PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis
Erika Vowinckel
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorDavid Reutens
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorBurkhard Becher
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorGail Verge
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorAlan Evans
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorTrevor Owens
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorCorresponding Author
Jack P. Antel
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Dept. of Neurology and Neurosurgery, Montreal Neurological Inst., McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4Search for more papers by this authorErika Vowinckel
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorDavid Reutens
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorBurkhard Becher
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorGail Verge
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorAlan Evans
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorTrevor Owens
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Search for more papers by this authorCorresponding Author
Jack P. Antel
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
Dept. of Neurology and Neurosurgery, Montreal Neurological Inst., McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4Search for more papers by this authorAbstract
Activated glial cells are implicated in regulating and effecting the immune response that occurs within the CNS as part of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The peripheral benzodiazepine receptor (PBR) is expressed in glial cells. We examined the utility of using in vitro and in vivo ligand binding to the PBR as a measure of lesion activity in autoimmune CNS demyelinating diseases. Applying a combined autoradiography and immunohistochemical approach to spinal cord and brain tissues from mice with EAE, we found a correlation at sites of inflammatory lesions between [3H]-PK11195 binding and immunoreactivity for the activated microglial/macrophage marker Mac-1/CD11b. In MS tissues, [3H]-PK11195 binding correlated with sites of immunoreactivity for the microglial/macrophage marker CD68, at the edges of chronic active plaques. Positron emission tomography (PET) imaging with [11C]-PK11195 showed ligand uptake only at sites of active MS lesions defined by magnetic resonance imaging criteria. Our results indicate the potential to develop markers suitable for both in vitro and in vivo use, which will serve to help correlate phenotypic and functional properties of cells which participate in disease or injury responses within the CNS. J. Neurosci. Res. 50:345–353, 1997. © 1997 Wiley-Liss, Inc.
References
- Anholt RRH, Pedersen PL, De Souza EB, Snyder SH (1986): The peripheral-type benzodiazepine receptor. J Biol Chem 261: 576–583.
- Benavides J, Cornu P, Dennis T, Dubois A, Hauw JJ, MacKenzie ET, Sazdovitch V, Scatton B (1988): Imaging of human brain lesions with an ω3 site radioligand. Ann Neurol 24: 708–712.
-
Black KL,
Idezaki K,
Santori E,
Becker DP,
Vinters HV
(1990):
Specific high-affinity binding of peripheral benzodiazepine receptor ligands to brain tumors in rat and man.
Cancer
65:
93–97.
10.1002/1097-0142(19900101)65:1<93::AID-CNCR2820650120>3.0.CO;2-1 CAS PubMed Web of Science® Google Scholar
- Braestrup C, Squires RF (1977): Specific benzodiazepine receptors in rat brain characterized by high-affinity [3H]diazepam binding. Proc Natl Acad Sci USA 74(9): 3805–3809.
- Cannella B, Raine CS (1995): The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 37: 424–435.
- Doble A, Malgouris C, Daniel M, Daniel N, Imbault F, Basbaum A, Uzan A, Gueremy C, LeFur G (1987): Labelling of peripheral-type benzodiazepine binding sites in human brain with [3H]PK 11195: Anatomical and subcellular distribution. Brain Res Bull 18: 49–61.
- Drugan RC (1994): Are the nonmitochondrial peripheral benzodiazepine receptors on leucocytes a novel intermediary of brain, behaviour, and immunity? Lab Invest 70: 1–3.
- Francis GS, Evans AC, Arnold DL (1995): Neuroimaging in multiple sclerosis. Neurol Clin 13: 147–171.
- Hardin-Pouzet H, Krakowski M, Boubonnière L, Didier-Bazes M, Tran E, Owens T (1997): Glutamate metabolism is down-regulated in astrocytes during experimental allergic myelitis. Glia 20: 79–85.
- Groom GN, Junck L, Foster NL, Frey KA, Kuhl DE (1995): PET of peripheral benzodiazepine binding sites in the microgliosis of Alzheimer's disease. J Nucl Med 36(12): 2207–10.
- Itzhak YB, Baker L, Norenberg MD (1993): Characterization of the peripheral-type benzodiazepine receptors in cultured astrocytes: evidence for multiplicity. Glia 9: 211–218.
- Klepner CA, Lippa AS, Benson DI, Sano MC, Beer B (1979): Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors. Pharmacol Biochem Behav 11: 457–462.
- Krueger KE (1995): Molecular and functional properties of mitochondrial benzodiazepine receptors. Biochim Biophys Acta 1241: 453–470.
- Leong DK, Le O, Oliva L, Butterworth RF (1994): Increased densities of binding sites for the “peripheral-type” benzodizepine receptor ligand [3H]PK11195 in vulnerable regions of the rat brain in thiamine deficiency encephalopathy. J Cereb Blood Flow Metab 14: 100–105.
