Tag Archives: anti-inflammatory

Interplay of liver-heart inflammatory axis and cannabinoid 2 receptor signalling in an experimental model of hepatic cardiomyopathy.

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Publication cover image“Hepatic cardiomyopathy, a special type of heart failure develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable model of hepatic cardiomyopathy in mice. Herein we aimed to characterize the detailed hemodynamics of mice with bile-duct ligation (BDL)-induced liver fibrosis, by monitoring echocardiography and intracardiac pressure-volume (PV) relationships and myocardial structural alterations. Treatment of mice with a selective cannabinoid-2 receptor (CB2 -R) agonist, known to attenuate inflammation and fibrosis, was used to explore the impact of liver inflammation, fibrosis on cardiac function.

MAIN RESULTS:

BDL induced massive inflammation (increased leukocyte infiltration, inflammatory cytokines and chemokines), oxidative stress, microvascular dysfunction, and fibrosis in the liver. These pathological changes were accompanied by impaired diastolic, systolic and macrovascular functions, cardiac inflammation (increased MIP1, interleukin-1, P-selectin, CD45+ cells) and oxidative stress (increased malondialdehyde, 3-nitrotyrosine and NADPH-oxidases). CB2 -R up-regulation was observed both in livers and hearts of mice exposed to BDL. CB2 -R activation markedly improved hepatic inflammation, impaired microcirculation, fibrosis. CB2 -R activation also decreased serum TNF-alpha levels, and improved cardiac dysfunction, myocardial inflammation and oxidative stress underlining the importance of inflammatory mediators in the pathology of hepatic cardiomyopathy.

CONCLUSION:

We propose BDL-induced cardiomyopathy in mice as a model for hepatic/cirrhotic cardiomyopathy. This cardiomyopathy, similarly to cirrhotic cardiomyopathy in humans, is characterized by systemic hypotension, impaired macro- and microvascular function accompanied by both systolic and diastolic dysfunction. Our results indicate that the liver-heart inflammatory axis has a pivotal pathophysiological role in the development of hepatic cardiomyopathy. Thus, controlling liver and/or myocardial inflammation (e.g. with selective CB2-R agonists) may delay/prevent the development of cardiomyopathy in severe liver disease. ”

https://www.ncbi.nlm.nih.gov/pubmed/31469200

https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30916

Cannabinoids Δ9-tetrahydrocannabinol and cannabidiol may be effective against methamphetamine induced mitochondrial dysfunction and inflammation by modulation of Toll-like type-4(Toll-like 4) receptors and NF-κB signaling.

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Medical Hypotheses“The neurodegeneration, neuro-inflammation and mitochondrial dysfunction which occur by methamphetamine (METH) abuse or administration are serious and motivation therapeutic approaches for inhibition of these types of neurodegeneration. As we know, METH through Toll-like receptors (TLRs), specially type 4, and NF-κB signaling pathway causes neuro-inflammation and mitochondrial dysfunction.

Neuroprotective approach for management of METH-induced neurodegeneration, inflammation and mitochondrial dysfunction, through a novel neuroprotective agent is continuously being superior to any kind of other therapeutic strategy. Therefore, the clarification, introduction and development of efficacious novel neuroprotective agent are demanded. During recent years, using new neuroprotective agent with therapeutic probability for treatment of METH-induced neuro-inflammation and mitochondrial dysfunction has been astoundingly increased.

Previous studies have stated the neuroprotective and anti-inflammatory roles of cannabinoid derivate such as cannabidiol (CBD) and delta-9-tetrahydrocannabinol (Δ9-THC) in multiple neurodegenerative events and diseases.

According to literature cannabinoid derivate, by inhibition of TLR4 and activation of NF-κB signaling pathway, exerts their anti-inflammatory and neuroprotective effects and cause mitochondrial biogenesis. Thus we hypothesized that by using cannabinoids in METH dependent subject it would provide neuroprotection against METH-induced neurodegeneration, neuro-inflammation and mitochondrial dysfunction and probably can manage sequels of METH-induced neurochemical abuses via modulation of TLR4/NF-κB signaling pathway.

In this article, we tried to discuss our hypothesis regarding the possible role of CBD and Δ9-THC, as a potent neuroprotective and anti-inflammatory agents, in inhibition or treatment of METH-induced neurodegeneration, neuro-inflammation and mitochondrial dysfunction through its effects on TLR4/NF-κB signaling pathway.”

https://www.ncbi.nlm.nih.gov/pubmed/31465975

https://www.sciencedirect.com/science/article/abs/pii/S030698771930739X?via%3Dihub

Therapeutic potential of cannabinoid receptor 2 in the treatment of diabetes mellitus and its complications.

