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Cannabidiol reduces tumor necrosis factor-α levels in lipopolysaccharide-treated rat retinal microglial cells. Culture medium of retinal microglial cells were collected at different time points after lipopolysaccharide (LPS) treatment and assayed for tumor necrosis factor-α (TNF-α) with ELISA. A: TNF-α levels were measured at different times in LPS-treated microglial cells and were compared with the control. B: TNF-α levels were compared in the presence or absence of 1 μM cannabidiol (CBD). Data shown is the mean of 6 samples measured at 6 h±SEM. Asterisk represents that it is significantly different when compared with the 0 time or control at p<0.05.
Source publication
Degenerative retinal diseases are characterized by inflammation and microglial activation. The nonpsychoactive cannabinoid, cannabidiol (CBD), is an anti-inflammatory in models of diabetes and glaucoma. However, the cellular and molecular mechanisms are largely unknown. We tested the hypothesis that retinal inflammation and microglia activation are...
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Disc degeneration is a multifactorial process that involves hypoxia, inflammation, neoinnervation, accelerated catabolism, and reduction in water and glycosaminoglycan content. Cannabidiol is the main non-psychotropic component of the Cannabis sativa with protective and anti-inflammatory properties. However, possible therapeutic effects of cannabid...
The retinal pigment epithelium (RPE) interacts closely with the photoreceptors in fulfilling tasks of visual function. Since an understanding of the RPE function is essential for understanding the patho-mechanisms involved in vision loss, we explored the regulation of the vanilloid receptor subtype transient receptor potential TRPV2 channels that t...
Citations
... 54 Moreover, similar evidence was observed in a mouse model of endotoxininduced uveitis which levels of TNF-α decreased and infiltration of macrophages was inhibited. 55 Also, it has been shown that CBD could decrease the levels of IL-1α, IL-6, and TNF-α in the LPS-treated microglial cells which seems to be achieved through modulating NF-κB. 56 In the mitogen-activated human peripheral blood mononuclear cells (PBMC), CBD decreased IL-1β and TNF-α. ...
Background
Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it.
Objective
This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways.
Findings
Among the pro‐inflammatory cytokines, studies have shown solid roles for interleukin 1β (IL‐β), IL‐6, and tumor necrosis factor α (TNF‐α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre‐existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia‐inducible factor 1α (HIF‐1α), transforming growth factor β1 (TGF‐β1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non‐psychoactive member of cannabinoids which has well‐known and notable anti‐inflammatory and antiangiogenic properties. This agent has been shown to decrease IL‐1β, IL‐6, TNF‐α, VEGF, TGFβ, and MMPs in different animal models of diseases.
Conclusion
It seems that CBD could be a possible treatment for endometriosis due to its anti‐inflammatory and antiangiogenic activity, however, further studies are needed.
... In addition, LPS-treated rat retinas accumulated macrophages and activated microglia, increased levels of ROS and nitrotyrosine, and activated p38 MAPK and neuronal apoptosis. Treatment with CBD blocked all these effects (El-Remessy et al., 2008). ...
Inflammation often develops from acute, chronic, or auto-inflammatory disorders that can lead to compromised organ function. Cannabis (Cannabis sativa) has been used to treat inflammation for millennia, but its use in modern medicine is hampered by a lack of scientific knowledge. Previous studies report that cannabis extracts and inflorescence inhibit inflammatory responses in vitro and in pre-clinical and clinical trials. The endocannabinoid system (ECS) is a modulator of immune system activity, and dysregulation of this system is involved in various chronic inflammations. This system includes cannabinoid receptor types 1 and 2 (CB1 and CB2), arachidonic acid-derived endocannabinoids, and enzymes involved in endocannabinoid metabolism. Cannabis produces a large number of phytocannabinoids and numerous other biomolecules such as terpenes and flavonoids. In multiple experimental models, both in vitro and in vivo, several phytocannabinoids, including Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabigerol (CBG), exhibit activity against inflammation. These phytocannabinoids may bind to ECS and/or other receptors and ameliorate various inflammatory-related diseases by activating several signaling pathways. Synergy between phytocannabinoids, as well as between phytocannabinoids and terpenes, has been demonstrated. Cannabis activity can be improved by selecting the most active plant ingredients (API) while eliminating parts of the whole extract. Moreover, in the future cannabis components might be combined with pharmaceutical drugs to reduce inflammation.
... The analysis of a gene networks assigned to kinases indicated that cannabis in the context of HIV decreased transcription of components of the p38 MAPK pathway, which is involved in a diversity of biological functions (Cuadrado and Nebreda, 2010). The blockage of p38 MAPK by cannabinoids has been previously reported in other models, with both suppressor and stimulating effects (El-Remessy et al., 2008;Herrera et al., 2005;Derkinderen et al., 2001). Suppression of this pathway may be associated with blockage of oxidative stress (Cuadrado and Nebreda, 2010;El-Remessy et al., 2008). ...
