Adrenergic modulation of the immune response Marco Cosentino. Center for Research in Medical Pharmacology University of Insubria, Varese, Italy

Transcription

1 Adrenergic modulation of the immune response Marco Cosentino, Varese, Italy Institut Pasteur, Paris, France 13 June 2014

2 Varese

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4 Neuroimmune pharmacology Clinical pharmacology and pharmacogenetics Pharmacoepidemiology and pharmacovigilance Pharmacology of herbal medicines

5 STRESS Physiological or biological stress is an organism's response to a stressor such as an environmental condition or a stimulus. Stress is a body's method of reacting to a challenge. According to the stressful event, the body's way to respond to stress is by sympathetic nervous system activation which results in the fight-or-flight response. In humans, stress typically describes a negative condition or a positive condition that can have an impact on a person's mental and physical well-being. Communication pathways between the nervous and immune systems Humoral HPA axis regulating the systemic concentration of cortisol and epinephrine (red lines), and efferent neuronal hypothalamus autonomic nervous system axis locally influencing immune function via neurotransmitters in lymphoid organs and inflamed tissue (blue lines). The cytokines IL-1, IL-6 and TNF-alpha modulate the CNS either directly or via receptors on sensory afferents such as the vagal nerve (feedback mechanisms, for example in inflamed tissue: green lines). These afferent sensory nerves are also present in lymphoid organs (not shown). Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; HPA, hypothalamus pituitary adrenal axis; IL-1, interleukin 1; TNF-alpha, tumour necrosis factor alpha. Straub et al., Immunol. Today 1998, 19:

6 STRESS Physiological or biological stress is an organism's response to a stressor such as an environmental condition or a stimulus. Stress is a body's method of reacting to a challenge. According to the stressful event, the body's way to respond to stress is by sympathetic nervous system activation which results in the fight-or-flight response. In humans, stress typically describes a negative condition or a positive condition that can have an impact on a person's mental and physical well-being.

7 STRESS Physiological or biological stress is an organism's response to a stressor such as an environmental condition or a stimulus. Stress is a body's method of reacting to a challenge. According to the stressful event, the body's way to respond to stress is by sympathetic nervous system activation which results in the fight-or-flight response. In humans, stress typically describes a negative condition or a positive condition that can have an impact on a person's mental and physical well-being.

8 STRESS Physiological or biological stress is an organism's response to a stressor such as an environmental condition or a stimulus. Stress is a body's method of reacting to a challenge. According to the stressful event, the body's way to respond to stress is by sympathetic nervous system activation which results in the fight-or-flight response. In humans, stress typically describes a negative condition or a positive condition that can have an impact on a person's mental and physical well-being.

9 STRESS Physiological or biological stress is an organism's response to a stressor such as an environmental condition or a stimulus. Stress is a body's method of reacting to a challenge. According to the stressful event, the body's way to respond to stress is by sympathetic nervous system activation which results in the fight-or-flight response. In humans, stress typically describes a negative condition or a positive condition that can have an impact on a person's mental and physical well-being.

10 STRESS Physiological or biological stress is an organism's response to a stressor such as an environmental condition or a stimulus. Stress is a body's method of reacting to a challenge. According to the stressful event, the body's way to respond to stress is by sympathetic nervous system activation which results in the fight-or-flight response. In humans, stress typically describes a negative condition or a positive condition that can have an impact on a person's mental and physical well-being.

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12 Psychological stress, immune response, and atherosclerosis Pathways linking psychological stressors and inflammation Immune system molecules involved in the process of atherosclerosis H.-f. Gu et al., Atherosclerosis 2012, 223: 69-77

13 Classification and characteristics of adrenoceptors α 1 -AR α 2 -AR β-ar Marino and Cosentino, Amino Acids 2013, 45: 55-71

14 Pharmacology of adrenoceptors α 1 -AR agonists Methoxamine, methylnorepinephrine, midodrine, oxymetazoline, metaraminol, phenylephrine vasoconstriction and mydriasis, used as vasopressors, nasal decongestants and eye exams antagonists alfuzosin, doxazosin, phenoxybenzamine, phentolamine, prazosin, tamsulosin, terazosin, trazodone hypertension, benign prostatic hyperplasia

15 Pharmacology of adrenoceptors α 2 -AR agonists dexmedetomidine, medetomidine, romifidine, clonidine, brimonidine, detomidine, lofexidine, xylazine, tizanidine, guanfacine, amitraz antihypertensives, sedatives and treatment of opiate dependence and alcohol withdrawal symptoms antagonists phentolamine, yohimbine, idazoxan, atipamezole, trazodone, mianserin, mirtazapine aphrodisiac, antidepressants, reversal of α 2 -AR agonist-induced sedation

16 Pharmacology of adrenoceptors β 1 -AR agonists dobutamine, isoprenaline, noradrenaline bradycardia, heart failure, cardiogenic shock antagonists metoprolol, atenolol, bisoprolol, propranolol, timolol, nebivolol cardiac arrhythmia, congestive heart failure, glaucoma, myocardial infarction, migraine prophylaxis * agents with intrinsic sympathomimetic action (ISA) acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol * agents with greater aqueous solubility (hydrophilic beta blockers) atenolol, celiprolol, nadolol, sotalol * agents with membrane stabilizing effect acebutolol, betaxolol, pindolol, propranolol * agents with antioxidant effect carvedilol, nebivolol

17 Pharmacology of adrenoceptors β 2 -AR agonists * short-acting salbutamol (albuterol), levosalbutamol (levalbuterol), terbutaline (Bricanyl), pirbuterol (Maxair), procaterol, clenbuterol, metaproterenol (Alupent), fenoterol, bitolterol mesylate, ritodrine, isoprenaline * long-acting salmeterol (Serevent Diskus), formoterol (Foradil, Symbicort), bambuterol, clenbuterol * ultra-long-acting Indacaterol asthma (effects: dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle, and release of insulin) antagonists butoxamine, timolol, propranolol glaucoma, heart attacks, hypertension, migraine headache; investigational: stage fright, PTSD

18 Pharmacology of adrenoceptors β 3 -AR agonists amibegron, investigational: antidepressant, anxiolytic solabegron overactive bladder, irritable bowel syndrome antagonists SR 59230A

19 The adrenergic synapse

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21 Adrenergic modulation of the immune response

22 What is Neuroimmune Pharmacology The field of neuroimmune pharmacology encompasses interdisciplinary research in pharmacology, immunology and neuroscience, providing original therapeutic approaches to investigations of the neuroimmune network. The over-arching goal of the discipline is to identify novel phar-macological targets or to exploit more established medicines for unique indications.

23 Neuroimmune pharmacology Clinical pharmacology and pharmacogenetics Pharmacoepidemiology and pharmacovigilance Pharmacology of herbal medicines