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Pharmacological Comparisons Between Cannabidiol and KLS-13019

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Abstract

Cannabidiol (CBD) exhibits neuroprotective properties in many experimental systems. However, development of CBD as a drug has been confounded by the following: (1) low potency; (2) a large number of molecular targets; (3) marginal pharmacokinetic properties; and (4) designation as a schedule 1 controlled substance. The present work compared the properties of CBD with a novel molecule (KLS-13019) that has structural similarities to CBD. The design strategy for KLS-13019 was to increase hydrophilicity while optimizing neuroprotective potency against oxidative stress toxicity relevant to hepatic encephalopathy. The protective responses of CBD and KLS-13019 were compared in dissociated rat hippocampal cultures co-treated with toxic levels of ethanol and ammonium acetate. This comparison revealed that KLS-13019 was 31-fold more potent than CBD in preventing neuronal toxicity from the combined toxin treatment, while both compounds exhibited complete protective efficacy back to control values. In addition, treatment with KLS-13019 alone was 5-fold less toxic (TC50) than CBD. Previous studies suggested that CBD targeted the Na+-Ca2+ exchanger in mitochondria (mNCX) to regulate intracellular calcium levels, an important determinant of neuronal survival. After treatment with an inhibitor of mNCX (CGP-37157), no detectable neuroprotection from ethanol toxicity was observed for either CBD or KLS-13019. Furthermore, AM630 (CB2 antagonist) significantly attenuated CBD-mediated neuroprotection, while having no detectable effect on neuroprotection from KLS-13019. Our studies indicated KLS-13019 was more potent and less toxic than CBD. Both compounds can act through mNCX. KLS-13019 may provide an alternative to CBD as a therapeutic candidate to treat diseases associated with oxidative stress.

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References

  • Aghaei I, Shabani M, Doustar N, Nazeri M, Dehpour A (2014) Peroxisome proliferator-activated receptor-γ-activation attenuates motor and cognition impairments inducted by bile duct ligation in a rat model of hepatic cirrhosis. Pharmacol Biochem Behav 120:133–139

    Article  CAS  PubMed  Google Scholar 

  • Ahrens J, Demir R, Leuwer M, de la Roche J, Krampfl K, Foadi N, Karst M, Haeseler G (2009) The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-beta glycine receptor function. Pharmacology 83:217–222

    Article  CAS  PubMed  Google Scholar 

  • Alsenz J, Kansy M (2007) High throughput solubility measurement in drug discovery and development. Adv Drug Deliv Rev 59:546–567

    Article  CAS  PubMed  Google Scholar 

  • Avraham Y, Grigoriadis NC, Poutahidis T, Vorobiev L, Magen I, Ilan Y, Mechoulam R, Berry EM (2011) Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice. Br J Pharmacol 162:1650–1658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bih CI, Chen T, Nunn AVW, Bazelot M, Dallas M, Whalley BJ (2015) Molecular targets of cannabidiol in neurological disorders. Neurotherapy 12:699–730

    Article  CAS  Google Scholar 

  • Booz GW (2011) Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med 51:1054–1061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brenneman DE, Smith GR, Zhang Y, Du Y, Kondaveeti SK, Zdilla MJ, Reitz AB (2012) Small-molecule anticonvulsant agents with potent in vitro neuroprotection. J Mol Neurosci 47:368–379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brewer GJ, Torricelli JR, Evege EK, Price PJ (1993) Optimized survival of hippocampal neurons in B27 supplemented neurobasal, a new serum-free medium combination. J Neurosci Res 35:567–576

    Article  CAS  PubMed  Google Scholar 

  • Castillo A, Tolon MR, Fernandez-Ruiz J, Romero J, Martinez-Organd J (2010) The neuroprotective effect of cannabidiol in an in vitro model of hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis 37:434–440

    Article  CAS  PubMed  Google Scholar 

  • Clarke SW, Jeffrey P (2001) Utility of metabolic stability screening: comparison of in vitro and in vivo clearance. Xenobiotica 31:591–598

