THC Total Health Care

A comprehensive encyclopedia of THC related medical research articles

Cannabidiol reduces lung injury induced by hypoxic-ischemic brain damage in newborn piglets.

Posted on April 8, 2017 by David Worrell

“Brain hypoxic-ischemic (HI) damage induces distant inflammatory lung damage in newborn pigs. We aimed to investigate the effects of cannabidiol (CBD) on lung damage in this scenario.

RESULTS:

CBD prevented HI-induced deleterious effects on TLC and OI and reduced lung histological damage, modulating inflammation (decreased leukocyte infiltration and IL-1 concentration) and reducing protein content in BALF and EVLW. These effects were related to CBD-induced anti-inflammatory changes in the brain. HI did not increase oxidative stress in the lungs. In the lungs, WAY100635 blunted CBD’s beneficial effects on histological damage, IL-1 concentration and EVLW.

CONCLUSIONS:

CBD reduced brain HI-induced distant lung damage, with 5-HT_1A receptor involvement in these effects. Whether CBD’s effects on lungs were due to anti-inflammatory effects on the brain or to direct effects on lungs remains to be elucidated.” https://www.ncbi.nlm.nih.gov/pubmed/28388598 “Hypoxic-ischemic brain injury is a diagnostic term that encompasses a complex constellation of pathophysiological and molecular injuries to the brain induced by hypoxia, ischemia, cytotoxicity, or combinations of these conditions. The typical causes of hypoxic-ischemic brain injury – cardiac arrest, respiratory arrest, near-drowning, near-hanging, and other forms of incomplete suffocation, carbon monoxide and other poisonous gas exposures, and perinatal asphyxia – expose the entire brain to potentially injurious reductions of oxygen (i.e., hypoxia) and/or diminished blood supply (ischemia).” http://www.internationalbrain.org/articles/hypoxicischemic-brain-injury/

“Hypoxic-ischemic brain damage induces distant inflammatory lung injury in newborn piglets.” https://www.ncbi.nlm.nih.gov/pubmed/25950454

“Cannabidiol reduces lung injury induced by hypoxic-ischemic brain damage in newborn piglets.” https://www.ncbi.nlm.nih.gov/pubmed/28388598

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Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.

Posted on April 8, 2017 by David Worrell

“The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a ‘peripherally’ restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN.

RESULTS.:

Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells.

CONCLUSION.:

‘Peripheral’ CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.” https://www.ncbi.nlm.nih.gov/pubmed/28387811]]>

Metabolic Syndrome Induced Bladder Cannabinoid Receptor Changes in the Fructose-Fed Rats.

Posted on April 8, 2017 by David Worrell

“To investigate the effect of metabolic syndrome on the bladder cannabinoid receptors 1 and 2 (CB1/CB2) expression and function in the fructose-fed rats (FR).

CONCLUSION:

CB1/CB2 receptors mediate rat bladder relaxation through the PKA and K_ATP pathway. The CB1 receptor may play a more prominent role. The response is decreased in the FR bladder due to reduced expressions of the cannabinoid receptors.” https://www.ncbi.nlm.nih.gov/pubmed/28386998]]>

Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice.

Posted on April 6, 2017 by David Worrell

“Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (-/-) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)-/- mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.” https://www.ncbi.nlm.nih.gov/pubmed/28380440

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Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus.

Posted on April 6, 2017 by David Worrell

“Phytocannabinoids, such as THC and endocannabinoids, are well known to promote feeding behavior and to control energy metabolism through cannabinoid type 1 receptors (CB₁R). However, the underlying mechanisms are not fully understood. Generally, cannabinoid-conducted retrograde dis-inhibition of hunger-promoting neurons has been suggested to promote food intake, but so far it has not been demonstrated due to technical limitations.

Our immunohistochemical and ultrastructural study demonstrates the morphological substrate for cannabinoid-conducted feeding behavior via retrograde dis-inhibition of hunger-promoting AgRP/NPY neurons.”

https://www.ncbi.nlm.nih.gov/pubmed/28377876

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Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.

Posted on April 6, 2017 by David Worrell

“Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered. The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance. In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant. Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine. Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.” https://www.ncbi.nlm.nih.gov/pubmed/28377074]]>

Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep.

