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S.08.03 Neuroprotective effects of CB2 receptors
S.08. Cannabinoid CB1 and CB2 receptors as targets for treatment of neurological and psychiatric disorders such as multiple sclerosis could be alleviated by augmenting the concentration of endocannabinoids at their receptors and/or by targeting allosteric sites on CB1 receptors. References [1] Pertwee, R.G., 2005, The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. AAPS J 7, E625–E654. [2] Lunn, C.A., Reich, E-P., Fine, J.S., Lavey, B., Kozlowski, J.A., Hipkin, R.W., Lundell, D.J., Bober, L., 2008, Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists. Br J Pharmacol 153, 226–239. [3] Pertwee, R.G., 2008, The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta-9-tetrahydrocannabinol, cannabidiol and delta-9-tetrahydrocannabivarin. Br J Pharmacol 153, 199–215.
S.08.03 Neuroprotective effects of CB2 receptors J. Fernandez-Ruiz1 ° , M.R. Pazos1 , M. Garc´ıa-Arencibia1 , C. Garc´ıa1 , O. Sagredo1 , J.A. Ramos1 . 1 Universidad Complutense de Madrid, Departamento de Bioquimica y Biologia Molecular III and CIBERNED, Madrid, Spain CB2 receptors, the so-called peripheral cannabinoid receptor type, were first described in the immune system (Raitio et al., 2005, for review), but they have been recently identified in the brain in healthy conditions and, in particular, after several types of damaging stimuli (Fern´andez-Ruiz et al., 2007, for review). Specifically, CB2 receptors were identified in microglial cells, astrocytes and, to a lesser extent, in certain subpopulations of neurons. Given the lack of psychoactivity demonstrated by CB2 receptor agonists, this receptor becomes an interesting target for the treatment of neurological diseases. This is the case of inflammatory and neuropathic pain (Guindon and Hohmann, 2008, for review) and, in particular, of neurodegenerative disorders such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis and others, in which CB2 receptors are up-regulated in response to brain damage (Fern´andez-Ruiz et al., 2007). In these disorders, the activation of CB2 receptors has been associated with a slower progression of neurodegenerative events, although this effect has been evaluated only in preclinical studies. This effect would be exerted through limiting the toxic influence of microglial cells on neuronal homeostasis, in particular, by reducing the generation of nitric oxide, proinflammatory cytokines and reactive oxygen species (Fern´andez-Ruiz et al., 2007). In conclusion, the evidence reported so far support that CB2 receptors are a key element in the endogenous response against different neurotoxic stimuli, and that this receptor type may be a clinically-promising target for the control of brain damage in neurodegenerative disorders. References [1] Fern´andez-Ruiz J, Romero J, Velasco G, Tol´on RM, Ramos JA, Guzm´an M, Cannabinoid CB2 receptor: a new target for the control of neural cell survival? Trends Pharmacol. Sci. 28, 39−45 (2007) [2] Guindon J, Hohmann AG, Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br. J. Pharmacol. 153, 319–334 (2008) [3] Raitio KH, Salo OM, Nevalainen T, Poso A, J¨arvinen T, Targeting the cannabinoid CB2 receptor: mutations, modeling and development of CB2 selective ligands. Curr. Med. Chem. 12, 1217–1237 (2005)
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S.08.04 Cannabidiol as antipsychotic F.M. Leweke1 ° , C.W. Gerth1 , B.M. Nolden1 , D. Schreiber1 , F. Schultze-Lutter1 , M. Hellmich2 , J. Klosterk¨otter1 , D. Koethe1 . 1 University of Cologne, Department of Psychiatry and Psychotherapy, Cologne, Germany; 2 University of Cologne, Inst. for Med. Statistics Informatics and Epidemiology, Cologne, Germany Background: The human endocannabinoid system interacts with various neurotransmitter systems and the endocannabinoid anandamide was found significantly elevated in CSF and inversely correlated to psychopathology (Giuffrida et al. 2004) providing a link to the neurobiology of schizophrenia. While delta-9-tetrahydrocannabinol, the psychoactive compound of Cannabis sativa, shows psychedelic properties, the major herbal cannabinoid compound cannabidiol was suggested recently a re-uptake inhibitor of anandamide. In addition potential antipsychotic properties have been hypothezised. Methods: We performed an explorative, 4-week, double-blind, controlled clinical trial on the effects of purified cannabidiol in acute schizophrenia compared to the antipsychotic amisulpride. The antipsychotic properties of both drugs were the primary target of the study. Furthermore, side-effects and anxiolytic capabilities of both treatments were investigated. Results: 42 patients fulfilling DSM-IV criteria of acute paranoid schizophrenia or schizophreniform psychosis participated in the study. Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by BPRS and PANSS. However, there was no statistical difference between both treatment groups. In contrast, cannabidiol induced significantly less side effects (EPS, increase in prolactin, weight gain) when compared to amisulpride. Conclusions: Cannabidiol proved substantial antipsychotic properties in acute schizophrenia. This is in line with our suggestion of an adaptive role of the endocannabinoid system in paranoid schizophrenia, and raises further evidence that this adaptive mechanism may represent a valuable target for antipsychotic treatment strategies. The Stanley Medical Research Institute (00–093 to FML) and the Koeln Fortune Program (107/2000 + 101/2001 to FML) funded this study. References [1] Giuffrida, A., Leweke, F.M., Gerth, C.W., Schreiber, D., Koethe, D., Faulhaber, J., Klosterk¨otter, J., Piomelli, D., 2004 Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 29, 2180–2114.
