Cannabis and the Endocannabinoid System in Neuroprotection
An important function of the endocannabinoid system is that of neuroprotection. Chemical reactions occur in neurons when there is a lack of blood flow (ischemia) or decreased oxygen (hypoxia) caused by some type of injury or stroke. There is emerging evidence that indicates our endocannabinoids can reduce the subsequent damage that is caused by the body's response to an injury through the neuroprotective role of the endocannabinoids. It seems likely that similar neuroprotective processes take place with the use of cannabis to slow the progression of neurodegenerative diseases such as multiple sclerosis or Alzheimer's disease.
Faculty Presentations on Neuroprotection
Video - Cannabinoid System in Neuroprotection, Raphael Mechoulam, PhD -
Professor at Hebrew University in Jerusalem, Dr. Mechoulam gives a brief history of Medical Cannabis, then describes the role of Cannabinoids as anti-inflammatory for arthritis, as neuroprotectant for brain injury and as a possible treatment for PTSD. Dr. Mechoulam first isolated THC in 1964. Presented to the Third Clinical Conference on Cannabis Therapeutics - 2004, in Charlottesville, VA.
Cannabinoids and Movement Disorders, Juan Sanchez-Ramos, PhD, MD - An expert in movement disorders like Parkinson's and Huntington's, Dr. Juan Sanchez-Ramos brings research on the cannabinoid system in brains of rats and humans. Presenting animated graphics on the distribution of cannabinoid receptor CB-1 in the Basal Ganglia, he then describes effects of cannabinoids on normal and abnormal movement. Dr. Sanchez-Ramos explores the re-discovery of cannabinoids as a treatment for movement disorders and their potential as neuroprotective agents, pointing out that N.I.H. holds a patent on neuroprotective uses of cannabinoids. Presented at the second conference of our series - 2002, in Portland, Oregon.
Benito,C., Núñez, E., Tolo, R.M., Carrier, E.J., Ráabano, A., Hillard, CJ & Romero, J. (2003). Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J. Neurosci, 23(35): 11136 –11141.
Benito C, Romero JP, Tolón RM, Clemente D, Docagne F, Hillard, CJ, Guaza, C & Romero, J. (2007). Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci., 27(9), 2396-402.
Centonze, D., Finazzi-Agro, A., Bernardi, G., & Maccarrone, M. (2007). The endocannabinoid system in targeting inflammatory neurodegenerative diseases. Trends in Pharmacological Science, 28(4) 180-187.
Chen J, Lee CT, Errico S, Deng X, Cadet JL, & Freed WJ. (2005). Protective effects of Delta(9)-tetrahydrocannabinol against N-methyl-D-aspartate-induced AF5 cell death. Brain Res Mol Brain Res.,134(2), 215-25.
Eubanks, L. M., Rogers, C. J., Beuscher, A. E. t., Koob, G. F., Olson, A. J., Dickerson, T. J., et al. (2006). A molecular link between the active component of marijuana and Alzheimer's disease pathology. Mol Pharm, 3(6), 773-777.
Karanian DA, Brown QB, Makriyannis A, Kosten TA & Bahr BA. (2005). Dual modulationof endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity. The Journal of Neuroscience. 25(34): 7813-20.
Kim SH, Won SJ, Mao XO, Jin K, & Greenberg DA. (2005). Involvement of protein kinase A in cannabinoid receptor-mediated protection from oxidative neuronal injury. Journal of Pharmacology and Experimental Therapeutics., 313(1):88-94.
Kim, SH, Won, SJ, Mao, XO, Ledent, C, Jin, K & Greenberg, DA. (2006). Role for neuronal nitric-oxide synthesis in cannabinoid-induced neurogenesis. The Journal of Pharmacology and Experimental Therapeutics. 319(1): 150-154.
Mechoulam R, & Hanu L. (2001). The cannabinoids: an overview. Therapeutic implications in vomiting and nausea after cancer chemotherapy, in appetite promotion, in multiple sclerosis and in neuroprotection. Pain Res Manag., 6(2), 67-73.
Shouman B, Fontaine RH, Baud O, Schwendimann L, Keller M, Spedding, M, Lelièvre, V & Gressens,P. (2006). Endocannabinoids potently protect the newborn brain against AMPA-kainate receptor-mediated excitotoxic damage. Brtish Journal of Pharmacology., 148(4), 442-51.
Sun, Y., Alexander, S.P.H., Garle, M.J., Gibson, C.L., Hewitt, K., Murphy, S.P., Kendall, D.A. & Bennett, A.J. (2007). Cannabinoid activation of PPAR alpha, a novel neuroprotective mechanism. British Journal of Pharmacology. 152: 734-743.
van der Stelt M, Veldhuis WB, Bär PR, Veldink GA, Vliegenthart JF, & Nicolay,K. (2001). Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. Journal of Neuroscience. 21(17), 6475-9.
