Kinetics of acetylcholinesterase inhibition by hemp seed protein-derived peptides.

Journal of Food Biochemistry banner“The aim of this work was to enhance the acetylcholinesterase (AChE)-inhibitory activity of a pepsin-produced hemp seed protein hydrolysates (HPH) through reverse-phase HPLC separation followed by identification of peptide sequences present in the most active fraction. The HPH was separated into eight fractions (F1-F8) with F7 exhibiting significantly (p < 0.05) the strongest (97.5%) in vitro inhibition of electric eel AChE (eeAChE) activity in comparison to 53.8% for HPH. The HPH consisted mostly of low molecular weight peptides of < 11 amino acid residues and most contained at least one hydrophobic amino acid. Kinetics of enzyme inhibition revealed a mixed-type inhibition of eeAChE activity by HPH whereas F7 acted through an uncompetitive mode; in contrast inhibition of human AChE by HPH and F7 was uncompetitive. The stronger inhibitory potency of the F7 peptides fraction against both enzymes was confirmed through reduced maximal velocity, catalytic efficiency, and inhibition constant values when compared to the HPH.

PRACTICAL APPLICATIONS: The use of natural products for the prevention or treatment of human diseases continues to be an area of intense research activities. Food protein-derived peptides obtained through enzymatic hydrolysis of hemp seed proteins were shown in vitro to be strong inhibitors of activities of both the eel and human forms of acetylcholinesterase (AChE). AChE is an important therapeutic target because excessive activity of this enzyme is a causative factor of neurodegenerative diseases such as dementia and Alzheimer’s. This work showed that peptides in the most active fraction are small in sizes, which may favor their absorption into blood circulation and possible permeation of the blood-brain barrier. Therefore, the hemp seed peptides are potential agents that can be used to formulate functional foods and nutraceuticals against neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/31353736

https://onlinelibrary.wiley.com/doi/abs/10.1111/jfbc.12897

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Cannabinoids for Treating Cardiovascular Disorders: Putting Together a Complex Puzzle.

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“Cannabinoids have been increasingly gaining attention for their therapeutic potential in treating various cardiovascular disorders. These disorders include myocardial infarction, hypertension, atherosclerosis, arrhythmias, and metabolic disorders.

The aim of this review is to cover the main actions of cannabinoids on the cardiovascular system by examining the most recent advances in this field and major literature reviews.

It is well recognized that the actions of cannabinoids are mediated by either cannabinoid 1 or cannabinoid 2 receptors (CB2Rs). Endocannabinoids produce a triphasic response on blood pressure, while synthetic cannabinoids show a tissue-specific and species-specific response.

Blocking cannabinoid 1 receptors have been shown to be effective against cardiometabolic disorders, although this should be done peripherally. Blocking CB2Rs may be a useful way to treat atherosclerosis by affecting immune cells. The activation of CB2Rs was reported to be useful in animal studies of myocardial infarction and cardiac arrhythmia.

Although cannabinoids show promising effects in animal models, this does not always translate into human studies, and therefore, extensive clinical studies are needed to truly establish their utility in treating cardiovascular disease.”

https://www.ncbi.nlm.nih.gov/pubmed/30464888

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LH-21, A Peripheral Cannabinoid Receptor 1 Antagonist, Exerts Favorable Metabolic Modulation Including Antihypertensive Effect in KKAy Mice by Regulating Inflammatory Cytokines and Adipokines on Adipose Tissue.

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“Patients with obesity are susceptible to hypertension and diabetes. Over-activation of cannabinoid receptor 1 (CB1R) in adipose tissue is proposed in the pathophysiology of metabolic disorders, which led to the metabolic dysfunction of adipose tissue and deregulated production and secretion of adipokines.

In the current study, we determined the impact of LH-21, a representative peripheral CB1R antagonist, on the obesity-accompanied hypertension and explored the modulatory action of LH-21 on the adipose tissue in genetically obese and diabetic KKAy mice.

