Abstract
The endogenous neurotransmitter noradrenaline (NA) is known to exert potent anti-inflammatory effects in glial cells, as well as provide neuroprotection against excitatory and inflammatory stimuli. These properties raise the possibility that increasing levels of NA in the central nervous system (CNS) could provide benefit in neurological diseases and conditions containing an inflammatory component. In the current study, we tested this possibility by examining the consequences of selectively modulating CNS NA levels on the development of clinical signs in experimental autoimmune encephalomyelitis (EAE). In mice immunized with myelin oligodendrocyte glycoprotein peptide to develop a chronic disease, pretreatment to selectively deplete CNS NA levels exacerbated clinical scores. Elevation of NA levels using the selective NA reuptake inhibitor atomoxetine did not affect clinical scores, while treatment of immunized mice with the synthetic NA precursor l-threo-3,4-dihydroxyphenylserine (l-DOPS) prevented further worsening. In contrast, treatment of mice with a combination of atomoxetine and l-DOPS led to significant improvement in clinical scores as compared to the control group. The combined treatment reduced astrocyte activation in the molecular layer of the cerebellum as assessed by staining for glial fibrillary protein but did not affect Th1 or Th17 type cytokine production from splenic T cells. These data suggest that selective elevation of CNS NA levels could provide benefit in EAE and multiple sclerosis without influencing peripheral immune responses.
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Abramsky O, Wertman E, Reches A, Brenner T, Ovadia H (1987) Effect of hypothalamic lesions on experimental autoimmune diseases in rats. Ann N Y Acad Sci 496:360–365
Barkhatova VP, Zavalishin IA, Askarova LS, Shavratskii VK, Demina EG (1998) Changes in neurotransmitters in multiple sclerosis. Neurosci Behav Physiol 28:341–344
Berne-Fromell K, Fromell H, Lundkvist S, Lundkvist P (1987) Is multiple sclerosis the equivalent of Parkinson's disease for noradrenaline? Med Hypotheses 23:409–415
Carnevale D, De SR, Minghetti L (2007) Microglia-neuron interaction in inflammatory and degenerative diseases: role of cholinergic and noradrenergic systems. CNS Neurol Disord Drug Targets 6:388–397
Chelmicka-Schorr E, Checinski M, Arnason BG (1988) Chemical sympathectomy augments the severity of experimental allergic encephalomyelitis. J Neuroimmunol 17:347–350
Chelmicka-Schorr E, Kwasniewski MN, Thomas BE, Arnason BG (1989) The beta-adrenergic agonist isoproterenol suppresses experimental allergic encephalomyelitis in Lewis rats. J Neuroimmunol 25:203–207
Chelmicka-Schorr E, Wollmann RL, Kwasniewski MN, Kim DH, Dupont BL (1993) The beta 2-adrenergic agonist terbutaline suppresses acute passive transfer experimental autoimmune myasthenia gravis (EAMG). Int J Immunopharmacol 15:19–24
Cosentino M, Zaffaroni M, Marino F, Bombelli R, Ferrari M, Rasini E, Lecchini S, Ghezzi A, Frigo G (2002) Catecholamine production and tyrosine hydroxylase expression in peripheral blood mononuclear cells from multiple sclerosis patients: effect of cell stimulation and possible relevance for activation-induced apoptosis. J Neuroimmunol 133:233–240
Debeir T, Marien M, Ferrario J, Rizk P, Prigent A, Colpaert F, Raisman-Vozari R (2004) In vivo upregulation of endogenous NGF in the rat brain by the alpha2-adrenoreceptor antagonist dexefaroxan: potential role in the protection of the basalocortical cholinergic system during neurodegeneration. Exp Neurol 190:384–395
Dinter H, Tse J, Halks-Miller M, Asarnow D, Onuffer J, Faulds D, Mitrovic B, Kirsch G, Laurent H, Esperling P, Seidelmann D, Ottow E, Schneider H, Tuohy VK, Wachtel H, Perez HD (2000) The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents. J Neuroimmunol 108:136–146
Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT (2002a) Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. Ann Neurol 51:694–702
Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E (2002b) Noradrenergic regulation of inflammatory gene expression in brain. Neurochem Int 41:357–365
Fritschy JM, Grzanna R (1991) Experimentally-induced neuron loss in the locus coeruleus of adult rats. Exp Neurol 111:123–127
Galea E, Heneka MT, Dello Russo C, Feinstein DL (2003) Intrinsic regulation of brain inflammatory responses. Cell Mol Neurobiol 23:625–635
Genain CP, Roberts T, Davis RL, Nguyen MH, Uccelli A, Faulds D, Li Y, Hedgpeth J, Hauser SL (1995) Prevention of autoimmune demyelination in non-human primates by a campspecific phosphodiesterase inhibitor. Proc Natl Acad Sci USA 92:3601–3605
Goldstein DS (2006) l-Dihydroxyphenylserine (l-DOPS): a norepinephrine prodrug. Cardiovasc Drug Rev 24:189–203
Gould TJ, Rukstalis M, Lewis MC (2005) Atomoxetine and nicotine enhance prepulse inhibition of acoustic startle in C57BL/6 mice. Neurosci Lett 377:85–90
Hashioka S, Klegeris A, Monji A, Kato T, Sawada M, McGeer PL, Kanba S (2007) Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide. Exp Neurol 206:33–42
Heneka MT, Galea E, Gavriluyk V, Dumitrescu-Ozimek L, Daeschner J, O'Banion MK, Weinberg G, Klockgether T, Feinstein DL (2002) Noradrenergic depletion potentiates betaamyloid-induced cortical inflammation: implications for Alzheimer's disease. J Neurosci 22:2434–2442
Heneka MT, Gavrilyuk V, Landreth GE, O'Banion MK, Weinberg G, Feinstein DL (2003) Noradrenergic depletion increases inflammatory responses in brain: effects on IkappaB and HSP70 expression. J Neurochem 85:387–398
Honegger CG, Isler H (1984) Neurotransmitters, precursors and metabolites in spinal cord and brain of Lewis rats with EAE. Prog Clin Biol Res 146:131–138
Jonsson G, Hallman H, Ponzio F, Ross S (1981) DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) a useful denervation tool for central and peripheral noradrenaline neurons. Eur J Pharmacol 72:173–188
Jovanova-Nesic K, Nikolic V, Jankovic BD (1993) Locus ceruleus and immunity. II. Suppression of experimental allergic encephalomyelitis and hypersensitivity skin reactions in rats with lesioned locus ceruleus. Int J Neurosci 68:289–294
Kalinin S, Polak PE, Madrigal JL, Gavrilyuk V, Sharp A, Chauhan N, Marien M, Colpaert F, Feinstein DL (2006) Beta-amyloid-dependent expression of NOS2 in neurons: prevention by an alpha2-adrenergic antagonist. Antioxid Redox Signal 8:873–883
Kato T, Katsuyama M, Karai N, Hirose A, Nakamura M, Katsube J (1986) Reversal of the reserpine-induced ptosis by l-threo-3, 4-dihydroxy-phenylserine (l-threo-DOPS), a (−)-norepinephrine precursor, and its potentiation by imipramine or nialamide. Naunyn Schmiedebergs Arch Pharmacol 332:243–246
Khoruzhaia TA, Saakov BA (1975) Change in monoamine content and monoamine oxidase activity in brain structures during experimental allergic encephalomyelitis. Biull Eksp Biol Med 79:80–82
Konkol RJ, Wesselmann U, Karpus WJ, Leo GL, Killen JA, Roerig DL (1990) Suppression of clinical weakness in experimental autoimmune encephalomyelitis associated with weight changes, and post-decapitation convulsions after intracisternal-ventricular administration of 6-hydroxydopamine. J Neuroimmunol 26:25–34
Krenger W, Honegger CG, Feurer C, Cammisuli S (1986) Changes of neurotransmitter systems in chronic relapsing experimental allergic encephalomyelitis in rat brain and spinal cord. J Neurochem 47:1247–1254
Leonard JP, MacKenzie FJ, Patel HA, Cuzner ML (1991) Hypothalamic noradrenergic pathways exert an influence on neuroendocrine and clinical status in experimental autoimmune encephalomyelitis. Brain Behav Immun 5:328–338
Lewerenz J, Letz J, Methner A (2003) Activation of stimulatory heterotrimeric G proteins increases glutathione and protects neuronal cells against oxidative stress. J Neurochem 87:522–531