Witting A, Chen L, Cudaback E, Straiker A, Walter L, Rickman, B, Möller, T, Brosnan, C & Stella, N. (2006). Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. Proc Natl Acad Sci U S A., 103(16), 6362-7.
Zani, A., Braida, D., Capurro, V. & Sala, M. ( 2007). ?9-tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors. British Journal of Pharmacology. 152: 1301-1311.
Zhang M, Martin BR, Adler MW, Razdan RK, Ganea D, & Tuma, RF. (2008). Modulation of the balance between cannabinoid CB(1) and CB(2) receptor activation during cerebral ischemic/reperfusion injury. Neurosci.,152(3), 753-60.
Aguado T, Romero E, Monory K, Palazuelos J, Sendtner M, et.al. (2007). The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis. J Biol Chem., 282(33), 23892-8.
Alger BE. (2004). Endocannabinoids and their implications for epilepsy. Epilepsy Curr., 4(5), 169-73.
Amtmann et al (2004). Survey of cannabis use in patients with amyotrophic lateral sclerosis. The American Journal of Hospice and Palliative Care. 21: 95-104
Carter, G. T., & Rosen, B. S. (2001). Marijuana in the management of amyotrophic lateral sclerosis. Am J Hosp Palliat Care, 18(4), 264-270.
Carter GT & Rosen BS (2003). Drug therapy for amyotrophic lateral sclerosis: Where are we now? The Investigational Drugs Journal, 6: 147-153.
Chen J, Lee CT, Errico SL, Becker KG, & Freed WJ. (2007). Increases in expression of 14-3-3 eta and 14-3-3 zeta transcripts during neuroprotection induced by delta9-tetrahydrocannabinol in AF5 cells. J Neurosci Res., 85(8), 1724-33.
Croxford & Yamamura (2005). Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases. Journal of Neuroimmunology. 166: 3-18.
Curtis A & Rickards H. (2006). Nabilone could treat chorea and irritability in Huntington’s disease. Journal Neuropsychiatry Clin Neurosci. 18(4):553-4.
Ehrhart, J, Obregon, D, Mori, T, Hou, H, Sun, N, Bai, Y, Klein, T, Fernandez, F, Tan, J & Shytle, RD. (2005). Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J. Neuroinflam., 2(29), doi:10.1186/1742-2094-2-29.
El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB. Caldwell RW, Green K & Liou GI. (2003). Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. American Journal of Pathology. 163(5), 1997-2008.
Guzman, M., Duarte, M. J., Blazquez, C., Ravina, J., Rosa, M. C., Galve-Roperh, I., et al. (2006). A pilot clinical study of Delta(9)-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer, 95(2), 197-203.
Hampson, A. J., Grimaldi, M., Axelrod, J., & Wink, D. (1998). Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A, 95(14), 8268-8273.
Lu et al. (2006). The cannabinergic system as a target for anti-inflammatory therapies. Current Topics in Medicinal Chemistry 13: 1401-1426.
Palazuelos, J., Davoust, N., Julien, B., Hatterer, E., Aguado, T., Mechoulam, R., Benito, C., Romero, J., Silva, A., Guzmán, M., Nataf, S. & Galve-Roperh, I. (2008). The CB2 cannabinoid receptor controls myeloid progenitor trafficking. The Journal of Biological Chemistry. 283(19): 13320-13329.
Panikashvile D, Mechoulam R, Beni SM, Alexandrovich A & Shohami E. (2005). CB1 cannabinoid receptors are involved in neuroprotection via NF-?B inhibition. Journal of Cerebral Blood Flow & Metabolism. 25: 477-84.
Pryce G, Ahmed Z, Hankey DJ, Jackson SJ, Croxford JL, Pocock, JM, Ledent, C, Petzold, A, Thompson, AJ, Giovannoni, G, Cusner, ML & Baker, D. (2003). Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain, 126(10), 2191-202.
Raman C, McAllister SD, Rizvi G, Patel SG, Moore DH & Abood ME (2004). Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid. Amyotrophic Lateral Sclerosis & Other Motor Neuron Disorders, 5: 33-39.
Ramírez, B.G., Blázquez, C., del Pulgar, T.G., Guzmán, M. & de Ceballos, M.L. (2005). Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. The Journal of Neuroscience, 25(8): 1904-1913.
Venderova, K., Ruzicka, E., Vorisek, V., & Visnovsky, P. (2004). Survey on cannabis use in Parkinson's disease: Subjective improvement of motor symptoms. Mov Disord, 19(9), 1102.
Volicer, L., Stelly, M., Morris, J., McLaughlin, J., & Volicer, B. J. (1997). Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. Int J Geriatr Psychiatry, 12(9), 913-919.
Walther, S., Mahlberg, R., Eichmann, U., & Kunz, D. (2006). Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology (Berl), 185(4), 524-528.