... The blockage of p38 MAPK by cannabinoids has been previously reported in other models, with both suppressor and stimulating effects (El-Remessy et al., 2008;Herrera et al., 2005;Derkinderen et al., 2001). Suppression of this pathway may be associated with blockage of oxidative stress (Cuadrado and Nebreda, 2010;El-Remessy et al., 2008). The anti-oxidant activity of cannabis and cannabinoid compounds has been previously acknowledged (Raja et al., 2020;Abdel-Salam et al., 2012;Cassol et al., 2010), although healthy cannabis users do not differ from non-users regarding oxidative stress markers (Bayazit et al., 2017). ...
In spite of suppressive antiretroviral therapies (ART), Human Immunodeficiency Virus (HIV)-infected subjects still experience the consequences of viral persistence and chronic inflammation. In the brain, where most HIV-1 targets are of innate immune origin, neurological and cognitive impairments are detectable and enhanced by highly prevalent substance use disorders. Cannabis is one of the most prevalent substances among HIV+ subjects, compared to non-infected populations, either prescribed for improving various symptoms or used recreationally, as well as a component of polysubstance use. The mechanisms by which addictive substances and HIV interact are multifactorial and poorly understood. Importantly, the HIV brain target cells, macrophages and microglia, express receptors to neurotransmitters elevated by such drugs, and express receptors to cannabinoids, particularly CB2R. We have tested a panel of 784 transcripts associated with neurological disorders, digitally multiplexed and detectable in peripheral blood cells from a small cohort (n = 102) of HIV-positive (HIV+) and HIV-negative (HIV-) specimens, stratified based on criteria of lifetime (LT) dependence of cannabis (CAN+) or not (CAN-). Demographic homogeneity and low incidence of co-morbidities helped increase power and allowed the identification of key differences consistent with HIV infection, cannabis exposure, or their interactions. A small percentage of these subjects used cannabis as well as other drugs. The data was analyzed using robust systems and visualization strategies to detect orchestrated patterns in gene networks connected based on molecular interfaces with higher power than in single genes. We found that the effects of cannabis differed drastically between HIV- and HIV+ groups, particularly in gene networks playing a role in inflammation, neurodegeneration, apoptosis and leukocyte adhesion and transmigration. At the level of individual genes, we identified detrimental effects that were associated with polysubstance use as a covariate, particularly methamphetamine. Transcription factor usage predictions suggest that the effects of cannabis are associated with transcriptional co-regulation at the gene promoters by multiple factors that vary by context. Overall, we have found that the effects of cannabis may be context-dependent, with potential benefits in the context of HIV reflected by improvements in cognition, but in the absence of the polysubstance use component.
... However, clinical trials targeting IL-17A in uveitis have not been successful, which might be because the IL-17A-targeted drug improved EAU by inducing IL-24 in vivo, but silencing IL-24 in Th17 cells enhanced the disease. Some studies on inhibiting EAU by blocking the p38 signaling pathway, cannabidiol (El-Remessy et al., 2008), and IL-27 (Meka et al., 2015) have reported related results. These experiments have verified that the TNF-α signaling pathway is related to the pathogenesis of experimental uveitis, especially the NF-κB pathways (Li S. et al., 2010). ...
Uveitis is an inflammation of the iris, ciliary body, vitreous, retina, or choroid, which has been shown to be the first manifestation of numerous systemic diseases. Studies about the immunopathogenesis and treatment of uveitis are helpful to comprehend systemic autoimmune diseases, and delay the progression of systemic autoimmune diseases, respectively. Tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, plays a pivotal role in intraocular inflammation based on experimental and clinical data. Evidence of the feasibility of using anti-TNF-α agents for uveitis management has increased. Although there are numerous studies on TNF-α in various autoimmune diseases, the pathological mechanism and research progress of TNF-α in uveitis have not been reviewed. Therefore, the objective of this review is to provide a background on the role of TNF-α in the immunopathogenesis of uveitis, as well as from bench to clinical research progress, to better guide TNF-α-based therapeutics for uveitis.
... NDMA-induced retinal toxicity involves both JNK and p38 MAPK, with the inhibitors of each being found as protective in this study. Similarly, JNK inhibition was protective against RGC loss in another ocular hypertensive model in a dose-dependent manner [69]. As reported above, the presence of VGLCR is able to significantly activate p38/MAPK and JNK, favoring the survival of RGC cells and eye tissues when added both before and after injury. ...
Background:
Glaucoma is currently the leading cause of irreversible blindness; it is a neuropathy characterized by structural alterations of the optic nerve, leading to visual impairments. The aim of this work is to develop a new oral formulation able to counteract the early changes connected to glaucomatous degeneration. The composition is based on gastrodin and vitamin D3 combined with vitamin C, blackcurrant, and lycopene.
