The β2-adrenergic receptor (β2AR) is a seven-transmembrane (7TM) G-protein coupled receptor that is expressed on cells of the pulmonary, cardiac, skeletal muscle, and immune systems. Previous work has shown that stimulation of this receptor on immune cells has profound effects on the regulatory activity of both adaptive and innate immune cells. This review examines the functional dichotomy associated with stimulation of β2AR and microglial cells. As well, recent studies targeting these receptors with long-acting agonists are considered with respect to their therapeutic potential in management of Parkinsonμs disease. 1. Introduction Neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s disease, are characterized by the progressive loss of the structure and function of neurons. Specifically, Parkinson’s disease is characterized by the death of dopaminergic (DA) neurons (cell groups A8 and A9) in the midbrain, substantia nigra (SN), and striatum. Over time, this leads to impaired motor skills, shaking, slowness of movement, and postural instability, well known symptoms of PD. In addition, many patients experience dementia and executive dysfunction. A recent study of an unselected population-representative cohort ( ) highlights the poor prognosis of PD patients as evidenced by a 55% mortality rate within 10 years of diagnosis [1]. Of the survivors, 68% and 46% had postural instability and dementia, respectively; 23% had not yet progressed to either of these irreversible disease milestones. Since the late 1960s, levodopa has been a key treatment and is the gold standard nearly 50 years later [2]. Converted to dopamine within the brain, it is used to control the motor symptoms of the disease but is ineffective with respect to dementia, freezing, or autonomic functions. A host of other treatments have been developed centered primarily around maintaining or increasing dopamine concentrations within the brain, such as dopamine agonists, MAO B inhibitors, catechol o-methyltransferase (COMT) inhibitors, anticholinergics, and amantadine. Stem cell transplant therapy and deep brain stimulation have also been explored with varying results. What is known about neurodegenerative disorders in general and in Parkinson’s disease in particular is that the progressive nature is in part associated with chronic inflammation and microglial activation [3]. Although a variety of triggers, including inherited genetic mutations and environmental toxins, can initiate the advent of neurodegeneration, inflammation is now recognized as an underlying mechanism
References
[1]
C. H. Williams-Gray, S. L. Mason, J. R. Evans, et al., “The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 84, no. 11, pp. 1258–1264, 2013.
[2]
O. Rascol, A. Lozano, M. Stern, and W. Poewe, “Milestones in Parkinson's disease therapeutics,” Movement Disorders, vol. 26, no. 6, pp. 1072–1082, 2011.
[3]
M. L. Block and J.-S. Hong, “Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism,” Progress in Neurobiology, vol. 76, no. 2, pp. 77–98, 2005.
[4]
A. L. Bartels and K. L. Leenders, “Neuroinflammation in the pathophysiology of Parkinson's disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET,” Movement Disorders, vol. 22, no. 13, pp. 1852–1856, 2007.
[5]
W. Dauer and S. Przedborski, “Parkinson's disease: mechanisms and models,” Neuron, vol. 39, no. 6, pp. 889–909, 2003.
[6]
H.-M. Gao, J. Jiang, B. Wilson, W. Zhang, J.-S. Hong, and B. Liu, “Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease,” Journal of Neurochemistry, vol. 81, no. 6, pp. 1285–1297, 2002.
[7]
H.-M. Gao and J.-S. Hong, “Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression,” Trends in Immunology, vol. 29, no. 8, pp. 357–365, 2008.
[8]
P. L. McGeer, S. Itagaki, B. E. Boyes, and E. G. McGeer, “Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains,” Neurology, vol. 38, no. 8, pp. 1285–1291, 1988.
[9]
P. L. McGeer, S. Itagaki, H. Akiyama, and E. G. McGeer, “Rate of cell death in parkinsonism indicates active neuropathological process,” Annals of Neurology, vol. 24, no. 4, pp. 574–576, 1988.
[10]
J. W. Langston, I. Irwin, E. B. Langston, and L. S. Forno, “1-Methyl-4-phenylpyridinium ion (MPP+): identification of a metabolite of MPTP, a toxin selective to the substantia nigra,” Neuroscience Letters, vol. 48, no. 1, pp. 87–92, 1984.
[11]
J. W. Langston, L. S. Forno, J. Tetrud, A. G. Reeves, J. A. Kaplan, and D. Karluk, “Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure,” Annals of Neurology, vol. 46, no. 4, pp. 598–605, 1999.
[12]
P. L. McGeer, C. Schwab, A. Parent, and D. Doudet, “Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration,” Annals of Neurology, vol. 54, no. 5, pp. 599–604, 2003.
[13]
A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Neuroscience: resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science, vol. 308, no. 5726, pp. 1314–1318, 2005.
[14]
M. K. McCoy and M. G. Tansey, “TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease,” Journal of Neuroinflammation, vol. 5, article 45, 2008.
[15]
L. Qian and P. M. Flood, “Microglial cells and Parkinson's disease,” Immunologic Research, vol. 41, no. 3, pp. 155–164, 2008.
