The endocannabinoid (eCB) system is a marvel in the field of neuroscience. One of the functions of the eCB system is to modulate neurotransmission – that is, to keep excitability in check when it is no longer needed [1,2]. Its discovery is relatively recent, with a multitude of studies confirming two receptor subtypes and two notable ligands (known as ‘endocannabinoids’) . Two eCBs of interest are anandamide (derived from the word ‘bliss’ in Sanskrit) and 2-arachidonoylglycerol (2-AG) [4,5]. eCB receptors are found widely throughout the brain, with expression seen in areas such as the cortex, hippocampus, and amygdala . It is not surprising that the eCB system has been studied within the context of various aspects of behaviour such as stress response, anxiety, and spatial memory [6, 7, 8].
The eCB system’s notoriety derives from the finding that delta-9-tetrahydrocannabinol, the psychoactive constituent in the Cannabis sativa plant, acts as an agonist that stimulates the cannabinoid-1 (CB1) receptor . To conceptualize the mechanism of action of an eCB, imagine zooming in on single a synapse in the brain, with a presynaptic neuron that is releasing an excitatory transmitter (such as glutamate), and a postsynaptic neuron that receives that glutamatergic input . eCBs, which are derived from the lipid bilayer of the postsynaptic neuron, are retrograde messengers that act on the presynaptic neuron . CB1 receptors are situated around the presynaptic terminal and are activated by eCBs. The end result is that neurotransmitter release is turned off via a second messenger cascade, effectively preventing excitatory neurotransmission . In addition to this mechanism of action, the eCB system attracts attention through the finding that its components may have neuroprotective effects in disease states such as multiple sclerosis (MS) [10,11].
MS is a neurodegenerative disease characterized by demyelination of neurons in the central nervous system . MS is typically diagnosed in young adults, with females twice as likely to be affected . The target of MS is myelin, which is a fatty substance that surrounds the axon and acts as an insulator, allowing for efficient neuronal transmission . In MS, immune cells see myelin as foreign bodies, propagating an autoimmune assault resulting in myelin destruction and inflammation . Degeneration of axons may also occur, and is secondary to demyelination . Relapse-remitting MS particularly describes a disease state in which there are periods of demyelination (relapse) followed by remission, during which debilitating symptoms lessen in severity . Drugs used to treat relapse-remitting MS primarily act as immunosuppressants, and include interferon beta , and the recently-approved drug Fingolimod .
The link between the eCB system and MS is not immediately apparent. People living with MS have been reported to self-medicate with Cannabis, with claims that use of the drug decreased pain and spasticity . Clinical studies have comprised of largely anecdotal evidence, and have ascribed a therapeutic rather than preventative role to Cannabis . The link becomes more interesting with the use of synthetic cannabinoids, which mimic eCBs without the psychoactive effects of Cannabis . To explore this idea, an animal model of MS called experimental autoimmune encephalomyelitis (EAE) has been used, in which an autoimmune assault is initiated through peripheral injection of myelin-associated proteins such as myelin basic protein (MBP) or myelin oligodendrocyte glycoprotein (MOG) . EAE animals display symptoms similar to those seen in MS, such as limb weakness and paralysis , as well as corresponding pathologies such as demyelinating lesions in the brain . A tie between EAE and the eCB system was displayed by showing that 2-AG administration decreased disease progression, pointing to a possible protective role of eCBs against neurodegeneration .
Anandamide may also function within a neuroprotective mechanism at the neuronal level . Anandamide levels have been shown to increase during high disease states in EAE . As previously stated, eCBs largely function to inhibit release of neurotransmitters such as glutamate at excitatory synapses . In EAE, demyelination of axons makes neurons prone to death due to excitotoxicity. Cell excitotoxicity, in turn, is mediated by increased glutamate release . When CB1 receptors, which bind anandamide, are knocked out in transgenic mice, rapid axonal degeneration is seen compared to mice that do express the receptor .
The mechanism of action by which anandamide and associated agonists prevent excitotoxicity involves N-methyl-D-aspartate (NMDA) receptors on the postsynaptic membrane . The ion channel of an NMDA receptor can be stimulated to open upon activation by glutamate and glycine . Through the use of electrophysiological recordings, application of a CB1 receptor agonist was found to decrease Ca2+ influx through the NMDA ion channel when the receptor was electrically stimulated to open, suggesting that eCBs are able to inhibit NMDA receptor activity. In contrast to this, cerebellar neurons taken from CB1-deficient mice showed increased Ca2+ influx with NMDA activation . In sum, eCBs may play a role in ameliorating glutamate-induced cytotoxicity in EAE, pointing to a potential target in slowing neurodegeneration.
It is worth questioning what such evidence means within a larger scale. EAE is an animal model, and though its use shows promise when using eCB agonists, difficulties arise when translating results to MS . MS is a disease with a complex pathogenesis, and as such, the cellular underpinnings have yet to be fully elucidated. Targeting the eCB system as a drug treatment for MS requires further research, but the promise it displays is invaluable and worth pursuing in order to combat the debilitating disease.
- Wilson, Rachel I., and Roger A. Nicoll. 2002. “Endocannabinoid Signaling in the Brain.” Science 296 (5568): 678–82.
- Freund, Tamás F., István Katona, and Daniele Piomelli. 2003. “Role of Endogenous Cannabinoids in Synaptic Signaling.” Physiological Reviews 83 (3): 1017–66.
