ThePineapple - Journal Club #39: Microglia | Epilepsy | Diabetes | Analgesia

Journal Club #39: Microglia, Epilepsy, Diabetes, Analgesia

Week of 04-24-22

Welcome to journal club. A weekly curation of scientific research papers in the field of cannabis science. Fair warning, these are unedited, freshly destilled scientifc publications. In other words, this post is for the cannabis scientists among you, who are likely going to spent at least one day this week eating free pizza and discussing new publications in your respective biomedical graduate departments. So, if you are a graduate student, feel free to save yourself some time and pick one of these :)

Also, if you feel we missed a particularly juicy paper, then leave a comment with the doi: number or pubmed ID ! We'll update the "journal club" as the week goes on.

Protective effects of cannabinoid type 2 receptor against microglia overactivation and neuronal pyroptosis in sepsis-associated encephalopathy.

Yang L, Li Z, Xu Z, Zhang B, Liu A, Zheng F, Zhan J. 

Neuroscience. 2022 Apr 20:S0306-4522(22)00192-0. 

Sepsis-associated encephalopathy (SAE) has close association with long-term cognitive deficits, resulting in increased mortality. The mechanism of SAE is complicate, including excessive microglial activation and neuroinflammation. Pyroptosis is a type of proinflammatory cell death program. Cannabinoid type 2 receptor (CB2R) has been proved to be effective in neuronal protection and survival promotion. Microglia play a role in CB2R mediated neuronal protection when neurons are exposed to noxious stimuli. However, the underlying mechanisms involved in this process still remain to be explored. Previous studies have demonstrated that CB2R can reduce sepsis-induced lung injury by inhibiting pyroptosis. Here, SAE model was established by cecal ligation and puncture (CLP). Open field test (OFT), novel object recognition test (NORT), and morris water maze (MWM) test were performed to assess cognitive function. Brain samples were obtained to detect cell injury, cytokine, CB2R and pyroptosis-associated protein expression by Hematoxylin-Eosin (HE) Staining, Enzyme-linked immunosorbent assay (ELISA), Western blotting and Immunofluorescence staining. CLP could induce microglia hyperactivation and neuronal pyroptosis, aggravating brain tissue destruction and cognitive dysfunction. The activation of CB2R could have a protective effect against SAE by inhibiting microglia activity and neuronal pyroptosis. This will provide a new therapeutic option for the treatment of SAE.

doi: 10.1016/j.neuroscience.2022.04.011. Epub ahead of print. PMID: 35460837.

Neuroplastic alterations in cannabinoid receptors type 1 (CB1) in animal models of epileptic seizures.

Lazarini-Lopes W, Silva-Cardoso GK.

Neurosci Biobehav Rev. 2022 Apr 20:104675. 

Currently, there is an urgent need to better comprehend neuroplastic alterations in cannabinoid receptor type 1 (CB1) and to understand the biological meaning of these alterations in epileptic disorders. The present study reviewed neuroplastic changes in CB1 distribution, expression, and functionality in animal models of epileptic seizures. Neuroplastic alterations in CB1 were consistently observed in chemical, genetic, electrical, and febrile seizure models. Most studies assessed changes in hippocampal and cortical CB1, while thalamic, hypothalamic, and brainstem nuclei were rarely investigated. Additionally, the relationship between CB1 alteration and the control of brain excitability through modulation of specific neuronal networks, such as nigrotectal and thalamocortical pathways and inhibitory projections to hippocampal pyramidal neurons were presented and discussed. Neuroplastic alterations in CB1 detected in animal models of epilepsy may reflect two different scenarios: (1) endogenous adaptations aimed to control neuronal hyperexcitability in epilepsy or (2) pathological alterations which facilitate neuronal hyperexcitability. Additionally, a better comprehension of neuroplastic and functional alterations in CB1 can improve pharmacological therapies for epilepsies.

doi: 10.1016/j.neubiorev.2022.104675. Epub ahead of print. PMID: 35460705.

Cannabinoid receptor 2 activation alleviates diabetes-induced cardiac dysfunction, inflammation, oxidative stress, and fibrosis. 

Rajesh M, Mukhopadhyay P, Bátkai S, Arif M, Varga ZV, Mátyás C, Paloczi J, Lehocki A, Haskó G, Pacher P. 

Geroscience. 2022 Apr 22.

