Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells

Posted on February 26, 2017 by David

“While cannabinoids have been shown to ameliorate liver fibrosis, their effects in chronic pancreatitis and on pancreatic stellate cells (PSC) are unknown.

The activity of the endocannabinoid system was evaluated in human chronic pancreatitis (CP) tissues.

Augmentation of the endocannabinoid system via exogenously administered cannabinoid receptor agonists specifically induces a functionally and metabolically quiescent pancreatic stellate cell phenotype and may thus constitute an option to treat inflammation and fibrosis in chronic pancreatitis.

Because drugs for the treatment of chronic pancreatitis should ideally exert anti-fibrotic and anti-inflammatory properties, their bimodal effects rather contradict a therapeutic use of CB-receptor antagonists and promote the hypothesis that (re-)activation of the (endo-)cannabinoid system in chronic pancreatitis may be beneficial for suppressing disease progress.

In conclusion, we show that the endocannabinoid system is downregulated in chronic pancreatitis and that its augmentation via exogenously administered cannabinoids specifically reduces activation of pancreatic stellate cells.

These experiments lay a basis for testing the value of synthetic cannabinoids in the treatment of chronic pancreatitis.”

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001701

Inhibition of pancreatic oxidative damage by stilbene derivative dihydro-resveratrol: implication for treatment of acute pancreatitis

Posted on February 26, 2017 by David

Image result for nature scientific reports

“Trans-resveratrol is a natural stilbenoid possessing multifarious pharmacological benefits; however, when orally consumed, it is rapidly metabolised by colonic microflora and converted to dihydro-resveratrol. Thus, this microbial metabolite is of great therapeutic relevance.

Trans-resveratrol (trans-3,5,4′-trihydroxystilbene) is a natural phenolic derivative of the stilbenoid family found in skins of red grapes, berries and peanuts. As a renowned antioxidant used in a number of preclinical and clinical studies, its remarkable antioxidant activities are often related to its nature as a potent Sirtuin1 activator.

Aside from being detected as a colonic metabolite of trans-resveratrol, dihydro-resveratrol is indeed produced by a number of plant species including Orchidaceae and Cannabis sativa L. as a phytoalexin against abiotic and biotic stress factors.

In the present study, we aimed to examine whether dihydro-resveratrol, as a remedial agent, attenuates oxidative damage in pancreatic tissues of rats with cerulein-induced acute pancreatitis and to delineate its underlying molecular actions.

Collectively, the current findings accentuate new mechanistic insight of dihydro-resveratrol in pancreatic oxidative damage, and advocate its therapeutic potential for the management of acute pancreatitis, particularly for patients unresponsive to trans-resveratrol due to the lack of proper microbial strains.

In conclusion, we suggest that dihydro-resveratrol may serve as a therapeutic or an adjuvant agent for the management of acute pancreatitis, in particular to patients who have microbial restriction in metabolizing trans-resveratrol and received unresponsiveness.”

http://www.nature.com/articles/srep22859

Cannabinoids and Cystic Fibrosis

Posted on February 26, 2017 by David

“Cannabis stimulates appetite and food intake. This property has been exploited to benefit AIDS and cancer patients suffering from wasting disease, by administering the whole plant or its major active ingredient ?-tetrahydrocannabinol (THC). Endogenous cannabinoids (“endocannabinoids”) are found in maternal milk. We have recently shown that endocannabinoids are critical for milk ingestion and survival of newborns because blocking CB1 receptors resulted in death from malnutrition. Lack of appetite resulting in malnutrition is a contributing factor to mortality in many Cystic Fibrosis (CF) patients. It is proposed here for the first time, to administer THC to CF patients. It is hoped that the cannabinoid will alleviate malnutrition and thus help prevent wasting in CF patients. Recent findings suggest that a lipid imbalance (high arachidonic acid/low DHA) is a primary factor in the etiology of CF and that defective CFTR (CF transmembrane conductor regulator) that characterizes the CF condition is responsible for the dysregulation. Endocannabinoids are all fatty acid derivatives. Therefore, it is further proposed here that the CFTR gene product also modulates endocannabinoid synthesis, through regulation of fatty acid biosynthesis. According to this hypothesis, CF patients display decreased levels of endocannabinoids and by elevating these levels, symptoms may improve. Indeed, a number of physiological mechanisms of cannabinoids and endocannabinoids coincide with the pathology of CF. Thus it is suggested that potential benefits from THC treatment, in addition to appetite stimulation, will include antiemetic, bronchodilating, anti-inflammatory, anti-diarrheal and hypo-algesic effects.” https://www.researchgate.net/publication/233294071_Cannabinoids_and_Cystic_Fibrosis

“Cannabinoids and Cystic Fibrosis. A Novel Approach to Etiology and Therapy” http://www.tandfonline.com/doi/abs/10.1300/J175v02n01_03

Improved Social Interaction, Recognition and Working Memory with Cannabidiol Treatment in a Prenatal Infection (poly I:C) Rat Model.