S.08.03 Neuroprotective effects of CB2 receptors J. Fernandez-Ruiz1 ° , M.R. Pazos1 , M. Garc´ıa-Arencibia1 , C. Garc´ıa1 , O. Sagredo1 , J.A. Ramos1 . 1 Universidad Complutense de Madrid, Departamento de Bioquimica y Biologia Molecular III and CIBERNED, Madrid, Spain CB2 receptors, the so-called peripheral cannabinoid receptor type, were first described in the immune system (Raitio et al., 2005, for review), but they have been recently identified in the brain in healthy conditions and, in particular, after several types of damaging stimuli (Fern´andez-Ruiz et al., 2007, for review). Specifically, CB2 receptors were identified in microglial cells, astrocytes and, to a lesser extent, in certain subpopulations of neurons. Given the lack of psychoactivity demonstrated by CB2 receptor agonists, this receptor becomes an interesting target for the treatment of neurological diseases. This is the case of inflammatory and neuropathic pain (Guindon and Hohmann, 2008, for review) and, in particular, of neurodegenerative disorders such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis and others, in which CB2 receptors are up-regulated in response to brain damage (Fern´andez-Ruiz et al., 2007). In these disorders, the activation of CB2 receptors has been associated with a slower progression of neurodegenerative events, although this effect has been evaluated only in preclinical studies. This effect would be exerted through limiting the toxic influence of microglial cells on neuronal homeostasis, in particular, by reducing the generation of nitric oxide, proinflammatory cytokines and reactive oxygen species (Fern´andez-Ruiz et al., 2007). In conclusion, the evidence reported so far support that CB2 receptors are a key element in the endogenous response against different neurotoxic stimuli, and that this receptor type may be a clinically-promising target for the control of brain damage in neurodegenerative disorders. References [1] Fern´andez-Ruiz J, Romero J, Velasco G, Tol´on RM, Ramos JA, Guzm´an M, Cannabinoid CB2 receptor: a new target for the control of neural cell survival? Trends Pharmacol. Sci. 28, 39−45 (2007) [2] Guindon J, Hohmann AG, Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br. J. Pharmacol. 153, 319–334 (2008) [3] Raitio KH, Salo OM, Nevalainen T, Poso A, J¨arvinen T, Targeting the cannabinoid CB2 receptor: mutations, modeling and development of CB2 selective ligands. Curr. Med. Chem. 12, 1217–1237 (2005)
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S.08.04 Cannabidiol as antipsychotic F.M. Leweke1 ° , C.W. Gerth1 , B.M. Nolden1 , D. Schreiber1 , F. Schultze-Lutter1 , M. Hellmich2 , J. Klosterk¨otter1 , D. Koethe1 . 1 University of Cologne, Department of Psychiatry and Psychotherapy, Cologne, Germany; 2 University of Cologne, Inst. for Med. Statistics Informatics and Epidemiology, Cologne, Germany Background: The human endocannabinoid system interacts with various neurotransmitter systems and the endocannabinoid anandamide was found significantly elevated in CSF and inversely correlated to psychopathology (Giuffrida et al. 2004) providing a link to the neurobiology of schizophrenia. While delta-9-tetrahydrocannabinol, the psychoactive compound of Cannabis sativa, shows psychedelic properties, the major herbal cannabinoid compound cannabidiol was suggested recently a re-uptake inhibitor of anandamide. In addition potential antipsychotic properties have been hypothezised. Methods: We performed an explorative, 4-week, double-blind, controlled clinical trial on the effects of purified cannabidiol in acute schizophrenia compared to the antipsychotic amisulpride. The antipsychotic properties of both drugs were the primary target of the study. Furthermore, side-effects and anxiolytic capabilities of both treatments were investigated. Results: 42 patients fulfilling DSM-IV criteria of acute paranoid schizophrenia or schizophreniform psychosis participated in the study. Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by BPRS and PANSS. However, there was no statistical difference between both treatment groups. In contrast, cannabidiol induced significantly less side effects (EPS, increase in prolactin, weight gain) when compared to amisulpride. Conclusions: Cannabidiol proved substantial antipsychotic properties in acute schizophrenia. This is in line with our suggestion of an adaptive role of the endocannabinoid system in paranoid schizophrenia, and raises further evidence that this adaptive mechanism may represent a valuable target for antipsychotic treatment strategies. The Stanley Medical Research Institute (00–093 to FML) and the Koeln Fortune Program (107/2000 + 101/2001 to FML) funded this study. References [1] Giuffrida, A., Leweke, F.M., Gerth, C.W., Schreiber, D., Koethe, D., Faulhaber, J., Klosterk¨otter, J., Piomelli, D., 2004 Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 29, 2180–2114.