    Article  CAS  PubMed  Google Scholar 

  • Cox DA, Conforti L, Sperelakis N, Matlib MA (1993) Selectivity of inhibition of Na+-Ca2+ exchange of heart mitochondria by benzothiazepine CGP-37157. J Cardiovasc Pharmacol 21:595–599

    Article  CAS  PubMed  Google Scholar 

  • Darkovska-Serafimovska M, Serafimovska T, Arsova-Sarafinovska Z, Stefanoski S, Keskovski Z, Balkanov T (2018) Pharmacotherapeutic considerations for use of cannabinoids to relieve pain in patients with malignant diseases. J Pain Res 11:837–842

    Article  PubMed  PubMed Central  Google Scholar 

  • Finlayson K, Turnbull L, January CT, Sharkey J, Kelley JS (2001) [3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. Eur J Pharmacol 430:147–148

    Article  CAS  PubMed  Google Scholar 

  • Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (-)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 95:8268–8273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hidalgo C, Arias-Cavieres A (2016) Calcium, reactive oxygen species and synaptic plasticity. Physiology (Bethesda) 31:201–205

    CAS  Google Scholar 

  • Iffland K, Grotenhermen F (2017) An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis Cannabinoid Res 2(1):139–154

    Article  PubMed  PubMed Central  Google Scholar 

  • Kinney WA, McDonnell ME, Zhong HM, Liu C, Yang L, Ling W, Qian T, Chen Y, Cai Z, Petkanas D, Brenneman DE (2016) Discovery of KLS-13019, a cannabidiol-derived neuroprotective agent, with improved potency, safety, and permeability. ACS Med Chem Lett 7:424–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim K, See YM, Lee J (2017) A systematic review of the effectiveness of medical cannabis for psychiatric, movement and neurodegenerative disorders. Clin Psychopharm Neurosci 15:301–312

    Article  Google Scholar 

  • Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Wu PP, Yang MJ, Men L, Lin HL, Zhao YL, Tang X, Yu ZG (2016) Application of a UPLC-MS/MS method to the protein binding study of TM-2 in rat, human and beagle dog plasma. J Pharm Anal 6:32–38

    Article  CAS  PubMed  Google Scholar 

  • Mecha M, Feliu A, Inigo PM, Mestre L, Carrillo-Salinas FJ, Guaza C (2013) Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol Dis 59:141–150

    Article  CAS  PubMed  Google Scholar 

  • Neumann JT, Diaz-Sylvester PL, Fleischer S, Copello JA (2011) CGP-37157 inhibits the sarcoplasmic reticulum Ca2+ ATPase and activates ryanodine receptor channels in striated muscle. Mol Pharmacol 79:141–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niknahad H, Jamshidzadeh A, Heidari R, Zarei M, Ommati MM (2017) Ammonia-induced mitochondrial dysfunction and energy metabolism disturbances in isolated brain and liver mitochondria, and the effect of taurine administration: relevance to hepatic encephalopathy treatment. Clin Exp Hepatol 3:141–151

    Article  PubMed  PubMed Central  Google Scholar 

  • Norris C, Loureiro M, Kramar C, Zunder J, Renard J, Rushlow W, Laviolette SR (2016) Cannabidiol modulates fear memory formation through interactions with serotonergic transmission in the mesolimbic system. Neuropsychopharmacol 41:2839–2850

    Article  CAS  Google Scholar 

  • Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F, Arroliga AC, Mullen KD (2003) Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 114:188–193

    Article  CAS  PubMed  Google Scholar 

  • Pazos MR, Mohammed N, Lafuente H, Santos M, Martinez-Pinilla E, Moreno E, Valdizan E, Romero J, Pazos A, Franco R, Hillard CJ, Alvarez FJ, Martinez-Orgado J (2013) Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors. Neuropharm 71:282–291

    Article  CAS  Google Scholar 

  • Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol 168:1–51

    Article  CAS  Google Scholar 

  • Petroski RE, Geller HM (1994) Selective labeling of embryonic neurons cultures on astrocyte monolayers with 5(6)-carboxyfluorescein diacetate (CFDA). J Neurosci Methods 52:23–32