Posted on February 24, 2017 by David

Image result for neuropsychopharmacology journal

“Neuropsychiatric disorders such as schizophrenia are associated with cognitive impairment, including learning, memory and attention deficits. Antipsychotic drugs are limited in their efficacy to improve cognition; therefore, new therapeutic agents are required.

Cannabidiol (CBD), the non-intoxicating component of cannabis, has anti-inflammatory, neuroprotective and antipsychotic-like properties, however, its ability to improve the cognitive deficits of schizophrenia remains unclear. Using a prenatal infection model, we examined the effect of chronic CBD treatment on cognition and social interaction.

CBD treatment significantly improved recognition, working memory and social interaction deficits in the poly I:C model, did not affect total body weight gain, food or water intake, and had no effect in control animals.

In conclusion, chronic CBD administration can attenuate the social interaction and cognitive deficits induced by prenatal poly I:C infection.

These novel findings present interesting implications for potential use of CBD in treating the cognitive deficits and social withdrawal of schizophrenia.”

https://www.ncbi.nlm.nih.gov/pubmed/28230072

Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons

Posted on February 23, 2017 by David

fx1

“Deficient bioenergetics and diminished redox conservation have been implicated in the development of cerebral ischemia/reperfusion injury.

In this study, the mechanisms underlying the neuroprotective effects of cannabidiol (CBD), a nonpsychotropic compound derived from Cannabis sativa with FDA-approved antiepilepsy properties, were studied in vitro using an oxygen–glucose-deprivation/reperfusion (OGD/R) model in a mouse hippocampal neuronal cell line.

This study is the first to document the neuroprotective effects of CBD against OGD/R insult, which depend in part on attenuating oxidative stress, enhancing mitochondrial bioenergetics, and modulating glucose metabolism via the pentose-phosphate pathway, thus preserving both energy and the redox balance.

Cannabidiol (CBD) is a nonpsychoactive cannabinoid derived from Cannabis sativa and a weak CB1 and CB2 cannabinoid receptor antagonist, with very low toxicity for humans. It has recently been demonstrated in vivo and in vitro that CBD has a variety of therapeutic properties, exerting antidepressant, anxiolytic, anti-inflammatory, immunomodulatory, and neuroprotective effects. Our results provide novel insight into the neuroprotective properties of CBD, which involves the regulation of the mitochondrial bioenergetics and the glucose metabolism of hippocampal neurons during OGD/R injury.

In summary, our results suggest that CBD exerts a potent neuroprotective effect against ischemia/reperfusion injury by attenuating intracellular oxidative stress, enhancing mitochondrial bioenergetics, and optimizing glucose metabolism via the pentose-phosphate pathway, thus strengthening the antioxidant defenses and preserving the energy homeostasis of neurons. More in-depth studies are required to investigate the precise mechanism underlying the success of CBD treatment and to determine the actual role of CBD in cerebral ischemia.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247568/

“Cannabidiol may soon be used in the emergency room to fight effects of stroke and cardiac emergencies” http://www.naturalnews.com/2017-02-21-cannabidiol-may-soon-be-used-in-the-emergency-room-to-fight-effects-of-stroke-cardiac-emergencies.html

Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice.

Posted on February 22, 2017 by David

Image result for Mol Psychiatry

“Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood.

The use of antipsychotics and benzodiazepines against CIAPS is limited by side effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed.

Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy.

The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Δ⁹-tetrahydrocannabinol (THC), the main psychoactive component of cannabis.

We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS.” https://www.ncbi.nlm.nih.gov/pubmed/28220044

“Pregnenolone can protect the brain from cannabis intoxication. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057431/

Acetylcholinesterase inhibitors in Alzheimer’s disease

Posted on February 22, 2017 by David

“Alzheimer’s Disease (AD) is the most common single cause of dementia in our ageing society. On full assessment and diagnosis of AD, initiation of an AChe inhibitor is recommended as early as possible, it is important that AChe inhibitor therapy is considered for patients with mild to moderate AD.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014378/

“Characterization of Lignanamides from Hemp (Cannabis sativa L.) Seed and Their Antioxidant and Acetylcholinesterase Inhibitory Activities. Hempseed is known for its content in fatty acids, proteins and fiber, which contribute to its nutritional value. Lignanamides 2, 7, 9-14 showed good antioxidant activity among which 7, 10 and 13 also inhibited acetylcholinesterase in vitro. The new identified compounds in this study added to the diversity of hempseed composition and the bioassays implied that hempseed, with lignanamides as nutrients, may be a good source of bioactive and protective compounds.” http://www.ncbi.nlm.nih.gov/pubmed/26585089

“The Effects of Hempseed Meal Intake and Linoleic Acid on Drosophila Models of Neurodegenerative Diseases and Hypercholesterolemia. Our results indicate that hempseed meal (HSM) and linoleic acid are potential candidates for the treatment of Alzheimer’s disease (AD) and cardiovascular disease. These results show that HSM may prove of great utility as a health food, with potential for the prevention of AD and cardiovascular disease.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933972/

In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer’s Disease.

