Feb 3, Here, we summarize the current status quo of in vivo effects of CBD in established .. that CBD may be able to reduce iNOS protein expression and NO release as a However, CBD did not influence TNF-α gene expression. Jan 14, The antinociceptive effects of CBD were associated with less of an NF-κB and its consequences, e.g. expression of ICAM-1, iNOS, VCAM species generation, inducible nitric-oxide synthase expression, nitrotyrosine formation . Here, we have studied the effects of CBD on cisplatin- induced.
has effect expression of iNOS CBD the on no
In acute inflammation and experimental chronic pain, it has had a beneficial effect upon edema and hyperalgesia 17 , Considering the bowel loops inflammation and the immaturity of the myenteric plexus that occur in fetal GS 19 , 20 , our aim was to evaluate the effect of maternal administration of CBD in an experimental rat model of the disease. Female Sprague - Dawley rats were submitted to mating.
The following morning, a vaginal swab was performed and the presence of sperm marked day zero of pregnancy time of gestation, 22 days. Surgery was performed at The abdominal cavity was opened by median laparotomy in 2 layers. Fetuses were counted from the uterine isthmus, and GS was created on the second fetus of each horn according to the technique described by Correia-Pinto et al. The lower body of the fetus was exposed and a right para-umbilical laparotomy with standardized extension of 5 mm was performed, opening the fetal abdominal cavity with caution not to damage the umbilical vessels and liver.
The bowel loops were gently exposed by the delicate compression of the fetal abdomen with cotton swabs. After creating the defect, the fetus was carefully placed back into the uterine cavity, and a previously placed purse string suture closed the uterus. CBD was provided in powder form with The concentration was based on previous studies in rat neonates and adapted to this model CBD was administrated in the pregnant rat by ip injection on Pregnant rats were submitted to harvesting on day Fetuses were removed, weighed, and dissected to harvest the ileum.
The intestinal segment was removed from ileum until the proximal colon, approximately 2 cm. For weight analysis, the whole intestine was considered wet weight. Twelve fields per slide were analyzed in a total of 4 slides per group. Twelve fields per slide and four slides per group were analyzed by three blind investigators. The immunohistochemistry score was graded according to the intensity of staining from 0 to 4: The slides were deparaffinized in xylol and dehydrated with ethanol.
To avoid the process of tyrosine nitration and S-nitrosocysteine formation observed in biological samples submitted to slow freezing, we rapidly froze our samples in liquid nitrogen The software used was GraphPad Prism 6. Figure 1 shows macroscopical and microscopical differences of the bowel loop between G and GCBD groups.
A , Macroscopic view of the intestinal evisceration of the gastroschisis G group time of harvest. Note the different aspect and thickness of the bowel loop macroscopically and microscopically between the 2 groups. Masson's trichrome staining from ileum segment.
Results are shown in Figure 2. A , body weight BW; g. B , intestinal weight IW, g. Histometric analysis of the intestinal layers.
Immunohistochemistry score for iNOS expression and the histological transversal slides stained by immunohistochemistry. Maternal therapy with dexamethasone in a GS rat model showed reversion of intrauterine growth restriction IUGR , reduction of intestinal weight and mucosal thickness 3 , 5. Treatment with hydrogel associated to an NO donor covering the GS fetal bowel loops as well as low concentration release of NO in the amniotic fluid reduced morphological parameters and intestinal wall thickness 4 , Enteric glial cells actively mediate acute and chronic inflammation in the intestine promoting proliferation and release of neurotrophins, growth factors and pro-inflammatory chemokines that in turn may increase the immunological response, representing a very important link between the nervous and immune system in the intestine.
CBD is an interesting compound due to its capacity to control reactive gliosis in the central nervous system, without psychotropic effects and safe toxicological profile 15 , 28 , While the effect of CBD in IUGR in clinical and experimental fetuses is not well known, it has been demonstrated that longer exposure to CBF of the amniotic fluid worsens IUGR in an experimental model in rats 30 , which might be linked to fetal alterations responsible for glucose and insulin receptors modification by fetal inflammation Such modification could mean that CBD injection, even if intraperitoneal, in a control healthy organism in growth phase could have an effect on body mass gain, without the same effect seen in the GCBD group treated disease.