- Di Marzo, Vincenzo. 2006. “A Brief History of Cannabinoid and Endocannabinoid Pharmacology as Inspired by the Work of British Scientists.” Trends in Pharmacological Sciences 27 (3): 134–40.
- Devane, W. A., L. Hanus, A. Breuer, R. G. Pertwee, L. A. Stevenson, G. Griffin, D. Gibson, A. Mandelbaum, A. Etinger, and R. Mechoulam. 1992. “Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor.” Science 258 (5090): 1946–49.
- Sugiura, T., S. Kondo, A. Sukagawa, S. Nakane, A. Shinoda, K. Itoh, A. Yamashita, and K. Waku. 1995. “2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain.” Biochemical and Biophysical Research Communications 215 (1): 89–97.
- Patel, Sachin, Craig T Roelke, David J Rademacher, William E Cullinan, and Cecilia J Hillard. 2004. “Endocannabinoid Signaling Negatively Modulates Stress-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis.” Endocrinology 145 (12): 5431–38.
- Bitencourt, Rafael M., Fabrício A. Pamplona, and Reinaldo N. Takahashi. 2008. “Facilitation of Contextual Fear Memory Extinction and Anti-Anxiogenic Effects of AM404 and Cannabidiol in Conditioned Rats.” European Neuropsychopharmacology 18 (12): 849–59.
- Robinson, Lianne, Susan McKillop-Smith, Nicola L. Ross, Roger G. Pertwee, Robert E. Hampson, Bettina Platt, and Gernot Riedel. 2008. “Hippocampal Endocannabinoids Inhibit Spatial Learning and Limit Spatial Memory in Rats.” Psychopharmacology 198 (4): 551–63.
- Luchicchi, Antonio, and Marco Pistis. 2012. “Anandamide and 2-Arachidonoylglycerol: Pharmacological Properties, Functional Features, and Emerging Specificities of the Two Major Endocannabinoids.” Molecular Neurobiology 46 (2): 374–92.
- Pryce, Gareth, Zubair Ahmed, Deborah J. R. Hankey, Samuel J. Jackson, J. Ludovic Croxford, Jennifer M. Pocock, Catherine Ledent, et al. 2003. “Cannabinoids Inhibit Neurodegeneration in Models of Multiple Sclerosis.” Brain 126 (10): 2191–2202.
- Lourbopoulos, Athanasios, Nikolaos Grigoriadis, Roza Lagoudaki, Olga Touloumi, Eleni Polyzoidou, Ioannis Mavromatis, Nikolaos Tascos, et al. 2011. “Administration of 2-Arachidonoylglycerol Ameliorates Both Acute and Chronic Experimental Autoimmune Encephalomyelitis.” Brain Research 1390: 126–41.
- Constantinescu, Cris S, Nasr Farooqi, Kate O’Brien, and Bruno Gran. 2011. “Experimental Autoimmune Encephalomyelitis (EAE) as a Model for Multiple Sclerosis (MS).” British Journal of Pharmacology 164 (4): 1079–1106.
- Compston, Alastair, and Alasdair Coles. 2002. “Multiple Sclerosis.” The Lancet 359 (9313): 1221–31.
- Compston, Alastair, and Alasdair Coles. 2008. “Multiple Sclerosis.” The Lancet 372 (9648): 1502–17.
- Trapp, Bruce D., and Klaus-Armin Nave. 2008. “Multiple Sclerosis: An Immune or Neurodegenerative Disorder?” Annual Review of Neuroscience 31 (1): 247–69.
- Brinkmann, Volker, Andreas Billich, Thomas Baumruker, Peter Heining, Robert Schmouder, Gordon Francis, Shreeram Aradhye, and Pascale Burtin. 2010. “Fingolimod (FTY720): Discovery and Development of an Oral Drug to Treat Multiple Sclerosis.” Nature Reviews Drug Discovery 9 (11): 883–97.
- Pertwee, Roger G. 2002. “Cannabinoids and Multiple Sclerosis.” Pharmacology & Therapeutics 95 (2): 165–74.
- Consroe, Paul. 1998. “Brain Cannabinoid Systems as Targets for the Therapy of Neurological Disorders.” Neurobiology of Disease 5 (6): 534–51.
- Rao, Praveen, and Benjamin M. Segal. 2004. “Experimental Autoimmune Encephalomyelitis.” In Autoimmunity, edited by Andras Perl MD, 363–75. Methods in Molecular MedicineTM 102. Humana Press.
- Centonze, Diego, Monica Bari, Silvia Rossi, Chiara Prosperetti, Roberto Furlan, Filomena Fezza, Valentina De Chiara, et al. 2007. “The Endocannabinoid System Is Dysregulated in Multiple Sclerosis and in Experimental Autoimmune Encephalomyelitis.” Brain 130 (10): 2543–53.
- Cull-Candy, Stuart, Stephen Brickley, and Mark Farrant. 2001. “NMDA Receptor Subunits: Diversity, Development and Disease.” Current Opinion in Neurobiology 11 (3): 327–35.
Anmats. 2013. Wikimedia Commons.http://commons.wikimedia.org/wiki/File:Glial_Cell_Types.png.
Kenneth Han (Kenneth.jh.han). 2012. Wikimedia Commons.http://commons.wikimedia.org/wiki/File:Endocannabinoid.svg.