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The Journal of Neuroscience, February 28, 2007, 27(9):2396-2402; doi:10.1523/JNEUROSCI.4814-06.2007

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Neurobiology of Disease
Cannabinoid CB₁ and CB₂ Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

Cristina Benito,¹ Juan Pablo Romero,^1,2 Rosa María Tolón,¹ Diego Clemente,³ Fabián Docagne,³ Cecilia J. Hillard,⁴ Camen Guaza,³ and Julián Romero^1,2

¹Laboratorio de Apoyo a la Investigación, Fundación Hospital Alcorcón, 28922 Madrid, Spain, ²Department of Biochemistry, Francisco de Vitoria University, Pozuelo de Alarcón, 28223 Madrid, Spain, ³Neuroimmunology Group, Neural Plasticity Department, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain, and ⁴Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Correspondence should be addressed to Julián Romero, Laboratorio de Apoyo a la Investigación, Fundación Hospital Alcorcón, 28922 Alcorcón/Madrid, Spain. Email: jromerop{at}fhalcorcon.es

Increasing evidence supports the idea of a beneficial effect of cannabinoid compounds for the treatment of multiple sclerosis (MS). However, most experimental data come from animal models of MS. We investigated the status of cannabinoid CB₁ and CB₂ receptors and fatty acid amide hydrolase (FAAH) enzyme in brain tissue samples obtained from MS patients. Areas of demyelination were identified and classified as active, chronic, and inactive plaques. CB₁ and CB₂ receptors and FAAH densities and cellular sites of expression were examined using immunohistochemistry and immunofluorescence. In MS samples, cannabinoid CB₁ receptors were expressed by cortical neurons, oligodendrocytes, and also oligodendrocyte precursor cells, demonstrated using double immunofluorescence with antibodies against the CB₁ receptor with antibodies against type 2 microtubule-associated protein, myelin basic protein, and the platelet-derived growth factor receptor-, respectively. CB₁ receptors were also present in macrophages and infiltrated T-lymphocytes. Conversely, CB₂ receptors were present in T-lymphocytes, astrocytes, and perivascular and reactive microglia (major histocompatibility complex class-II positive) in MS plaques. Specifically, CB₂-positive microglial cells were evenly distributed within active plaques but were located in the periphery of chronic active plaques. FAAH expression was restricted to neurons and hypertrophic astrocytes. As seen for other neuroinflammatory conditions, selective glial expression of cannabinoid CB₁ and CB₂ receptors and FAAH enzyme is induced in MS, thus supporting a role for the endocannabinoid system in the pathogenesis and/or evolution of this disease.

Key words: cannabinoid receptors; multiple sclerosis; immunohistochemistry; neuroinflammation; FAAH; glia

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Received Nov. 6, 2006; revised Jan. 24, 2007; accepted Jan. 27, 2007.

Correspondence should be addressed to Julián Romero, Laboratorio de Apoyo a la Investigación, Fundación Hospital Alcorcón, 28922 Alcorcón/Madrid, Spain. Email: jromerop{at}fhalcorcon.es

This article has been cited by other articles:

				J. Palazuelos, T. Aguado, M. R. Pazos, B. Julien, C. Carrasco, E. Resel, O. Sagredo, C. Benito, J. Romero, I. Azcoitia, et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity Brain, November 1, 2009; 132(11): 3152 - 3164. [Abstract] [Full Text] [PDF]

				J. Palazuelos, N. Davoust, B. Julien, E. Hatterer, T. Aguado, R. Mechoulam, C. Benito, J. Romero, A. Silva, M. Guzman, et al. The CB2 Cannabinoid Receptor Controls Myeloid Progenitor Trafficking: INVOLVEMENT IN THE PATHOGENESIS OF AN ANIMAL MODEL OF MULTIPLE SCLEROSIS J. Biol. Chem., May 9, 2008; 283(19): 13320 - 13329. [Abstract] [Full Text] [PDF]

				D. Centonze, M. Bari, S. Rossi, C. Prosperetti, R. Furlan, F. Fezza, V. De Chiara, L. Battistini, G. Bernardi, S. Bernardini, et al. The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis Brain, October 1, 2007; 130(10): 2543 - 2553. [Abstract] [Full Text] [PDF]

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