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European Journal of Pharmacology“The biological effects of endocannabinoid system are mediated by two types of receptors, cannabinoid 1 (CB1) and cannabinoid 2 receptor (CB2). They play a pivotal role in the management of pain, inflammation, cancer, obesity and diabetes mellitus.

CB2 receptor activity downregulation is hallmark of inflammation and oxidative stress. Strong evidence display the relation between activation of CB2 receptors with decrease in the pro-inflammatory cytokines and pro-apoptotic factors. Numerous in vitro and in vivo studies have been validated to confirm the role of CB2 receptor in the management of obesity, hyperlipidemia and diabetes mellitus by regulating glucose and lipid metabolism.

Activation of CB2 receptor has led to reduction of inflammatory cytokines; tumor necrosis factor-alpha (TNF-α), Interleukin 6 (IL-6), Nuclear factor kappa beta (NF-κβ) and also amelioration of reactive oxygen species and reactive nitrogen species playing role in apoptosis. Many studies confirmed the role of CB2 receptors in the insulin secretion via facilitating calcium entry into the pancreatic β-cells. CB2 receptors also displayed improvement in the neuronal and renal functions by decreasing the oxidative stress and downregulating inflammatory cascade.

The present review addresses, potential role of CB2 receptor activation in management of diabetes and its complications. It also includes the role of CB2 receptors as an anti-oxidant, anti-apoptotic and anti-inflammatory for the treatment of DM and its complications. Also, an informative summary of CB2 receptor agonist drugs is provided with their potential role in the reduction of glucose levels, increment in the insulin levels, decrease in the hyperglycaemic oxidative stress and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31461639

https://www.sciencedirect.com/science/article/pii/S0014299919305801?via%3Dihub

Cannabidivarin Treatment Ameliorates Autism-Like Behaviors and Restores Hippocampal Endocannabinoid System and Glia Alterations Induced by Prenatal Valproic Acid Exposure in Rats.

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 Image result for frontiers in cellular neuroscience“Autism spectrum disorder (ASD) is a developmental condition whose primary features include social communication and interaction impairments with restricted or repetitive motor movements. No approved treatment for the core symptoms is available and considerable research efforts aim at identifying effective therapeutic strategies.

Emerging evidence suggests that altered endocannabinoid signaling and immune dysfunction might contribute to ASD pathogenesis. In this scenario, phytocannabinoids could hold great pharmacological potential due to their combined capacities to act either directly or indirectly on components of the endocannabinoid system and to modulate immune functions.

Among all plant-cannabinoids, the phytocannabinoid cannabidivarin (CBDV) was recently shown to reduce motor impairments and cognitive deficits in animal models of Rett syndrome, a condition showing some degree of overlap with autism, raising the possibility that CBDV might have therapeutic potential in ASD.

Here, we investigated the ability of CBDV treatment to reverse or prevent ASD-like behaviors in male rats prenatally exposed to valproic acid (VPA; 500 mg/kg i.p.; gestation day 12.5).

CBDV in symptomatic rats recovered social impairments, social novelty preference, short-term memory deficits, repetitive behaviors and hyperlocomotion whereas preventative treatment reduced sociability and social novelty deficits, short-term memory impairments and hyperlocomotion, without affecting stereotypies.

As dysregulations in the endocannabinoid system and neuroinflammatory markers contribute to the development of some ASD phenotypes in the VPA model, neurochemical studies were performed after symptomatic treatment to investigate possible CBDV’s effects on the endocannabinoid system, inflammatory markers and microglia activation in the hippocampus and prefrontal cortex.

Prenatal VPA exposure increased CB1 receptor, FAAH and MAGL levels, enhanced GFAP, CD11b, and TNFα levels and triggered microglia activation restricted to the hippocampus. All these alterations were restored after CBDV treatment.

These data provide preclinical evidence in support of the ability of CBDV to ameliorate behavioral abnormalities resembling core and associated symptoms of ASD. At the neurochemical level, symptomatic CBDV restores hippocampal endocannabinoid signaling and neuroinflammation induced by prenatal VPA exposure.”

https://www.ncbi.nlm.nih.gov/pubmed/31447649

https://www.frontiersin.org/articles/10.3389/fncel.2019.00367/full

The protective effect of cannabinoid type 2 receptor activation on renal ischemia-reperfusion injury.