Additionally, blocking CB2 receptors slows skeleton elongation, which could explain body growth changes in the healthy newborns treated with CBD found in our research. At first, this could be an evidence that this treatment has no risk of impairment related to weight.
Such findings might demonstrate that CBD use resulted in benefits to the GCBD group with a potential reversion of the inflammatory reaction caused by the exposure of the bowels to the amniotic fluid.
Additionally, no significant difference was found between groups GCBD and C in any of the parameters. Therefore, the results of the morphological analysis demonstrated potential benefits induced by the treatment with CBD. Furthermore, the histometric analysis showed a reduction of the intestinal layer thickness in the GCBD group compared to the G group and had similar results to the other control groups.
The normality of this parameter of intestinal inflammation corroborates the hypothesis that CBD not only was effective in reducing the intestinal inflammation, but also did not cause any impairment to intestinal development. In addition, a study showed that inhibition of NOS was correlated with reduction of intestinal thickness and improvement of bowel loops macroscopic appearance of GS in chick embryos In the literature, the inhibiting effect of CBD over iNOS has previously been described in an in vivo model of neuroinflammation; mice that suffered beta-amyloid protein-induced neurological inflammation received treatment with intraperitoneal CBD and showed reduction of iNOS expression in relation to the non-treated diseased group A diabetes neuropathy study in rats suggests that NOS could have an inhibitory effect over cannabinoid receptor agonists.
According to the authors, the use of a specific nNOS inhibitor 7-Ni and a relatively selective inhibitor of iNOS L-NIL showed a positive impact over the analgesic effect of two cannabinoid receptors agonists.
Such finding suggests that CBD might not only modulate the expression and activity of NOS isoforms, but also have an inhibitory effect on the analgesia and anti-inflammatory pathways activated by cannabinoids agonists Compared to the non-aged controls, vehicle-treated aged mice demonstrated impaired cognition in the two-object recognition task.
AD is a debilitating neurodegenerative disease that is becoming increasingly common in today's society. Unfortunately, there is still no effective treatment that stops or reverses the disease progression. However, further dose-dependent investigations into transgenic mouse models of AD are necessary to understand the full potential and the long-term effects of CBD. Importantly, many of the discussed studies were conducted in mice aged between 3 and 6 months, which is quite young considering AD diagnosis is usually relatively late in the disease progression.
Furthermore, it is necessary to investigate the effects of CBD in tauopathy mouse models specific to AD and in female mouse models as all studies reviewed were conducted in male mice only. Nevertheless, the studies discussed here provide promising preliminary data and the translation of this preclinical work into the clinical setting could be realized relatively quickly: CBD is readily available, appears to only have limited side effects Bergamaschi et al.
TK and GW were both involved in the conceptualization, reference search, and writing of this mini review. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Cooper Limited Research Foundation. We thank Jerry Tanda for critical comments on the manuscript.
National Center for Biotechnology Information , U. Journal List Front Pharmacol v. Published online Feb 3. Author information Article notes Copyright and License information Disclaimer. This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology. Received Oct 12; Accepted Jan The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Alzheimer's disease AD is a debilitating neurodegenerative disease that is affecting an increasing number of people. The problem Alzheimer's Disease AD is a debilitating neurodegenerative disease that is characterized by cognitive decline.
Current treatments Despite the increase in our understanding of disease mechanism, the current approved AD treatments only provide limited therapeutic benefits. Cannabidiol The phytocannabinoid cannabidiol CBD is a prime candidate for this new treatment strategy.
Open in a separate window. CBD effects in transgenic mouse models of AD Although pharmacological models of AD are useful in producing AD-like symptoms, it is necessary to investigate the effects of CBD in transgenic mouse models as they result from gene mutations, which are seen in familial AD e. Conclusions AD is a debilitating neurodegenerative disease that is becoming increasingly common in today's society. Author contributions TK and GW were both involved in the conceptualization, reference search, and writing of this mini review.
Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Cannabinoids in late-onset Alzheimer's disease. Delineating the efficacy of a cannabis-based medicine at advanced stages of dementia in a murine model.
Cannabinoids for treatment of Alzheimer's disease: The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer's disease. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Genetic insights in Alzheimer's disease. The endocannabinoid system in normal and pathological brain ageing. Molecular targets for cannabidiol and its synthetic analogues: Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy.
Genes, models and Alzheimer's disease. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer's disease transgenic mice. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Endocannabinoid signalling and the deteriorating brain. Neuropharmacology 47 , — Animal models of Alzheimer's disease and frontotemporal dementia.
Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity. The amyloid hypothesis of Alzheimer's disease: Science , — Neurotoxicology 33 , — Multiple causes have been postulated, ranging from genetic components, environmental pollutants, infection, exposure to certain medicines and tobacco smoke.
Symptoms include progressive respiratory difficulty as the disease advances. Blood oxygenation levels gradually fall, initially in common activities and then even with the most minimal movements. This evolution is generally rapid, taking between some months and some years, but in some cases, it is much slower. Other symptoms include a generally dry cough, fatigue and fever.
When oxygenation levels fall, cyanosis appears i. As in other pulmonary conditions, clubbing of the fingers may occur. Pulmonary fibrosis with the loss of the fine lung vasculature eventually affects the heart as the result of an increase in pressure in the pulmonary arteries which the heart must overcome to pump blood to the lung for oxygenation.
Treatment is oriented towards relieving the symptoms and trying to delay evolution of the disease. Basically, two drugs are used which have been approved for treating IPF: As the disease advances, patients will require an oxygen supply at home and portable devices to provide oxygen wherever they go.
Respiratory rehabilitation and physiotherapy can help relieve the symptoms for a time. A lung transplant may be considered in some cases. A study was presented at the ICRS conference in Montreal in June , which I consider to be particularly important given the present state of our knowledge and the therapeutic possibilities for treating IPF.
At present, we have little to offer such patients, who have a very delicate prognosis. I found the study especially interesting as I have had two consultations regarding this disease. Patients quite often consult their physicians about the possibility of using additional cannabis-based treatments when their prognosis is unpromising and when treatment has proved either ineffective or has many adverse side effects.
My clinical reasoning had already led me to consider using cannabidiol, given its powerful anti-inflammatory action, despite the fact that assessments of anti-inflammatory treatment have not shown it to reduce the fibrotic response in this pathology this is probably because the mechanism whereby the fibrosis is activated does not appear to be a response to a triggering inflammatory process.
One group of American researchers have proposed the CB1 receptor as a therapeutic target for treating IPF in association with another therapeutic target to try to improve antifibrotic effectiveness Cinar R et al 1. Endocannabinoids acting by way of the CB1 receptor are known to promote fibrosis at a hepatic, cardiac and renal level and in radiation-induced pulmonary fibrosis. Given that the role of these compounds in IPF is unclear, the authors tried to identify its role in the complex and multifactorial pathogenesis of this disease, and hypothesised that it might be possible to improve the therapeutic effectiveness by addressing several of the mechanisms involved.
Inducible nitrous oxide synthase iNOS activity is increased in IPF and this increase correlates with the progress of the disease.
Inhibitors of this enzyme have shown to have an antifibrotic effect in animal models mice.
Idiopathic pulmonary fibrosis, the endocannabinoid system and cannabinoids
In this study, we have investigated the effects of cannabidiol (CBD) on myocardial .. (A) Expression of inducible nitric oxide synthase (iNOS) was determined by. species generation, inducible nitric-oxide synthase expression,. nitrotyrosine formation . Here, we have studied the effects of CBD on cisplatin-. induced. CBD (5 mg/kg) did not cause significant changes in the expression of COX-2 (Fig. appreciable detection of iNOS expression was observed in the colon of healthy The anti-inflammatory effect of CBD was found to be associated with the.