Methods:
Cells and tissues of the retina were used to study biological mechanisms involved in glaucoma, to slow down the progression of the disease. Experiments mimicking the conditions of glaucoma were carried out to examine the etiology of retinal degeneration.
Results:
Our results show a significant ability to restore glaucoma-induced damage, by counteracting ROS production and promoting cell survival by inhibiting apoptosis. These effects were confirmed by the intracellular mechanism that was activated following administration of the compound, either before or after the glaucoma induction. In particular, the main results were obtained as a preventive action of glaucoma, showing a beneficial action on all selected markers, both on cells and on eyecup preparations. It is therefore possible to hypothesize both the preventive and therapeutic use of this formulation, in the presence of risk factors, and due to its ability to inhibit the apoptotic cycle and to stimulate cell survival mechanisms, respectively.
Conclusion:
This formulation has exhibited an active role in the prevention or restoration of glaucoma damage for the first time.
... Thus, the previous report indicated that modulation of JNK pathway could protect against cerebral ischemia and other neurodegenerative conditions [41,42]. The p38 MAPK is a stress-activated kinase and is regarded as an important target of pro-inflammatory cytokines and oxidative stress in microglia [43]. The ERK1/2 pathway is known to participate in cell proliferation, differentiation, and cell survival. ...
In recent years, microalgae have drawn increasing attention as a valuable source of functional food ingredients. Intriguingly, Nitzschia laevis is rich in fucoxanthinol that is seldom found in natural sources. Fucoxanthinol, a marine xanthophyll carotenoid, possesses various beneficial bioactivities. Nevertheless, it’s not clear whether fucoxanthinol could exert anti-neuroinflammatory function. In light of these premises, the aim of the present study was to investigate the anti-inflammatory role of fucoxanthinol purified from Nitzschia laevis in Lipopolysaccharide (LPS)-stimulated microglia. The results showed that pre-treatment of fucoxanthinol remarkably attenuated the expression of LPS-induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and the production of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE-2), nitric oxide (NO) and reactive oxygen species (ROS) induction. Modulation mechanism studies revealed that fucoxanthinol hampered nuclear factor-kappa B (NF-κB), Akt, and mitogen-activated protein kinase (MAPK) pathways. Meanwhile, fucoxanthinol led to the enhancement of nuclear translocation of NF-E2-related factor 2 (Nrf2), and the upregulation of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO-1). Taken together, the results indicated that fucoxanthinol obtained from Nitzschia laevis had great potential as a neuroprotective agent in neuroinflammation and neurodegenerative disorders.
... Three animal studies (conducted in rats) in our review showed that cannabinoids have neuroprotective effects on the retina. 12,20,21 Liu and colleagues 12 used synthetic cannabinoid and measured neuroprotection in terms of the density of retinal ganglion cells in rats with glaucoma. They found that the density of ganglion cells was markedly reduced in the group exposed to synthetic cannabinoid. ...
... El-Remessy and colleagues 21 compared treatment with CBD (intraperitoneal injection) versus placebo in 72 rats with drug-induced uveitis. They found that CBD treatment reduced A c c e p t e d M a n u s c r i p t neuronal apoptosis in the retina, as well as inflammatory responses (e.g., reactive oxygen species) caused by the induced uveitis. ...
Purpose: Cannabis is the most prevalent drug in the world and its consumption is growing. Cannabinoid receptors are present in the human central nervous system. Recent studies show evidence of the effects of cannabinoids on the retina, and synthesizing the results of these studies may be relevant for ophthalmologists. Thus, this review adopts standardized, systematic review methodology to investigate the effects of exposure to cannabis and components on the retina.
Methods: We searched five online databases for the combined terms for outcome (“retina”) and exposure (“cannabis”). Eligibility of studies were conducted by two independent reviewers, and risk of bias was assessed.
Results: We retrieved 495 studies, screened 229 studies, assessed 52 studies for eligibility, and included 16 studies for qualitative analysis. The cannabinoids most frequently investigated were delta-9-tetrahydrocannabinol (THC), abnormal cannabidiol, synthetic cannabinoid, and cannabidiol (CDB). The outcomes most studied were neuroretinal dysfunction, followed by vascular effects. The studies also included investigation of neuroprotective and anti-inflammatory effects and teratogenic effects.
Conclusions: This review suggests that cannabinoids may have an important role in retinal processing and function.
... CDB also protects structural proteins against UV-induced decreases in their expression. This observation is in agreement with previous data showing that CBD, through the activation of p38 MAPK, induced actin reorganization and cellular motility in microglial cells [25]. CBD also affects other signalling pathways connected with kinase activity. ...