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“Kidney ischemia reperfusion (IR) injury is an important health problem resulting in acute renal failure. After IR, the inflammatory and apoptotic process is triggered.

The relation of Cannabinoid type 2 (CB2) receptor with inflammatory and apoptotic process has been determined. The CB2 receptor has been shown to be localized in glomeruli and tubules in human and rat kidney. Activation of CB2 receptor with JWH-133 has been shown to reduce apoptosis and inflammation.

In this study, it was investigated whether CB2 activation with selective CB2 receptor agonist JWH-133 was protective against renal IR injury.

We found that JWH-133 and CB2 receptor activation had a curative effect against kidney IR damage. JWH-133 may be a new therapeutic agent in preventing kidney IR damage.”

https://www.ncbi.nlm.nih.gov/pubmed/31446615

https://link.springer.com/article/10.1007%2Fs11010-019-03616-6

Cannabidiol differentially regulates basal and LPS-induced inflammatory responses in macrophages, lung epithelial cells, and fibroblasts.

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Toxicology and Applied Pharmacology“Cannabidiol (CBD) containing products are available in a plethora of flavors including oral, sublingual, and inhalable forms. Immunotoxicological effects of CBD containing liquids were assessed by hypothesizing that CBD regulates oxidative stress and lipopolysaccharide (LPS) induced inflammatory responses in macrophages, epithelial cells, and fibroblasts.

RESULTS:

CBD showed differential effects on IL-8 and MCP-1, and acellular and cellular ROS levels. CBD significantly attenuated LPS-induced NF-κB activity and IL-8 and MCP-1 release from macrophages. Cytokine array data depicted a differential cytokine response due to CBD. Inflammatory mediators, IL-8, serpin E1, CXCL1, IL-6, MIF, IFN-γ, MCP-1, RANTES, and TNF-α were induced, whereas MCP-1/CCL2, CCL5, eotaxin, IL-1ra, and IL-2 were reduced. CBD and dexamethasone treatments reduced the IL-8 level induced by LPS when the cells were treated individually, but showed antagonistic effects when used in combination via MCPIP (monocytic chemotactic protein-induced protein).

CONCLUSION:

CBD differentially regulated basal pro-inflammatory response and attenuated both LPS-induced cytokine release and NF-κB activity in monocytes, similar to dexamethasone. Thus, CBD has a differential inflammatory response and acts as an anti-inflammatory agent in pro-inflammatory conditions but acts as an antagonist with steroids, overriding the anti-inflammatory potential of steroids when used in combination.”

https://www.ncbi.nlm.nih.gov/pubmed/31437494

https://www.sciencedirect.com/science/article/pii/S0041008X19303217?via%3Dihub

Heavy Cannabis Use Associated With Reduction in Activated and Inflammatory Immune Cell Frequencies in Antiretroviral Therapy-Treated Human Immunodeficiency Virus-Infected Individuals.

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Issue Cover“Heavy cannabis users had decreased frequencies of human leukocyte antigen (HLA)-DR+CD38+CD4+ and CD8+ T-cell frequencies, compared to frequencies of these cells in non-cannabis-using individuals.

Heavy cannabis users had decreased frequencies of intermediate and nonclassical monocyte subsets, as well as decreased frequencies of interleukin 23- and tumor necrosis factor-α-producing antigen-presenting cells.

CONCLUSIONS:

While the clinical implications are unclear, our findings suggest that cannabis use is associated with a potentially beneficial reduction in systemic inflammation and immune activation in the context of antiretroviral-treated HIV infection.”

https://www.ncbi.nlm.nih.gov/pubmed/29471387

“We found that heavy cannabis use was associated with decreased frequencies of activated T cells and inflammatory antigen-presenting cell (APC) subsets, suggesting a potential immunologic benefit of cannabinoids through decreased immune activation in HIV-infected individuals.

In summary, our work demonstrates that heavy cannabis use is associated with lower markers of inflammation and immune activation in HIV-infected, ART-treated individuals.

These findings have clinical implications, as cannabinoids may have an immunological benefit and nonpsychoactive cannabis derivatives could be investigated as novel therapeutics to be used in conjunction with ART to aid in reduction of persistent inflammation.”

https://academic.oup.com/cid/article/66/12/1872/4869752

“Cannabinoids for the treatment of inflammation.” http://www.ncbi.nlm.nih.gov/pubmed/17520866

Cannabinoids and inflammation: Implications for People Living with HIV.