3-week LH-21 treatment significantly decreased blood pressure with a concomitant reduction in body weight, white adipose tissue (WAT) mass, and a slight loss on food intake in KKAy mice. Meanwhile, glucose handling and dyslipidemia were also markedly ameliorated after treatment. Gene expression of pro-inflammatory cytokines in WAT and the aortae were both attenuated apparently by LH-21, as well the mRNA expression of adipokines (lipocalin-2, leptin) in WAT. Concomitant amelioration on the accumulation of lipocalin-2 was observed in both WAT and aortae. In corresponding with this, serum inflammatory related cytokines (tumor necrosis factor α, IL-6, and CXCL1), and lipocalin-2 and leptin were lowered notably.

Thus according to current results, it can be concluded that the peripheral CB1R antagonist LH-21 is effective in managing the obesity-accompanied hypertension in KKAy mice. These metabolic benefits are closely associated with the regulation on the production and secretion of inflammatory cytokines and adipokines in the WAT, particularly alleviated circulating lipocalin-2 and its accumulation in aortae.”

https://www.ncbi.nlm.nih.gov/pubmed/29731737

https://www.frontiersin.org/articles/10.3389/fendo.2018.00167/full

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[The impact of cannabinoids on the endocrine system].

 

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“Cannabinoids are naturally occurring compounds, derivatives of Indian hemp, in which tetrahydrocannabinol (THC) is the most important. Marijuana, hashish and hash oil are among those most commonly used in the group.

Cannabinoids (marjhuana and hashish) have been used throughout recorded history as effective drugs in treating various diseases and conditions such as: malaria, hypertension, constipation, bronchial asthma, rheumatic pains, and as natural pain relief in labour and joint pains.

Marijuana acts through cannabinoid receptors CB 1 and CB2. Both receptors inhibit cAMP accummulation (through Gi/o proteins) and stimulate mitrogen- activated protein kinase. CB1 rceptors are located in CNS and in adipose tissue, digestive tract, muscles, heart, lungs, liver, kidneys, gonads, prostate gland and other peripheral tissues. CB2 cannabinoid receptors are located in the peripheral nervous system (at the ends of peripheral nerves), and on the surfaces of the cells of the immunological system.

The discovery of endogenous cannabinoids has contributed to a better understanding of their role in the regulation of the intake of food, energetic homeostasis and their significant influence on the endocrine system.”

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Role of cannabinoid receptor type 1 in rostral ventrolateral medulla in high-fat diet-induced hypertension in rats.

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“Stimulation of cannabinoid type 1 (CB1) receptor in the rostral ventrolateral medulla (RVLM) increases renal sympathetic activity (RSNA) and blood pressure (BP) in rats. Thus, we hypothesized that CB1 receptor in the RVLM may play a critical role in the development of obesity-induced hypertension.

METHODS:

To this end, we evaluated the levels of endocannabinoids and CB1 receptors in the RVLM in high-fat diet (HFD)-induced hypertensive rats. We then used pharmacological and molecular methods to examine the role of RVLM CB1 receptors in regulation of BP, heart rate (HR), and RSNA in obesity-induced hypertensive rats.

RESULTS:

We found that HFD-fed rats exhibited higher basal BP, HR, and RSNA than standard diet-fed rats, which were associated with increased levels of endocannabinoids and CB1 receptor expression in the RVLM. Furthermore, unilateral intra-RVLM microinjections of AM251 (0, 100, or 500 nM/0.5 μl/site) dose-dependently decreased BP, HR, and RSNA to a greater extent in HFD-fed rats than in standard diet-fed rats. Finally, siRNA-mediated knockdown of CB1 receptor expression in the RVLM robustly decreased BP, HR, and RSNA in HFD-fed rats.

CONCLUSION:

Taken together, our results suggested that enhanced CB1 receptor-mediated neurotransmissions in the RVLM may play a role in the development of obesity-induced hypertension.”

https://www.ncbi.nlm.nih.gov/pubmed/29493561

https://insights.ovid.com/crossref?an=00004872-201804000-00015

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The endocannabinoid system in cardiovascular function: novel insights and clinical implications.

Clinical Autonomic Research

“Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility, and endothelial vasomotor control. Growing evidence from animal studies supports the significance of the eCB system in cardiovascular disorders.

RESULTS:

Drugs targeting CB1R, CB2R, TRPV1 and PPARs are proven effective in animal models mimicking cardiovascular disorders such as hypertension, atherosclerosis and myocardial infarction. Despite the setback of two clinical trials that exhibited unexpected harmful side-effects, preclinical studies are accelerating the development of more selective drugs with promising results devoid of adverse effects.