[16]
K. F. Tanaka, H. Kashima, H. Suzuki, K. Ono, and M. Sawada, “Existence of functional β1- and β2-adrenergic receptors on microglia,” Journal of Neuroscience Research, vol. 70, no. 2, pp. 232–237, 2002.
[17]
M. T. Heneka, E. Galea, V. Gavriluyk et al., “Noradrenergic depletion potentiates β-amyloid-induced cortical inflammation: implications for Alzheimer's disease,” Journal of Neuroscience, vol. 22, no. 7, pp. 2434–2442, 2002.
[18]
J. L. M. Madrigal, D. L. Feinstein, and C. Dello Russo, “Norepinephrine protects cortical neurons against microglial-induced cell death,” Journal of Neuroscience Research, vol. 81, no. 3, pp. 390–396, 2005.
[19]
M. Johnson, “Beta2 -adrenoceptors: mechanisms of action of beta2-agonists,” Paediatric Respiratory Reviews, vol. 2, no. 1, pp. 57–62, 2001.
[20]
B. K. Kobilka, R. A. F. Dixon, and T. Frielle, “cDNA for the human β2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 1, pp. 46–50, 1987.
[21]
M. Johnson, “The β-adrenoceptor,” American Journal of Respiratory and Critical Care Medicine, vol. 158, no. 5, pp. S146–S153, 1998.
[22]
C. A. Izeboud, R. M. Vermeulen, A. Zwart, H.-P. Voss, A. S. J. P. Van Miert, and R. F. Witkamp, “Stereoselectivity at the β2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of β2-agonists,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 362, no. 2, pp. 184–189, 2000.
[23]
C. Culmsee, V. Junker, S. Thal et al., “Enantio-selective effects of clenbuterol in cultured neurons and astrocytes, and in a mouse model of cerebral ischemia,” European Journal of Pharmacology, vol. 575, no. 1-3, pp. 57–65, 2007.
[24]
I. Semkova, M. Schilling, P. Henrich-Noack, A. Rami, and J. Krieglstein, “Clenbuterol protects mouse cerebral cortex and rat hippocampus from ischemic damage and attenuates glutamate neurotoxicity in cultured hippocampal neurons by induction of NGF,” Brain Research, vol. 717, no. 1-2, pp. 44–54, 1996.
[25]
C. Culmsee, R. K. Stumm, M. K.-H. Sch？fer, E. Weihe, and J. Krieglstein, “Clenbuterol induces growth factor mRNA, activates astrocytes, and protects rat brain tissue against ischemic damage,” European Journal of Pharmacology, vol. 379, no. 1, pp. 33–45, 1999.
[26]
P. Follesa and I. Mocchetti, “Regulation of basic fibroblast growth factor and nerve growth factor mRNA by β-adrenergic receptor activation and adrenal steroids in rat central nervous system,” Molecular Pharmacology, vol. 43, no. 2, pp. 132–138, 1993.
[27]
C. Hodges-Savola, S. D. Rogers, J. R. Ghilardi, D. R. Timm, and P. W. Mantyh, “Beta-adrenergic receptors regulate astrogliosis and cell proliferation in the central nervous system in vivo,” Glia, vol. 17, no. 1, pp. 52–62, 1996.
[28]
P. W. Mantyh, S. D. Rogers, C. J. Allen et al., “β2-adrenergic receptors are expressed by glia in vivo in the normal and injured central nervous system in the rat, rabbit, and human,” Journal of Neuroscience, vol. 15, no. 1 I, pp. 152–164, 1995.
[29]
C. Culmsee, I. Semkova, and J. Krieglstein, “NGF mediates the neuroprotective effect of the β2-adrenoceptor agonist clenbuterol in vitro and in vivo: evidence from an NGF-antisense study,” Neurochemistry International, vol. 35, no. 1, pp. 47–57, 1999.
[30]
V. Junker, A. Becker, R. Hühne et al., “Stimulation of β-adrenoceptors activates astrocytes and provides neuroprotection,” European Journal of Pharmacology, vol. 446, no. 1–3, pp. 25–36, 2002.
[31]
H. Fujita, J. Tanaka, N. Maeda, and M. Sakanaka, “Adrenergic agonists suppress the proliferation of microglia through β2-adrenergic receptor,” Neuroscience Letters, vol. 242, no. 1, pp. 37–40, 1998.
[32]
H. Kato, M. Kawaguchi, S. Inoue, K. Hirai, and H. Furuya, “The effects of β-adrenoceptor antagonists on proinflammatory cytokine concentrations after subarachnoid hemorrhage in rats,” Anesthesia and Analgesia, vol. 108, no. 1, pp. 288–295, 2009.
[33]
C. Culmsee, “Targeting β2-adrenoceptors for neuroprotection after cerebral ischemia: is inhibition or stimulation best?” Anesthesia and Analgesia, vol. 108, no. 1, pp. 3–5, 2009.
[34]
A. Zlotnik, Y. Klin, B. F. Gruenbaum et al., “β2 Adrenergic-mediated reduction of blood glutamate levels and improved neurological outcome after traumatic brain injury in rats,” Journal of Neurosurgical Anesthesiology, vol. 24, no. 1, pp. 30–38, 2012.