Loder C, Allawi J, Horrobin DF (2002) Treatment of multiple sclerosis with lofepramine, l-phenylalanine and vitamin B (12): mechanism of action and clinical importance: roles of the locus coeruleus and central noradrenergic systems. Med Hypotheses 59:594–602
Madrigal JL, Russo CD, Gavrilyuk V, Feinstein DL (2006) Effects of noradrenaline on neuronal NOS2 expression and viability. Antioxid Redox Signal 8:885–892
Madrigal JL, Kalinin S, Richardson JC, Feinstein DL (2007) Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta. J Neurochem 103:2092–2101
Marien MR, Colpaert FC, Rosenquist AC (2004) Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res Rev 45:38–78
Nakamura K, Ahmed M, Barr E, Leiden JM, Kang UJ (2000) The localization and functional contribution of striatal aromatic l-amino acid decarboxylase to l-3, 4-dihydroxyphenylalanine decarboxylation in rodent parkinsonian models. Cell Transplant 9:567–576
Prince JB (2006) Pharmacotherapy of attention-deficit hyperactivity disorder in children and adolescents: update on new stimulant preparations, atomoxetine, and novel treatments. Child Adolesc Psychiatr Clin N Am 15:13–50
Puri BK, Bydder GM, Chaudhuri KR, Al Saffar BY, Curati WL, White SJ, Mitchell L, Hajnal JV, Horrobin DF (2001) MRI changes in multiple sclerosis following treatment with lofepramine and l-phenylalanine. Neuroreport 12:1821–1824
Rajda C, Bencsik K, Fuvesi J, Seres E, Vecsei L, Bergquist J (2006) The norepinephrine level is decreased in the lymphocytes of long-term interferon-beta-treated multiple sclerosis patients. Mult Scler 12:265–270
Russo-Neustadt A, Beard RC, Cotman CW (1999) Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression. Neuropsychopharmacol 21:679–682
Sharp AJ, Polak PE, Simonini V, Lin SX, Richardson JC, Bongarzone ER, Feinstein DL (2008) P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis. J Neuroinflammation 5:33
Sommer N, Martin R, McFarland HF, Quigley L, Cannella B, Raine CS, Scott DE, Loschmann PA, Racke MK (1997) Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease. J Neuroimmunol 79:54–61
Trojanowski JQ, Atkinson B, Lee VM (1986) An immunocytochemical study of normal and abnormal human cerebrospinal fluid with monoclonal antibodies to glial fibrillary acidic protein. Acta Cytol 30:235–239
Vollmar P, Nessler S, Kalluri SR, Hartung HP, Hemmer B (2008) The antidepressant venlafaxine ameliorates murine experimental autoimmune encephalomyelitis by suppression of pro-inflammatory cytokines. Int J Neuropsychopharmacol 1:1–12
White SR, Bhatnagar RK, Bardo MT (1983) Norepinephrine depletion in the spinal cord gray matter of rats with experimental allergic encephalomyelitis. J Neurochem 40:1771–1773
Wiegmann K, Muthyala S, Kim DH, Arnason BG, Chelmicka-Schorr E (1995) Beta-adrenergic agonists suppress chronic/relapsing experimental allergic encephalomyelitis (CREAE) in Lewis rats. J Neuroimmunol 56:201–206
Zeinstra E, Wilczak N, De Keyser J (2000) [3H]dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain. Neurosci Lett 289:75–77
Zoukos Y, Leonard JP, Thomaides T, Thompson AJ, Cuzner ML (1992) beta-Adrenergic receptor density and function of peripheral blood mononuclear cells are increased in multiple sclerosis: a regulatory role for cortisol and interleukin-1. Ann Neurol 31:657–662
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Guarantors: DL Feinstein and MV Simonini
This work was supported in part by a grant from Partnership for Cures (www.4cures.org) and the Grant Healthcare Foundation. Parts of this were presented in a poster at the 9th Annual Euroglia meeting, Sept 10th, 2009 and at the 39th annual Society for Neuroscience meeting, Oct 17th, 2009.
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Simonini, M.V., Polak, P.E., Sharp, A. et al. Increasing CNS Noradrenaline Reduces EAE Severity. J Neuroimmune Pharmacol 5, 252–259 (2010). https://doi.org/10.1007/s11481-009-9182-2
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DOI: https://doi.org/10.1007/s11481-009-9182-2