CONCLUSION:

Over the last years, increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function. Whereas new discoveries are paving the way for the identification of novel drugs and therapeutic targets, the close cooperation of researchers, clinicians and pharmaceutical companies is needed to achieve successful outcomes.”

https://www.ncbi.nlm.nih.gov/pubmed/29222605

https://link.springer.com/article/10.1007%2Fs10286-017-0488-5

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ACPA and JWH-133 modulate the vascular tone of superior mesenteric arteries through cannabinoid receptors, BKCa channels, and nitric oxide dependent mechanisms.

Pharmacological Reports

“Some cannabinoids, a family of compounds derived from Cannabis sativa (marijuana), have previously shown vasodilator effects in several studies, a feature that makes them suitable for the generation of a potential treatment for hypertension.

The mechanism underlying this vasodilator effect in arteries is still controversial. In this report, we explored how the synthetic cannabinoids ACPA (CB1-selective agonist) and JWH-133 (CB2-selective agonist) regulate the vascular tone of rat superior mesenteric arteries.

CB1 and CB2 receptor activation in superior mesenteric artery causes vasorelaxation by mechanisms involving BKCachannels and NO release.”

https://www.ncbi.nlm.nih.gov/pubmed/29128791

http://www.sciencedirect.com/science/article/pii/S1734114017300361?via%3Dihub

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New ACE inhibitory peptides from hemp seed (Cannabis sativa L.) proteins.

Journal of Agricultural and Food Chemistry

“An hemp seed protein isolate, prepared from defatted hemp seed meals by alkaline solubilization/acid precipitation, was subjected to extensive chemical hydrolysis under acid conditions (6 M HCl). The resulting hydrolysate was fractionated by semipreparative RP-HPLC and the purified fractions were tested as inhibitors of angiotensin converting enzyme (ACE). Mono- and bi-dimensional NMR experiments and LC-MS/MS analyses led to the identification of four potentially bioactive peptides, i.e. GVLY, IEE, LGV, and RVR. They were prepared by solid-phase synthesis, and tested for ACE-inhibitory activity. The IC50 values were GVLY 16 ± 1.5 µM, LGV 145 ± 13 µM, and RVR 526 ± 33 µM, confirming that hemp seed may be a valuable source of hypotensive peptides.”

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A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study.

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“Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans.

CONCLUSIONS:

This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR. These hemodynamic changes should be considered for people taking CBD. Further research is required to establish whether CBD has a role in the treatment of cardiovascular disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28614793

“Our data show that a single dose of CBD reduces resting blood pressure and the blood pressure response to stress. This may reflect the anxiolytic and analgesic effects of CBD, as well as any potential direct cardiovascular effects. CBD has multiple desirable effects on the cardiovascular system” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470879/

https://insight.jci.org/articles/view/93760

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A Systematic Review and Meta-Analysis of the Haemodynamic Effects of Cannabidiol

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“Cannabidiol (CBD) is the second most abundant phytocannabinoid, after Δ9-tetrahydrocannabinol (THC) and was first isolated from the cannabis extract in 1940.

Given the increasing clinical use of CBD, and the numerous effects of CBD in the cardiovascular system, the aim of the present study was to systematically review and analyse in vivo studies evaluating the effects of CBD on alterations in haemodynamics.

From the limited data available, we conclude that acute and chronic administration of CBD had no effect on BP or HR under control conditions, but reduces BP and HR in stressful conditions, and increases cerebral blood flow (CBF) in mouse models of stroke.

This meta-analysis and systematic review has highlighted the haemodynamic effects of CBD administration in vivo.

The positive effects induced by CBD include maintaining the fall in BP after global hypoxia, reducing the increase in MBP and HR post-stress, and increasing BF in ischaemia-reperfusion models.

It is possible that beneficial effects of CBD on haemodynamics occurs when the cardiovascular system is abnormally altered, suggesting that CBD may be used as a treatment for various cardiovascular disorders, such as hypertension, myocardial infarction and stroke.”

http://journal.frontiersin.org/article/10.3389/fphar.2017.00081/full

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