[35]
L. Qian, H. Wu, S.-H. Chen et al., “β2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway,” Journal of Immunology, vol. 186, no. 7, pp. 4443–4454, 2011.
[36]
L. Qian, S. T. Kai, S.-J. Wei et al., “Microglia-mediated neurotoxicity is inhibited by morphine through an opioid receptor-independent reduction of NADPH oxidase activity,” Journal of Immunology, vol. 179, no. 2, pp. 1198–1209, 2007.
[37]
M. T. Drake, J. D. Violin, E. J. Whalen, J. W. Wisler, S. K. Shenoy, and R. J. Lefkowitz, “β-arrestin-biased agonism at the β2-adrenergic receptor,” The Journal of Biological Chemistry, vol. 283, no. 9, pp. 5669–5676, 2008.
[38]
L. M. Luttrell and R. J. Lefkowitz, “The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals,” Journal of Cell Science, vol. 115, no. 3, pp. 455–465, 2002.
[39]
D. S. Witherow, T. R. Garrison, W. E. Miller, and R. J. Lefkowitz, “β-arrestin inhibits NF-κB activity by means of its interaction with the NF-κB inhibitor IκBα,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 23, pp. 8603–8607, 2004.
[40]
C.-H. Hung, Y.-T. Chu, Y.-M. Hua et al., “Effects of formoterol and salmeterol on the production of Th1- and Th2-related chemokines by monocytes and bronchial epithelial cells,” European Respiratory Journal, vol. 31, no. 6, pp. 1313–1321, 2008.
[41]
A. Severn, N. T. Rapson, C. A. Hunter, and F. Y. Liew, “Regulation of tumor necrosis factor production by adrenaline and β-adrenergic agonists,” Journal of Immunology, vol. 148, no. 11, pp. 3441–3445, 1992.
[42]
T. van der Poll, J. Jansen, E. Endert, H. P. Sauerwein, and S. J. H. van Deventer, “Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin 6 production in human whole blood,” Infection and Immunity, vol. 62, no. 5, pp. 2046–2050, 1994.
[43]
P. A. Baeuerle and D. Baltimore, “IκB: a specific inhibitor of the NF-κB transcription factor,” Science, vol. 242, no. 4878, pp. 540–546, 1988.
[44]
A. S. Baldwin Jr., “The NF-κB and IκB proteins: new discoveries and insights,” Annual Review of Immunology, vol. 14, pp. 649–681, 1996.
[45]
S. K. Shenoy, M. T. Drake, C. D. Nelson et al., “β-arrestin-dependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor,” The Journal of Biological Chemistry, vol. 281, no. 2, pp. 1261–1273, 2006.
[46]
K. S. Tan, A. G. Nackley, K. Satterfield, W. Maixner, L. Diatchenko, and P. M. Flood, “β2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-κB-independent mechanisms,” Cellular Signalling, vol. 19, no. 2, pp. 251–260, 2007.
[47]
L. Qian, X. Hu, D. Zhang et al., “β2 adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK-dependent/protein kinase A-independent pathway,” Glia, vol. 57, no. 15, pp. 1600–1609, 2009.
[48]
H. Sakurai, “Targeting of TAK1 in inflammatory disorders and cancer,” Trends in Pharmacological Sciences, vol. 33, no. 10, pp. 522–530, 2012.
[49]
M. Tipping, Y. Kim, P. Kyriakakis, M. Tong, S. Y. Shvartsman, and A. Veraksa, “β-arrestin Kurtz inhibits MAPK and Toll signalling in Drosophila development,” The EMBO Journal, vol. 29, no. 19, pp. 3222–3235, 2010.
[50]
T. Masuda, S. Nakagawa, S. Boku et al., “Noradrenaline increases neural precursor cells derived from adult rat dentate gyrus through beta2 receptor,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol. 36, no. 1, pp. 44–51, 2012.
[51]
S. Nakagawa, J.-E. Kim, R. Lee et al., “Regulation of Neurogenesis in Adult Mouse Hippocampus by cAMP and the cAMP Response Element-Binding Protein,” Journal of Neuroscience, vol. 22, no. 9, pp. 3673–3682, 2002.
[52]
Y. D. Teng, H. Choi, W. Huang et al., “Therapeutic effects of clenbuterol in a murine model of amyotrophic lateral sclerosis,” Neuroscience Letters, vol. 397, no. 1-2, pp. 155–158, 2006.
[53]
C. Culmsee, V. Junker, W. Kremers, S. Thal, N. Plesnila, and J. Krieglstein, “Combination therapy in ischemic stroke: synergistic neuroprotective effects of memantine and clenbuterol,” Stroke, vol. 35, no. 5, pp. 1197–1202, 2004.
[54]
R. J. Zeman, H. Peng, Y. Feng, H. Song, X. Liu, and J. D. Etlinger, “β2-adrenoreceptor agonist-enhanced recovery of locomotor function after spinal cord injury is glutathione dependent,” Journal of Neurotrauma, vol. 23, no. 2, pp. 170–180, 2006.
[55]
I. Semkova and J. Krieglstein, “Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors,” Brain Research Reviews, vol. 30, no. 2, pp. 176–188, 1999.
