ThePineapple - Journal Club #53: Menopause | IBS | endocannabinoid | ulcerative colitis

Journal Club #53: Menopause, IBS, endocannabinoid, ulcerative colitis

Week of 08-07-22

This week we have the following selection of papers for you. First, there is a survey on the use of cannabis by menopausal women. Next we have a paper on the effects of CB2 and TRPV1 stimulation in IBS.  Third, a neuroscience paper on looking at the interaction between noradrenergic, glucocorticoid and endocannabinoid systems. Finally, we’ll finish up with a study on the effectiveness of phycocyanin as a CB2R agonist in the context of ulcerative colitis.  Enjoy.

Note: This is a post for cannabis scientists. A weekly curation of fresh papers that help advance our understanding of cannabis and the endocannabinoid system. 

A survey of medical cannabis use during perimenopause and postmenopause. 

Dahlgren MK, El-Abboud C, Lambros AM, Sagar KA, Smith RT, Gruber SA. 

Menopause. 2022 Aug 2. 

Expanding access to legal cannabis has dovetailed with increased interest in medical cannabis (MC) use; however, there is a paucity of research examining MC use to alleviate menopause-related symptoms. This survey study assessed patterns of MC use in perimenopausal and postmenopausal individuals. Participants (perimenopausal, n = 131; postmenopausal, n = 127) completed assessments of menopause-related symptomatology and cannabis use, including modes of use, type of use, and menopause-related symptoms addressed by MC use. Most participants reported current cannabis use (86.1%) and endorsed using MC for menopause-related symptoms (78.7%). The most common modes of use were smoking (84.3%) and edibles (78.3%), and the top menopause-related symptoms for MC use were sleep disturbance (67.4%) and mood/anxiety (46.1%). Relative to postmenopausal participants, perimenopausal participants reported significantly worse menopause-related symptomatology on the vasomotor and psychosocial subscales of the Menopause-Specific Quality of Life Questionnaire (Ps ≤ 0.04), including greater burden of anxiety (P = 0.01) and hot flash (P = 0.04) symptoms. In addition, perimenopausal participants reported higher incidence of depression (P = 0.03) and anxiety diagnoses (P < 0.01), as well as increased use of MC to treat menopause-related mood/anxiety symptoms relative to postmenopausal participants (P = 0.01). Results suggest that many individuals are currently using MC as an adjunctive treatment for menopause-related symptoms, particularly sleep disturbance and mood/anxiety. Future research should examine the impact of different MC use characteristics (e.g., cannabinoid profiles) on the efficacy of MC use for menopause-related symptoms. Increased severity and prevalence of mood and anxiety symptoms in perimenopausal participants suggest promising targets for clinical trials of cannabinoid-based therapies.

doi: 10.1097/GME.0000000000002018. Epub ahead of print. PMID: 35917529.

Effects of CB2 and TRPV1 Stimulation on Osteoclast Overactivity Induced by Iron in Pediatric Inflammatory Bowel Disease.

Tortora C, Di Paola A, Creoli M, Argenziano M, Martinelli M, Miele E, Rossi F, Strisciuglio C. 

Inflamm Bowel Dis. 2022 Aug 1;28(8):1244-1253. 

The reduction of bone mineral density and osteoporosis have high impacts on the health of patients with inflammatory bowel diseases (IBD). We have previously shown that a dysregulated iron metabolism occurs in IBD and leads to a decrease in circulating iron concentration and excessive intracellular sequestration of iron. Studies suggest that iron overload significantly affects the bone, accelerating osteoclast (OC) differentiation and activation, promoting bone resorption. Moreover, we demonstrated that iron overload causes OC overactivity. The cannabinoid receptor type 2 (CB2) and the transient receptor potential vanilloid type-1 (TRPV1) are potential therapeutic targets for bone diseases. The aim of this study was to evaluate the roles of CB2 and TRPV1 receptors and of iron in the development of osteoporosis in pediatric IBD.  We differentiated OCs from peripheral blood mononuclear cells of patients with IBD and healthy donors and evaluated CB2 and TRPV1 receptor expression; OC activity, and iron metabolism by Western blot, TRAP assays, bone resorption assays, and iron assays. Moreover, we analyzed the effects of the pharmacological modulation of CB2 and TRPV1 receptors on OC activity and on the iron metabolism. We confirmed the well-known roles of CB2 and TRPV1 receptors in bone metabolism and suggested that their stimulation can reduce the OC overactivity induced by iron, providing new insights into the pathogenesis of pediatric IBD-related bone resorption. Stimulation of CB2 and TRPV1 could reduce IBD-related osteoporosis due to their direct effects on OC activity and to modulating the iron metabolism.

doi: 10.1093/ibd/izac073. PMID: 35472140; PMCID: PMC9340523.