Diabetes mellitus promotes accelerated cardiovascular aging and inflammation, which in turn facilitate the development of cardiomyopathy/heart failure. High glucose-induced oxidative/nitrative stress, activation of various pro-inflammatory, and cell death pathways are critical in the initiation and progression of the changes culminating in diabetic cardiomyopathy. Cannabinoid 2 receptor (CB2R) activation in inflammatory cells and activated endothelium attenuates the pathological changes associated with atherosclerosis, myocardial infarction, stroke, and hepatic cardiomyopathy. In this study, we explored the role of CB2R signaling in myocardial dysfunction, oxidative/nitrative stress, inflammation, cell death, remodeling, and fibrosis associated with diabetic cardiomyopathy in type 1 diabetic mice. Control human heart left ventricles and atrial appendages, similarly to mouse hearts, had negligible CB2R expression determine by RNA sequencing or real-time RT-PCR. Diabetic cardiomyopathy was characterized by impaired diastolic and systolic cardiac function, enhanced myocardial CB2R expression, oxidative/nitrative stress, and pro-inflammatory response (tumor necrosis factor-α, interleukin-1β, intracellular adhesion molecule 1, macrophage inflammatory protein-1, monocyte chemoattractant protein-1), macrophage infiltration, fibrosis, and cell death. Pharmacological activation of CB2R with a selective agonist attenuated diabetes-induced inflammation, oxidative/nitrative stress, fibrosis and cell demise, and consequent cardiac dysfunction without affecting hyperglycemia. In contrast, genetic deletion of CB2R aggravated myocardial pathology. Thus, selective activation of CB2R ameliorates diabetes-induced myocardial tissue injury and preserves the functional contractile capacity of the myocardium in the diabetic milieu. This is particularly encouraging, since unlike CB1R agonists, CB2R agonists do not elicit psychoactive activity and cardiovascular side effects and are potential clinical candidates in the treatment of diabetic cardiovascular and other complications.

doi: 10.1007/s11357-022-00565-9. Epub ahead of print. PMID: 35460032.

Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies. 

Nielsen S, Picco L, Murnion B, Winters B, Matheson J, Graham M, Campbell G, Parvaresh L, Khor KE, Betz-Stablein B, Farrell M, Lintzeris N, Le Foll B.

Neuropsychopharmacology. 2022 Apr 22.

Cannabinoid co-administration may enable reduced opioid doses for analgesia. This updated systematic review on the opioid-sparing effects of cannabinoids considered preclinical and clinical studies where the outcome was analgesia or opioid dose requirements. We searched Scopus, Cochrane Central Registry of Controlled Trials, Medline, and Embase (2016 onwards). Ninety-two studies met the search criteria including 15 ongoing trials. Meta-analysis of seven preclinical studies found the median effective dose (ED50) of morphine administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED50 of morphine alone. Six preclinical studies found no evidence of increased opioid abuse liability with cannabinoid administration. Of five healthy-volunteer experimental pain studies, two found increased pain, two found decreased pain and one found reduced pain bothersomeness with cannabinoid administration; three demonstrated that cannabinoid co-administration may increase opioid abuse liability. Three randomized controlled trials (RCTs) found no evidence of opioid-sparing effects of cannabinoids in acute pain. Meta-analysis of four RCTs in patients with cancer pain found no effect of cannabinoid administration on opioid dose (mean difference -3.8 mg, 95% CI -10.97, 3.37) or percentage change in pain scores (mean difference 1.84, 95% CI -2.05, 5.72); five studies found more adverse events with cannabinoids compared with placebo (risk ratio 1.13, 95% CI 1.03, 1.24). Of five controlled chronic non-cancer pain trials; one low-quality study with no control arm, and one single-dose study reported reduced pain scores with cannabinoids. Three RCTs found no treatment effect of dronabinol. Meta-analyses of observational studies found 39% reported opioid cessation (95% CI 0.15, 0.64, I2 95.5%, eight studies), and 85% reported reduction (95% CI 0.64, 0.99, I2 92.8%, seven studies). In summary, preclinical and observational studies demonstrate the potential opioid-sparing effects of cannabinoids in the context of analgesia, in contrast to higher-quality RCTs that did not provide evidence of opioid-sparing effects.

doi: 10.1038/s41386-022-01322-4. Epub ahead of print. PMID: 35459926.