Posted on February 22, 2017 by David

“Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is affecting an increasing number of people. It is characterized by the accumulation of amyloid-β and tau hyperphosphorylation as well as neuroinflammation and oxidative stress.

Current AD treatments do not stop or reverse the disease progression, highlighting the need for new, more effective therapeutics.

Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has demonstrated neuroprotective, anti-inflammatory and antioxidant properties in vitro. Thus, it is investigated as a potential multifunctional treatment option for AD.

Here, we summarize the current status quo of in vivo effects of CBD in established pharmacological and transgenic animal models for AD.

The studies demonstrate the ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as to promote neurogenesis.

Importantly, CBD also reverses and prevents the development of cognitive deficits in AD rodent models.

Interestingly, combination therapies of CBD and Δ⁹-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone.

The studies provide “proof of principle” that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies.” https://www.ncbi.nlm.nih.gov/pubmed/28217094

“It is unlikely that any drug acting on a single pathway or target will mitigate the complex pathoetiological cascade leading to AD. Therefore, a multifunctional drug approach targeting a number of AD pathologies simultaneously will provide better, wider-ranging benefits than current therapeutic approaches. Importantly, the endocannabinoid system has recently gained attention in AD research as it is associated with regulating a variety of processes related to AD, including oxidative stress, glial cell activation and clearance of macromolecules. The phytocannabinoid cannabidiol (CBD) is a prime candidate for this new treatment strategy. CBD has been found in vitro to be neuroprotective, to prevent hippocampal and cortical neurodegeneration, to have anti-inflammatory and antioxidant properties, reduce tau hyperphosphorylation and to regulate microglial cell migration. Furthermore, CBD was shown to protect against Aβ mediated neurotoxicity and microglial-activated neurotoxicity, to reduce Aβ production by inducing APP ubiquination and to improve cell viability,. These properties suggest that CBD is perfectly placed to treat a number of pathologies typically found in AD. The studies provide “proof of principle” that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies.” http://journal.frontiersin.org/article/10.3389/fphar.2017.00020/full

http://www.thctotalhealthcare.com/category/alzheimers-disease-ad/

The potential for clinical use of cannabinoids in treatment of cardiovascular diseases.

Posted on February 20, 2017 by David

Image result for Cardiovascular Therapeutics

“Cannabinoids, the constituents of the marijuana plant and their analogs, have not only neurobehavioral but also cardiovascular effects. Great advances in the last couple of decades have led to better understanding of the physiological effects of the cannabinoids and of their role in various cardiovascular pathologies. The potential therapeutic use of cannabinoids in various cardiac diseases, such as ischemic injury, heart failure, and cardiac arrhythmias, has been studied in animal models. The purpose of this article is to review the physiological cardiovascular properties of cannabinoids and to summarize the knowledge related to their potential therapeutic use.” https://www.ncbi.nlm.nih.gov/pubmed/20946323

“Cannabinoid system as a potential target for drug development in the treatment of cardiovascular disease.” https://www.ncbi.nlm.nih.gov/pubmed/15320476

Brain cannabinoid systems as targets for the therapy of neurological disorders.

Posted on February 20, 2017 by David

Image result for Neurobiology of Disease

“Unprecedented developments in cannabinoid research within the past decade include discovery of a brain (CB1) and peripheral (CB2) receptor; endogenous ligands, anandamide, and 2-arachidonylglycerol; cannabinoid drug-induced partial and inverse agonism at CB1 receptors, antagonism of NMDA receptors and glutamate, and antioxidant activity; and preferential CB1 receptor localization in areas subserving spasticity, pain, abnormal involuntary movements, seizures, and amnesia. These endogenous structures and chemicals and mechanisms are potentially new pathophysiologic substrates, and targets for novel cannabinoid treatments, of several neurological disorders.” https://www.ncbi.nlm.nih.gov/pubmed/9974182

“Endocannabinoid System in Neurological Disorders.” https://www.ncbi.nlm.nih.gov/pubmed/27364363

“Cannabinoids in the Treatment of Neurological Disorders” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604187/