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The role of stress effector systems in the initiation and progression of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model of MS, has strongly been suggested. To corroborate this notion, alterations in activity of the sympathoadrenal and sympathoneural axes of sympathoadrenal system (a major communication pathway between the central nervous system and the immune system), mirrored in altered release of their end-point mediators (adrenaline and noradrenaline, respectively), are shown to precede (in MS) and/or occur during development of MS and EAE in response to immune cell activation (in early phase of disease) and disease-related damage of sympathoadrenal system neurons and their projections (in late phase of disease). To add to the complexity, innate immunity cells and T-lymphocytes synthesize noradrenaline that may be implicated in a local autocrine/paracrine self-amplifying feed-forward loop to enhance myeloid-cell synthesis of proinflammatory cytokines and inflammatory injury. Furthermore, experimental manipulations targeting noradrenaline/adrenaline action are shown to influence clinical outcome of EAE, in a disease phase-specific manner. This is partly related to the fact that virtually all types of cells involved in the instigation and progression of autoimmune inflammation and target tissue damage in EAE/MS express functional adrenoceptors. Although catecholamines exert majority of immunomodulatory effects through β2-adrenoceptor, a role for α-adrenoceptors in EAE pathogenesis has also been indicated. In this review, we summarize all aforementioned aspects of immunopathogenetic action of catecholamines in EAE/MS as possibly important for designing new strategies targeting their action to prevent/mitigate autoimmune neuroinflammation and tissue damage.

Sympathetic dysfunction is suggested to contribute to development of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) alike. Considering important role of microglia in development/resolution of neuroinflammation, contribution of noradrenaline, the key sympathetic end-point mediator, in modulation of microglial phenotypic and functional properties in rat EAE model was examined. The study showed that noradrenaline acting in neurocrine and autocrine/paracrine way might influence microglia during EAE. Propranolol treatment over the effector phase moderated EAE course. This was associated with the increased proportion of microglia expressing CX3CR1, the key molecule in their immunomodulatory/neuroprotective action, and upregulation of CX3CR1 downstream Nrf2 gene. This correlated with the increased heme oxygenase-1 (HO-1) expression and phagocytic capacity of microglia, and their phenotypic changes mirrored in increased proportion of CD163- and CD83-expressing cells. The enhanced HO-1 expression was linked with the decreased proportion of microglial cells expressing IL-1β and IL-23, and possibly IL-6, followed by increased proportion of IL- 10–expressing microglia, and downregulated MCP-1/CCL2 expression. Consistently, spinal cord infiltration with blood-borne myeloid and CD4+ T cells, as well as CD4+ T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17+ cells co-producing IFN-γ and GM-CSF were decreased in propranolol-treated rats compared with saline-injected controls. The in vitro investigations of the effects of noradrenaline on microglia showed that noradrenaline through β-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests β-adrenoceptor–mediated neuroinflammation-promoting role of noradrenaline in EAE via modulation of microglial Nrf2 expression, and thereby forms the basis for further translational pharmacological research to improve multiple sclerosis therapy.

Original Article, Background: The smooth muscles of blood vessels express relaxant β-adrenoceptor, which functions as a negative feed-back system against α1-adrenoceptor-mediated contraction. Although β-adrenoceptor-mediated vascular smooth relaxation is generally thought to be triggered through a cyclic adenosine monophosphate (cAMP)-dependent pathway, a recent report has suggested a principal role for the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Thus, in this study, we examined whether the NO-cGMP pathway played an essential role in β-adrenoceptor-mediated smooth muscle direct relaxation in the rat thoracic aorta. Methods: The effects of an NO synthase inhibitor (L-NNA) or a soluble guanylyl cyclase inhibitor (ODQ) on the relaxation responses to β-adrenoceptor agonists were examined in endothelium-denuded rat thoracic aortas. The effects of β-adrenoceptor agonists on arterial cGMP content were also examined. Results: Both L-NNA and ODQ potently suppressed acetylcholine (ACh)-induced, endothelium-dependent relaxation. ODQ also largely suppressed endothelium-independent relaxation induced by an NO donor ((±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide [NOR3]). However, relaxation of the endothelium-denuded aortas in response to the β-adrenoceptor agonists isoprenaline, salbutamol, isoprenaline or CGP-12177A in the presence of propranolol, or noradrenaline was not substantially reduced by L-NNA or ODQ. Neither isoprenaline nor noradrenaline affected arterial cGMP content, whereas NOR3 caused an approximately 30-fold increase in cGMP content. Conclusions: Our findings suggested that the NO-cGMP pathway had an insignificant effect on endothelium-independent smooth muscle direct relaxation in the rat thoracic aorta in response to β-adrenoceptor agonists of any subtype (β1, β2, or β3).

The Harderian glands are innervated by sympathetic fibers originating in the superior cervical ganglia. The aim of this study is to characterize the /3-adrenergic receptors in the rat Harderian gland. The characteristics of/3-adrenergic receptors were determined in crude membrane preparations from rat 125 125 Harderian gland, using [ I]iodocyanopindolol ([ I]CYP) as radioligand. The binding of the ligand to the receptor is rapid, reversible, saturable, specific and dependent on time, temperature and membrane concentration. At 30~ stoichiometric data suggest the presence of one binding site with a K a value of 0.29 nM and Bmax of 32 pmol/L. The interaction shows a high degree of specificity for /3-adrenergic agonists and blockers, as suggested by competitive displacement experiments with isoproterenol (ICso = 19.1 nM), propranolol (ICso = 28.1 nM), and norepinephrine (ICso = 96.3 nM). Clonidine, yohimbine, methoxamine, and prazosin are ineffective at concentrations up to 1 IzM. In the other hand, binding of [125I]CYP by Harderian gland membranes exhibits day-night variations. Binding values are low during the daytime and increase progressively late in the evening to reach a maximum at 2200 h (2 h after the onset of dark period), but decreased to the end of the dark period (0600 h). In conclusion, the results presented in this paper show the functional and pharmacological characterization of/3-adrenergic receptors in the rat Harderian gland. This neurotransmitter may play a physiological role at this level regulating, at least, processes such as a thyroid hormone metabolism