Acute oral cannabidiolic acid methyl ester reduces depression-like behavior in two genetic animal models of depression

Hen-Shoval, Danielle; Amar, Sabrina; Shbiro, Liat; Smoum, Reem; Haj, Christeene; Mechoulam, Raphael; Zalsman, Gil; Weller, Aron; Shoval, Gal

doi:10.1016/j.bbr.2018.05.027

Cited by 35 publications

(32 citation statements)

References 19 publications

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“…While an exploration of the mechanism(s) underlying the anti‐nociceptive effects of CBDA‐ME was beyond the scope of the current investigation, it has been shown by others that this modified cannabinoid produces more potent 5‐HT 1A receptor‐mediated suppression of nausea, anxiety and depression in rats than CBDA (Hen‐Shoval et al, ; Pertwee et al, ). In both the peripheral and central nervous system, 5‐HT has long been considered to play an important role in modulating nociception.…”

Section: Discussionmentioning

confidence: 99%

“…However, its instability makes it a challenging compound to work with experimentally, especially in the context of in vivo studies that may require repeated treatment administration over a prolonged period of time. This limitation prompted the development of CBDA‐ME, which has been shown to elicit more potent suppression of anxiety, depression, and nausea in rats than CBDA (Hen‐Shoval et al, ; Pertwee et al, ). The established base of evidence provided a rationale to examine whether CBDA‐ME limits or delays the development of chronic hypersensitivity in a preclinical model of surgically induced peripheral neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

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An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

Zhu

Linher‐Melville

Niazmand

et al. 2020

British J Pharmacology

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Background and Purpose: Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.Experimental Approach: After 14 consecutive days of intraperitoneal CBDA-ME administration at 0.01, 0.1 and 1 μgÁkg −1 , commencing 1 day after surgically implanting a sciatic nerve-constricting cuff to induce NEP, the anti-nociceptive efficacy of this cannabinoid was assessed in male and female Sprague-Dawley rats relative to vehicle-treated counterparts. In females, 2 and 4 μgÁkg −1 daily doses of CBDA-ME were also evaluated. Behavioural tests were performed for hind paw mechanical and thermal withdrawal thresholds once a week for 8 weeks. At endpoint, in vivo electrophysiological recordings were obtained to characterize soma threshold changes in primary sensory neurons. Key Results:In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and nonnociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested. Conclusion and Implications:Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

Zhu

Linher‐Melville

Niazmand

et al. 2020

British J Pharmacology

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“…The endocannabinoid system plays a key role in mediation and the modulation of innate immune and hepatic function [ 20 , 21 , 27 , 34 ]. WKY rats exhibit alteration in key components of the endocannabinoid system within discrete brain regions [ 35 , 36 , 37 ] and cannabidiol has been demonstrated to attenuate depressive-like behaviour in this rat strain [ 38 , 39 ]. Our data confirm the stress-related phenotype of the WKY rats (anxiety-related behaviour) and extend the current literature demonstrating an altered hepatic endocannabinoid system both at baseline and in response to LPS/GalN, when compared to SD rats.…”

Section: Discussionmentioning

confidence: 99%

Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System

et al. 2020

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Acute liver injury (ALI) is a highly destructive and potentially life-threatening condition, exacerbated by physical and psychological stress. The endocannabinoid system plays a key role in modulating stress and hepatic function. The aim of this study was to examine the development of acute liver injury in the genetically susceptible stress-sensitive Wistar-Kyoto (WKY) rat compared with normo-stress-sensitive Sprague Dawley (SD) rats, and associated changes in the endocannabinoid system. Administration of the hepatotoxin lipopolysaccharide/D-Galactosamine (LPS/GalN) resulted in marked liver injury in WKY, but not SD rats, with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) plasma levels, significant histopathological changes, increased hepatic pro-inflammatory cytokine expression and caspase-3 activity and expression and reduced Glutathione (GSH) activity. Furthermore, compared to SD controls, WKY rats display increased anandamide and 2-Arachidonoylglycerol levels concurrent with decreased expression of their metabolic enzymes and a decrease in cannabinoid (CB)1 receptor expression following LPS/GalN. CB1 antagonism with AM6545 or CB2 agonism with JWH133 did not alter LPS/GalN-induced liver injury in SD or WKY rats. These findings demonstrate exacerbation of acute liver injury induced by LPS/GalN in a stress-sensitive rat strain, with effects associated with alterations in the hepatic endocannabinoid system. Further studies are required to determine if the endocannabinoid system mediates or modulates the exacerbation of liver injury in this stress-sensitive rat strain.

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“…The copyright holder for this preprint this version posted June 23, 2020. ; https://doi.org/10.1101/2020.06.22.165076 doi: bioRxiv preprint in the light-dark emergency test with doses between 0.1 and 100 mg/kg, but not in basal conditions [17]. Recently, Hen-Shoval et al (2018) found that an acute oral administration of CBDA methyl ester (HU-580) reduces despair-like behaviour in forced swimming test, using Wistar-Kyoto (WKY) and Flinders Sensitive Line (FSL) rat, which represent genetic models of depression [18]. A recent study showed that CBDA (0.01 mg/kg) reduces the carrageenan-induced hyperalgesia and oedema in a rodent model of inflammatory pain, by a TRPV1-mediated mechanism [19].…”

Section: Introductionmentioning

confidence: 99%

Behavioural and molecular effects of cannabidiolic acid in mice

2020

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Aims: Cannabidiolic acid (CBDA) is one of the most abundant phytocannabinoid acids in the Cannabis Sativa plant. It has been shown it is able to exert some therapeutic effects such as antiemetic, anti-inflammatory, anxiolytic or antidepressant, although some of them remain under debate. In the present study we aim to assess the potential effects of CBDA on different behaviours and on the modulation of neuroinflammatory markers in the prefrontal cortex (PFC). Main methods: the effects of acute and/or chronic CBDA (0.001-1 mg/kg i.p.) treatment were evaluated on cognitive, emotional, motivational and nociceptive behaviours in male CD1 mice. For this, Y-maze and elevated plus maze paradigms, spontaneous locomotor activity, social interaction, hot-plate, formalin and tail suspension tests were used. We also studied the effects of CBDA on the rewarding responses of cocaine in the conditioned place preference (CPP) paradigm. PFC was dissected after acute and chronic CBDA treatments to evaluate inflammatory markers. Key findings: acute CBDA treatment induced antinociceptive responses in the hot-plate test. A 10-day chronic CBDA treatment reduced despair-like behaviour in the tail suspension test. CBDA did not alter the remaining behavioural tests assayed, including cocaine-induced reward in the CPP. Regarding the biochemical analysis, chronic CBDA treatment diminished peroxisome proliferator-activated receptor gamma (PPAR-γ) and increased interleukin-6 (IL-6) protein levels in PFC. Significance: these results show that CBDA has limited in vivo effects modulating mice behaviour, highlighting the current disagreement regarding its therapeutic potential.

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Acute oral cannabidiolic acid methyl ester reduces depression-like behavior in two genetic animal models of depression

Cited by 35 publications

References 19 publications

An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System

Behavioural and molecular effects of cannabidiolic acid in mice

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