    Article  CAS  PubMed  Google Scholar 

  • Randall RD, Thayer SA (1992) Glutamate-induced calcium transient triggers calcium overload and neurotoxicity in rat hippocampal neurons. J Neurosci 12:1882–1895

    Article  CAS  PubMed  Google Scholar 

  • Rossignoli MT, Lopes-Aguiar C, Ruggiero RN, Do Val da Silva RA, Bueno-Junior LS, Kandratavicius L, Peixoto-Santos JE, Crippa JA, Cecilio-Hallak JE, Zuardi AW, Szawka RE, Anselmo-Franci J, Leite JP, Romcy-Pereira RN (2017) Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: reduced dopaminergic modulation and immediate gene expression in limbic circuits. Neuroscience 350:85–90

    Article  CAS  PubMed  Google Scholar 

  • Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5HT1a receptors. Neurochem Res 30:1037–1043

    Article  CAS  PubMed  Google Scholar 

  • Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29:2053–2063

    Article  CAS  PubMed  Google Scholar 

  • Sarafian TA, Kouyoumjian S, Tashkin D, Roth MD (2002) Synergistic cytotoxicity of 9-tetrahydrocannabianol and butylated hydroxyanisole. Toxicol Lett 133:171–179

    Article  CAS  PubMed  Google Scholar 

  • Stern CAJ, da Silva TR, Raymundi AM, de Souza CP, Hiroaki-Sato VA, Kato L, Guimaraes FS, Andreatini R, Takahashi RN, Bertoglio LJ (2017) Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampal CB1 and CB2 receptors. Neuropharmacology 125:220–230

    Article  CAS  PubMed  Google Scholar 

  • Stockings E, Zagie D, Campbell G, Weier M, Hall WD, Nielsen S, Herkes GK, Farrell M, Degenhardt L (2018) Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry 89:741–753

    Article  PubMed  Google Scholar 

  • Tomasini MC, Borelli AC, Beggiato S, Tanganelli S, Loche A, Cacciaglia R, Ferraro L, Antonelli T (2016) GET3 prevents ethanol-induced neurotoxicity in primary cultures of rat hippocampal neurons. Alcohol Alcohol 51:128–135

    Article  CAS  PubMed  Google Scholar 

  • Ward SJ, Riggs D, Tuma R, Kinney WA, Petkanas D, Brenneman DE (2017) Neuroprotective and anti-inflammatory effects of KLS-13019 and cannabidiol in in vitro and in vivo models of chemotherapy-induced neuropathic pain. International Cannabinoid Research Society Symposium, June 22, 2017, Montreal, Canada, 27:p 1–40

  • Weinstein A, Livny A, Weizman A (2016) Brain imaging studies on the cognitive, pharmacological and neurobiological effects of cannabis in humans: evidence from studies of adult users. Curr Pharm Des 22:6366–6379

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Rozenfeld R, Wu D, Devi LA, Zhang Z, Cederbaum A (2014) Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy. Free Radic Biol Med 68:260–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Advanced Neural Dynamics, Inc, Pennsylvania Biotechnology Center, 3805 Old Easton Road, Doylestown, PA, 18902, USA

    Douglas E. Brenneman

  2. Kannalife Sciences, Inc, Pennsylvania Biotechnology Center, Doylestown, PA, 18902, USA

    Douglas E. Brenneman, Dean Petkanas & William A. Kinney

Authors
  1. Douglas E. Brenneman
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  2. Dean Petkanas
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  3. William A. Kinney
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Correspondence to Douglas E. Brenneman.

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Brenneman, D.E., Petkanas, D. & Kinney, W.A. Pharmacological Comparisons Between Cannabidiol and KLS-13019. J Mol Neurosci 66, 121–134 (2018). https://doi.org/10.1007/s12031-018-1154-7

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  • DOI: https://doi.org/10.1007/s12031-018-1154-7

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