シンポジウム
58 New tools to target the endocannabinoid system for therapeutic benefit
座長：Bogna Ignatowska-Jankowska（沖縄科学技術大学院大学） |
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| 2022年7月1日 16:10～16:40 沖縄コンベンションセンター 会議場A2 第7会場
2S07e-01
Cannabigerol, its pharmacology and clinical promise.
*Ethan Budd Russo(1)
1. CReDO Science
Keyword: cannabinoids, cannabigerol, pain, anxiety
Introduction: Cannabigerol (CBG) is sometimes labeled the “mother of all cannabinoids.” Normally it is found in herbal cannabis only in trace amounts, as the plant most often acts as a high-throughput producer of tetrahydrocannabinol and cannabidiol. Despite its interesting and potentially useful pharmacology, CBG has remained a rare commodity until the last few years, when CBG-predominant plants and extracts began to appear, especially in the US Pacific Northwest. Methods: Participants were recruited via various listservs related to cannabis and cannabinoid research as well as social media. Participants completed an online survey assessing CBG use patterns, conditions treated with CBG-predominant cannabis, perceived efficacy, associated adverse events and withdrawal symptoms. A total of 127 US residents (44.9% male, 40.2% female, remaining gender minority or missing) aged 21+ who reported using CBG-predominant cannabis in the past 6 months completed the survey. Results: The majority of the sample (51.2%) reported use of CBG-predominant for medical purposes. The most common conditions people reported using CBG to treat were anxiety (51.2%), chronic pain (40.9%), depression (33.1%), and insomnia/disturbed sleep (30.7%). Efficacy was highly rated, with the majority reporting their conditions were “very much improved” or “much improved” by CBG. Further, 73.9% claimed superiority of CBG-predominant cannabis over conventional medicines for chronic pain, 80% for depression, 73% for insomnia, and 78.3% for anxiety. 44% of CBG-predominant cannabis users reported no adverse events, with 16.5% noting dry mouth, 15% sleepiness, 11.8% increased appetite, and 8.7% dry eyes. 84.3% reported no withdrawal symptoms, with sleep difficulties representing the most frequently endorsed withdrawal symptom (endorsed by 2 respondents). Conclusions: This is the largest patient survey of CBG-predominant cannabis use to date, and the first to document self-reported efficacy of CBG-predominant products, particularly for anxiety, chronic pain, depression, and insomnia. Most respondents claimed greater efficacy of CBG-predominant cannabis over conventional pharmacotherapy, with a very benign adverse event profile and negligible withdrawal symptoms. This study establishes that humans are employing CBG and suggests that CBG-predominant cannabis-based medicines can be safely utilized in randomized controlled trials. | | 2022年7月1日 16:40～17:10 沖縄コンベンションセンター 会議場A2 第7会場
2S07e-02
Revealing Potions: Phytocannabinoids in Osteoarthritis Treatment
*Katarzyna Starowicz(1)
1. Maj Institute of Pharmacology Polish Academy of Sciences
Keyword: Chronic pain, Osteoathritis , Cannabidiol
Chronic pain is a persistent, complex condition with no biological value, which exists longer than expected time of healing. It was estimated, that in 2019 that 20% of adults suffer from pain globally, and for 7,4% this condition limited patient’s life or work activities. A painful chronic disease of synovial joints and the most common form of arthritis is osteoarthritis (OA). It has been recognized by the World Health Organization as a “priority disease” (report WHO/EDM/PAR/2004.7) and one of the top 5 healthcare costs in Europe. Current treatment is mostly based on symptomatic care and are very limited. Given the fact that the endocannabinoid system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system holds promise as novel analgesics. Sadly, despite preclinical data supporting the hypothesis of cannabinoid analgesia, their safety failed to reach the threshold at which International Association for the Study of Pain (IASP) can endorse their general use for pain control. This timely directs our attention towards the role of phytocannabinoids. The plant Cannabis sativa (cannabis) contains more than 100 chemical compounds, known as cannabinoids. Cannabidiol (CBD) is the second most abundant constituent of cannabis, which do not produce the typical subjective effects of marijuana. CBD has complex pharmacological profile involving over 60 unique molecular targets. We suggest computational methods to study the network of CBD’s interactions within complex biological pathways. Despite the growing popularity of CBD, we still have much to discover, especially on the long-term effects of CBD. CBD lacks psychostimulant and addictive properties, thus representing an interesting pharmacological compound to be further investigated as potential treatment remedy for chronic pain and comorbidities. | | 2022年7月1日 17:10～17:40 沖縄コンベンションセンター 会議場A2 第7会場
2S07e-03
Neuroprotective Potential of Endocannabinoids Against HIV-1 Tat Toxicity
*Sylvia Fitting(1)
1. University of North Carolina at Chapel Hill, North Carolina, USA
Keyword: HIV, endocannabinoids, neuroprotection, FAAH enzyme inhibitor