- Marangos PJ, Patel J, Boulenger J-P, Clark-Rosenberg R (1981): Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro5-4864. Mol Pharmacol 22: 26–32.
- Martin R, McFarland HF, McFarlin D (1992): Immunological aspects of demyelinating disease. Annu Rev Immunol 10: 153–87.
- McCarthy KD, Harden TK (1981): Identification of two benzodiazepine binding sites on cells cultured from rat cerebral cortex. J Pharmacol Exp Ther 216: 183–191.
- Mohler H, Okada T (1977): Benzodiazepine receptors: demonstration in the central nervous system. Science 198: 849–851.
- Olsen JMM, Ciliax BJ, Mancini WR, Young AB (1988): Presence of peripheral-type benzodiazepine binding sites on human erythrocyte membranes. Eur J Pharmacol 152: 47–53.
- Owen F, Poulter M, Waddington JL, Mashal RD, Crow TJ (1983): 3HH-Ro5-4864 and 3H-flunitrazepam binding in kianate lesioned rat striatum and in temporal cortex of brains from patients with senile dementia of the Alzheimer type. Brain Res 273: 373–375.
- Owens T, Sriram S (1995): The immunology of MS and of its animal model, EAE. Neurol Clin 13: 51–73.
-
Park CH,
Carboni E,
Wood PL,
Gee KW
(1996):
Characterization of peripheral benzodiazepine type sites in a cultured murine BV-2 microglial cell line.
Glia
16:
65–70.
10.1002/(SICI)1098-1136(199601)16:1<65::AID-GLIA7>3.0.CO;2-A CAS PubMed Web of Science® Google Scholar
- Raine CS (1985): Experimental allergic encephalomyelitis and experimental allergic neuritis. In JC Koetsier (ed): “ Handbook of Clinical Neurology.” New York: Elsevier Science Publishing Co, Inc., pp 429–466.
- Ramsay SC, Weiller C, Myers C, Cremer JE, Luthra SK, Lammertsma AA, Frackowiak RSJ (1992): Monitoring by PET of macrophage accumulation in brain after ischemic stroke. Lancet 339: 1054–1055.
- Renno T, Taupin V, Bourbonniere L, Verge G, Krakowski M, De-Simone R, Rodriguez M, Peterson A, Owens T (1997): Transgenic expression of Interferon-gamma in the CNS results in persistent demyelination and neurological deficit following acute EAE. (submitted).
- Ruff MR, Pert BC, Weber RJ, Wahl LM, Wahl SM, Paul SM (1985): Benzodiazepine receptor-mediated chemotaxis of human monocytes. Science 229: 1281–1283.
- Schoemaker HM, Morelli M, Deshmukh P, Yamamura HI (1982): [3H]Ro5-4864 benzodiazepine binding in the kainate lesioned striatum and Huntington's diseased basal ganglia. Brain Res 248: 396–401.
- Sobel RA (1995): The pathology of multiple sclerosis. Neurol Clin 13: 1–21.
- Sriram S, Rodriguez M (1997): Indictment of the microglia as the villain in multiple sclerosis. Neurology 48: 464–470.
- Stephenson DT, Schober DA, Smalstig EB, Mincy RE, Gehlert DR, Clems JA (1995): Peripheral benzodiazepine receptors are colocalized with activated microglia following transient global forebrain ischemia in the rat. J Neurosci 15: 5263–5274.
- Tacite A, Mitsuka S, Diksic M, Yamamoto YL (1992): Autoradiographic study of peripheral benzodiazepine receptors in animal brain tumour models and human gliomas. Eur J Pharmacol 228: 131–139.
- Tallman JF, Pau SM, Skolnick P, Gallager DW (1980): Receptors for the age of anxiety: pharmacology of benzodiazepines. Science 207: 274–281.
- Taupin V, Renno T, Bourbonniere L, Peterson A, Rodriguez M, Owens T (1997): Increased severity of EAE, chronic macrophage/ microglial reactivity and demyelination in transgenic mice producing tumor necrosis factor-alpha in central nervous system. Eur J Immunol 27: 905–913.
- Verma A, Snyder SH (1989): Peripheral type benzodiazepine receptors. Annu Rev Pharmacol Toxicol 29: 307–322.
- Zavala F, Lenfant M (1987): Benzodiazepines and PK11195 exert immunomodulating activities by binding to a specific receptor on macrophages. Ann NY Acad Sci 496: 240–249.
- Zavala F, Haumont J, Lenfant M (1984): Interaction of benzodiazepines with mouse macrophages. Eur J Pharmacol 106: 561–566.
- Zavala F, Taupin V, Descamps-Latscha B (1990): In vivo treatment with benzodiazepines inhibits murine phagocyte oxidative metabolism and production of interleukin 1, tumor necrosis factor and interleukin-6. J Pharmacol Exp Ther 255: 442–450.
