we also assessed the effects of atomoxetine on learning and memory as measured by the Morris water maze in SHR. The results indicated that atomoxetine significantly ameliorated performance in the Morris water maze, consistent with its histamine-enhancing profile. In conclusion, the current study provides further support for the notion that the therapeutic effect of atomoxetine could involve activation of histamine neurotransmission within the prefrontal cortex.