Cannabidiol (CBD), as the only phytocannabinoid that has no psychoactive effect, has both antioxidant and anti-inflammatory effects, and thus might be suggested as a cytoprotective compound against UV-induced metabolic changes in skin cells. Therefore, the aim of this study was to investigate the level of protective CBD activity by evaluating the proteomic profile of 2D and 3D cultured skin fibroblasts models following exposure to UVA and UVB radiation. The CBD cytoprotective effect against UV-induced damage in 2D and 3D cultured fibroblasts were different. The main alterations focus on the range of cell reaction and involved different proteins associated with various molecular functions. In the 2D cultured cells, following UV radiation, the major changes were associated with proteins involved in antioxidant response and inflammation, while, in the 3D cultured fibroblasts, CBD action against UV induced changes were mainly associated with the activation of signalling pathways. Therefore, the knowledge of the CBD action in a multilayer skin cells model allowed for the prediction of changes in cell-cell interactions and skin cell metabolism. Knowledge about the lower protective effect of CBD in 3D cultured fibroblasts should be taken into account during the design of UV light protection.
... Several up-regulated proteins have been documented in a model of optic nerve transection regulating apoptotic pathways . Similarly, p38 MAPK activation has been implicated as an upstream of caspase mediator developing RGC injury in different experimental models of glaucoma, including optic nerve axotomy, ocular hypertension, and excitotoxic injury (Kikuchi et al., 2000, Manabe and Lipton, 2003, Harada et al., 2006, Levkovitch-Verbin et al., 2007, El-Remessy et al., 2008. Furthermore, recent reports describe the inhibition of p38 as a therapeutic target in filtering glaucoma surgery in rabbits (Nassar et al., 2015) and axonal dysfunction models (Dapper et al., 2013). ...
Glaucoma is a common cause of visual impairment and blindness, characterized by retinal ganglion cell (RGC) death. The mechanisms that trigger the development of glaucoma remain unknown and have gained significant relevance in the study of this neurodegenerative disease. P2X7 purinergic receptors (P2X7R) could be involved in the regulation of the synaptic transmission and neuronal death in the retina through different pathways. The aim of this study was to characterize the molecular signals underlying glaucomatous retinal injury. The time-course of functional, morphological, and molecular changes in the glaucomatous retina of the DBA/2J mice were investigated. The expression and localization of P2X7R was analysed in relation with retinal markers. Caspase-3, JNK, and p38 were evaluated in control and glaucomatous mice by immunohistochemical and western-blot analysis. Furthermore, electroretinogram recordings (ERG) were performed to assess inner retina dysfunction. Glaucomatous mice exhibited changes in P2X7R expression as long as the pathology progressed. There was P2X7R overexpression in RGCs, the primary injured neurons, which correlated with the loss of function through ERG measurements. All analyzed MAPK and caspase-3 proteins were upregulated in the DBA/2J retinas suggesting a pro-apoptotic cell death. The increase in P2X7Rs presence may contribute, together with other factors, to the changes in retinal functionality and the concomitant death of RGCs. These findings provide evidence of possible intracellular pathways responsible for apoptosis regulation during glaucomatous degeneration.
... Experimental autoimmune uveoretinitis (EAU) is another model for the investigation of ocular inflammatory response [52,144]. Within these two uveitis models, secretion of proinflammatory cytokines is thought to play an important role resulting in damage to ocular tissue [52,142]. Regarding the effects of AR on inflammatory responses, many studies using macrophages demonstrated that pharmacological inhibition or genetic ablation of AR attenuates LPS-induced cytokines secretion, oxidative stress and cell migration by suppressing MMP-9 and NF-κB activation [36][37][38][39][40]. ...
... In the eye, retinal microglia (RMG) are one of the major immune cells that participate in surveillance in retinal environment. While they are typically located in the inner and outer plexiform layers in a healthy condition [145,146], in uveitis they become activated [147] leading to morphological transformation [142] and migration into the outer nuclear layer (photoreceptor layer) where they secrete cytokines and peroxynitrites [144,146]. In vitro studies using primary cells showed that RMG can be activated by LPS exposure [40,148] and such activation can be suppressed by addition of an AR inhibitor or in mice lacking the functional allele of the AR gene [40]. ...
Aldose reductase (AR) is an NADPH-dependent aldo-keto reductase that has been shown to be involved in the pathogenesis of several blinding diseases such as uveitis, diabetic retinopathy (DR) and cataract. However, possible mechanisms linking the action of AR to these diseases are not well understood. As DR and cataract are among the leading causes of blindness in the world, there is an urgent need to explore therapeutic strategies to prevent or delay their onset. Studies with AR inhibitors and gene-targeted mice have demonstrated that the action of AR is also linked to cancer onset and progression. In this review we examine possible mechanisms that relate AR to molecular signaling cascades and thus explain why AR inhibition is an effective strategy against colon cancer as well as diseases of the eye such as uveitis, cataract, and retinopathy.