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Image result for wolters kluwer “Thanks to the success of modern antiretroviral therapy (ART), people living with HIV (PLWH) have life expectancies which approach that of persons in the general population. However, despite the ability of ART to suppress viral replication, PLWH have high levels of chronic systemic inflammation which drives the development of comorbidities such as cardiovascular disease, diabetes and non-AIDS associated malignancies.

Historically, cannabis has played an important role in alleviating many symptoms experienced by persons with advanced HIV infection in the pre-ART era and continues to be used by many PLWH in the ART era, though for different reasons.

Δ-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD) are the phytocannabinoids which have received most attention for their medicinal properties. Due to their ability to suppress lymphocyte proliferation and inflammatory cytokine production, there is interest in examining their therapeutic potential as immunomodulators.

CB2 receptor activation has been shown in vitro to reduce CD4 T-cell infection by CXCR4-tropic HIV and to reduce HIV replication.

Studies involving SIV-infected macaques have shown that Δ-THC can reduce morbidity and mortality and has favourable effects on the gut mucosal immunity. Furthermore, ΔTHC administration was associated with reduced lymph node fibrosis and diminished levels of SIV proviral DNA in spleens of rhesus macaques compared with placebo-treated macaques.

In humans, cannabis use does not induce a reduction in peripheral CD4 T-cell count or loss of HIV virological control in cross-sectional studies. Rather, cannabis use in ART-treated PLWH was associated with decreased levels of T-cell activation, inflammatory monocytes and pro-inflammatory cytokines secretion, all of which are related to HIV disease progression and co-morbidities.

Randomized clinical trials should provide further insights into the ability of cannabis and cannabinoid-based medicines to attenuate HIV-associated inflammation. In turn, these findings may provide a novel means to reduce morbidity and mortality in PLWH as adjunctive agents to ART.”

https://www.ncbi.nlm.nih.gov/pubmed/31408029

https://insights.ovid.com/crossref?an=00002030-900000000-96855

The Acute Activation of the CB1 Receptor in the Hippocampus Decreases Neurotoxicity and Prevents Spatial Memory Impairment in Rats Lesioned with β-Amyloid 25-35.

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Neuroscience“Given their anti-inflammatory properties, cannabinoids have been shown to be neuroprotective agents and to reduce excitotoxicity, through the activation of the Cannabinoid receptor type 1 (CB1r).

These properties have led to CB1r being proposed as pharmacological targets for the treatment of various neurodegenerative diseases.

This study aimed to evaluate the neuroprotective effect of an acute activation of CB1r on spatial memory and its impact on iNOS protein expression, NO● levels, gliosis and the neurodegenerative process induced by the injection of Aβ(25-35) into the CA1 subfield of the hippocampus.

The data obtained in the present research suggest that the acute early activation of CB1r is crucial for neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/31400487

https://www.sciencedirect.com/science/article/abs/pii/S0306452219305433?via%3Dihub

Association between cannabis use and complications related to ulcerative colitis in hospitalized patients: A propensity matched retrospective cohort study.

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 Image result for wolters kluwer“Ulcerative colitis (UC) is a chronic inflammatory process that is occasionally associated with complications that cause significant morbidity and mortality.

Studies in experimental animal models have demonstrated a beneficial effect of cannabis on intestinal inflammation. It is however unknown if this corresponds to fewer complications for patients with Ulcerative Colitis.

We aimed to compare the prevalence of UC related complications and certain key clinical endpoints among cannabis users and nonusers hospitalized with a primary diagnosis of UC, or primary diagnosis of a UC-related complication with a secondary diagnosis of UC. Using data from the Healthcare Cost and Utilization Project-National Inpatient Sample (NIS) during 2010-2014, a total of 298 cannabis users with UC were compared to a propensity score matched group of nonusers with UC. We evaluated several UC-related complications and clinical endpoints.

Within our matched cohort, prevalence of partial or total colectomy was lower in cannabis users compared to nonusers (4.4% vs 9.7%, P = .010) and there was a trend toward a lower prevalence of bowel obstruction (6.4% vs 10.7%, P = .057). 

Cannabis users had shorter hospital length-of-stay (4.5 vs 5.7 days P < .007) compared to their nonuser counterparts.

Cannabis use may mitigate some of the well described complications of UC among hospitalized patients. Our findings need further evaluation, ideally through more rigorous clinical trials.”

https://www.ncbi.nlm.nih.gov/pubmed/31393356

https://insights.ovid.com/crossref?an=00005792-201908090-00016