In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease with an inflammatory component that specifically targets the brain and causes a high prevalence of HIV-associated neurocognitive disorders (HAND). The endocannabinoid (eCB) system has attracted interest as a target for treatment of neurodegenerative disorders due to its neuroprotective and anti-inflammatory properties. To address this issue, we present work on the neuroprotective actions of targeted modulation of N-arachidonoylethanolamine (anandamide/AEA) against HIV-1 Tat toxicity in vitro and ex vivo. Our in vitro findings indicate that pretreatment with a highly selective and potent inhibitor (PF3845) of its primary hydrolytic enzyme, fatty acid amid hydrolyze (FAAH), has neuroprotective effects against HIV-1 Tat toxicity. Prefrontal cortex (PFC) neuronal cultures were directly treated with Tat ± PF3845 and indirectly with Tat ± PF3845 microglia conditioned media. Increase in eCB signaling resulted in neuroprotection through the reduction of Tat-induced increases in intracellular calcium, synaptodendritic damage, and neuronal injury. Interestingly, these observed neuroprotective effects appeared to be independent of cannabinoid receptor activity (CB1R & CB2R) when PFC neuron cultures were treated indirectly with Tat ± PF3845 microglia conditioned media. We found that a purported GPR18 antagonist, CID-85469571, blocked the neuroprotective effects of PF3845 in all of these experiments. Using the Tat transgenic mouse model for our in vivo studies significant behavioral deficits are displayed in transgenic Tat [Tat(+)] mice compared to their wild-type counterparts [Tat(-)]. This was consistent with ex vivo recordings from medial PFC slices of Tat mice (males, females) that indicated significant increases in glutamatergic neurotransmission (EPSCs) for Tat(+) slices. Importantly, bath application of PF3845 showed an enhanced decrease in sEPSCs frequency for Tat(+) compared to Tat(-) slices. Overall, results indicate that elevation of eCBs, such as AEA levels, elicit neuroprotective actions against Tat-induced toxicity structurally and functionally. Furthermore, our studies suggest that eCB catabolic enzymes should be further examined as promising targets for treatment of neurodegenerative disorders associated with neuroHIV. | | 2022年7月1日 17:40～18:10 沖縄コンベンションセンター 会議場A2 第7会場
2S07e-04
Distinct behavioral phenotypes induced by endocannabinoid modulation in high-precision 3D motion capture of freely moving mice
*Ignatowska-Jankowska Bogna(1)、Gurkan-Ozer Aysen(1)、Kuck Alexander (1)、Niphakis Micah(2)、Ogasawara Daisuke(2)、Cravatt Benjamin(2)、Uusisaari Marylka Yoe(1)
*Bogna Marta Ignatowska-Jankowska(1), Aysen Gurkan-Ozer(1), Alexander Kuck(1), Micah J Niphakis(2), Daisuke Ogasawara(2), Benjamin F Cravatt(2), Marylka Yoe Uusisaari(1)
1. Neuronal Rhythms in Movement Unit, Okinawa Institute of Science and Technology, 2. Department of Chemical Physiology, Scripps Research Institute, La Jolla, CA 92037, USA
Keyword: cannabinoid, endocannabinoid, motion capture, behavior
One of well-known behavioral effects of cannabinoid CB1 receptor activation is inhibition of locomotor activity. However, the effects of endogenous cannabinoids on behavior have not been extensively studied. Here we aimed to determine whether enhancing endocannabinoid signaling produces effects similar to exogenous cannabinoid agonists using a novel approach to study behavior. To elevate signaling of endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) we used selective inhibitors (MJN110 and PF3845, respectively) of enzymes responsible for their degradation: monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. High-speed, high-resolution marker-based 3D motion capture system (Qualisys, Sweden) was used to track movement (3D trajectories and velocity of markers) during voluntary locomotor tasks: open field exploration and vertical climbing, in C57BL/6 male mice. The results revealed distinct behavioral phenotypes induced by different treatments. We have previously shown that low doses of synthetic cannabinoid agonist CP55,940 (0.03, 0.1, 0.3 mg/kg) produced significant, task-dependent effects presented as a decrease of activity in the open field, but not in the vertical climbing task (n=10). Inhibition of endocannabinoid degradation with MJN110 (1.25, 2.5 mg/kg) and PF3845 (10, 30 mg/kg) produced distinct, opposite effects on locomotor behavior in both open field and climbing tasks (n=10-12). MJN110 (2.5 mg/kg) significantly increased locomotor activity in the open field and produced similar but less pronounced effect at a lower dose (1.25 mg/kg) and in the climbing task. PF3845 significantly reduced locomotor activity in the open field as well as climbing tasks at both doses. In the open field PF3845 reduced total number of steps, and number of locomotory bouts but did not affect the duration of the locomotory bouts. MJN110 and PF3845 had distinct effects on gait parameters. PF3845 decreased speed of ankle swing, shortened the distance and height of the swing. MJN110 increased swing distance but not height or speed of the swing. The results suggest that selective elevation of 2-AG and AEA signaling results in distinct, bidirectional effects on behavior that are different from exogenous cannabinoid agonists. Furthermore, the work highlights the strength of 3D motion capture as a precise and sensitive tool to evaluate a wide range of behaviors in rodents. | |
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