Interactions of Noradrenergic, Glucocorticoid and Endocannabinoid Systems Intensify and Generalize Fear Memory Traces.

Gazarini L, Stern CA, Takahashi RN, Bertoglio LJ. 

Neuroscience. 2022 Aug 10;497:118-133. 

Systemic administration of drugs that activate the noradrenergic or glucocorticoid system potentiates aversive memory consolidation and reconsolidation. The opposite happens with the stimulation of endocannabinoid signaling under certain conditions. An unbalance of these interacting neurotransmitters can lead to the formation and maintenance of traumatic memories, whose strength and specificity attributes are often maladaptive. Here we aimed to investigate whether originally low-intensity and precise contextual fear memories would turn similar to traumatic ones in rats systemically administered with adrenaline, corticosterone, and/or the cannabinoid type-1 receptor antagonist/inverse agonist AM251 during consolidation or reconsolidation. The high dose of each pharmacological agent evaluated significantly increased freezing times at test in the conditioning context one and nine days later when given alone post-acquisition or post-retrieval. Their respective low dose produced no relative changes when given separately, but co-treatment of adrenaline with corticosterone or AM251 and the three drugs combined, but not corticosterone with AM251, produced results equivalent to those mentioned initially. Neither the high nor the low dose of adrenaline, corticosterone, or AM251 altered freezing times at test in a novel, neutral context two and ten days later. In contrast, animals receiving the association of their low dose exhibited significantly higher freezing times than controls. Together, the results indicate that newly acquired and destabilized threat memory traces become more intense and generalized after a combined interference acting synergistically and mimicking that reported in patients presenting stress-related psychiatric conditions.

doi: 10.1016/j.neuroscience.2021.09.012. Epub 2021 Sep 22. PMID: 34560200.

Phycocyanin stimulates ulcerative colitis healing via selective activation of cannabinoid receptor-2, intestinal mucosal healing, Treg accumulation, and p38MAPK/MK2 signaling inhibition.

El-Maadawy WH, Hafiz E, Okasha H, Osman NA, Ali GH, Hussein RA. 

Life Sci. 2022 Sep 15;305:120741. 

Ulcerative colitis (UC) is a chronic inflammatory condition that until this date, lacks curative treatments. Previously, synthetic selective CB2 receptor (CB2R) agonists demonstrated effective preclinical anti-inflammatory activities in UC. Phycocyanin (PC), photosynthetic assistant protein isolated from Microcystis aeruginosa Kützing blue green algae, has multiple pharmacological effects, however, it's effect against UC remains unexplored. Our study aimed at investigating the therapeutic effectiveness of PC against UC, and correlating its mechanisms with CB2R agonistic activities. In silico; PC showed structural similarity with endocannabinoid receptors' ligand "Δ9-tetrahydrocannabinol", target prediction studies suggested high affinity for G-coupled protein family-receptors, and molecular docking affirmed preferable affinity towards CB2R vs CB1R. In LPS-exposed-Caco-2 cell line; PC demonstrated comparable interaction with CB2R, and downregulation of CB2R, p38 and MK2 gene expressions with reference agonist "6d", and exhibited preferred selectivity towards CB2R over CB1R. In DSS-induced mice; PC-treatment ameliorated DSS-induced colon shortening, elevated disease activity index, and colonic pathological alterations. PC showed effective CB2R activation through potent anti-inflammatory activities, Treg-cell accumulation, suppression in p38MAPK/MK2 signaling, and tight junction barrier restoration as indicated by ultrastructural examinations, elevated ZO-1 and occludin protein expressions, and Ki67 immunohistochemical expression in colonic tissues. Additionally, PC alleviated intestinal dysbiosis via downregulating LPS/TLR4/NF-κB signaling and gut microbiota maintenance. Notably, PC-protective activities were abolished when co-administered with SR144528 (selective CB2 antagonist) except for gut microbiota maintenance, which was independent from CB2R activation. Our findings provide evidence of PC effectiveness against UC through acting as CB2R agonist, thus expanding its possible therapeutic application against other inflammatory diseases.

doi: 10.1016/j.lfs.2022.120741. Epub 2022 Jun 28. PMID: 35777583.