Posted on April 5, 2017 by David Worrell

“A prior epidemiological study identified a reduction in opioid overdose deaths in US states that legalized medical cannabis (MC). One theory to explain this phenomenon is a potential substitution effect of MC for opioids. This study evaluated whether this substitution effect of MC for opioids also applies to other psychoactive medications. New England dispensary members ( n = 1,513) completed an online survey about their medical history and MC experiences. Among respondents that regularly used opioids, over three-quarters (76.7%) indicated that they reduced their use since they started MC. This was significantly ( p < 0.0001) greater than the patients that reduced their use of antidepressants (37.6%) or alcohol (42.0%). Approximately two-thirds of patients decreased their use of anti-anxiety (71.8%), migraine (66.7%), and sleep (65.2%) medications following MC which significantly ( p < 0.0001) exceeded the reduction in antidepressants or alcohol use. The patient’s spouse, family, and other friends were more likely to know about their MC use than was their primary care provider. In conclusion, a majority of patients reported using less opioids as well as fewer medications to treat anxiety, migraines, and sleep after initiating MC. A smaller portion used less antidepressants or alcohol. Additional research is needed to corroborate these self-reported, retrospective, cross-sectional findings using other data sources.” https://www.ncbi.nlm.nih.gov/pubmed/28372506

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Antihyperalgesic Activities of Endocannabinoids in a Mouse Model of Antiretroviral-Induced Neuropathic Pain.

Posted on April 5, 2017 by David Worrell

“Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstone of the antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). However, their use is sometimes limited by the development of a painful sensory neuropathy, which does not respond well to drugs. Smoked cannabis has been reported in clinical trials to have efficacy in relieving painful HIV-associated sensory neuropathy. The aim of this study was to evaluate whether the expression of endocannabinoid system molecules is altered during NRTI-induced painful neuropathy, and also whether endocannabinoids can attenuate NRTI-induced painful neuropathy. Conclusion: These data show that ddC induces thermal hyperalgesia, which is associated with dysregulation of the mRNA expression of some endocannabinoid system molecules. The endocannabinoids AEA and 2-AG have antihyperalgesic activity, which is dependent on cannabinoid receptor and GPR55 activation. Thus, agonists of cannabinoid receptors and GPR55 could be useful therapeutic agents for the management of NRTI-induced painful sensory neuropathy.” https://www.ncbi.nlm.nih.gov/pubmed/28373843]]>

Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS.

Posted on April 5, 2017 by David Worrell

“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system with limited therapeutic options. While an increasing number of ALS patients can be linked to a small number of autosomal-dominantly inherited cases, most cases are termed sporadic. Both forms are clinically and histopathologically indistinguishable, raising the prospect that they share key pathogenic steps, including potential therapeutic intervention points. The endocannabinoid system is emerging as a versatile, druggable therapeutic target in the CNS and its dysregulation is an early hallmark of neurodegeneration. Whether this is a defense mechanism or part of the pathogenesis remains to be determined. The neuroprotective and anti-inflammatory endocannabinoid 2-arachidonoylglycerol (2-AG), which is degraded by monoacylglycerol lipase (MAGL), accumulates in the spinal cords of transgenic models of ALS. We tested the hypothesis that this 2-AG increase is a protective response in the low-copy SOD1^G93A mouse model of ALS. We show that oral application of the MAGL inhibitor KML29 delays disease onset, progression and survival. Furthermore, we could demonstrate that KML29 reduced proinflammatory cytokines and increased brain-derived neurotrophic factor (BDNF) expression levels in the spinal cord, the major site of neurodegeneration in ALS. Moreover, treatment of primary mouse neurons and primary mousecroglia with 2-AG confirmed the neuroprotective and anti-inflammatory action by increasing BDNF and arginase-1 and decreasing proinflammatory cytokines in vitro. In summary, we show that elevating 2-AG levels by MAGL inhibition is a therapeutic target in ALS and demonstrate that the endocannabinoid defense mechanisms can be exploited therapeutically in neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pubmed/28373073]]>

Binding Site Characterization of AM1336, a Novel Covalent Inverse Agonist at Human Cannabinoid 2 Receptor, Using Mass Spectrometric Analysis.

Posted on April 5, 2017 by David Worrell

“Cannabinoid 2 receptor (CB2R), a Class A G-protein coupled receptor (GPCR), is a promising drug target in a wide array of pathological conditions. Rational drug design has been hindered due to our poor understanding of the structural features involved in ligand binding. Binding of a high-affinity biarylpyrazole inverse agonist AM1336 to a library of the human CB2 receptor (hCB2R) cysteine-substituted mutants provided indirect evidence that two cysteines in transmembrane helix-7 (H7) were critical for the covalent attachment. Here, we used proteomics analysis of the hCB2R with bound AM1336 to directly identify peptides with covalently attached ligand and applied in-silico modeling for visualization of the ligand-receptor interactions. The hCB2R, with affinity tags (FlaghCB2His6), was produced in a baculovirus-insect cell expression system and purified as a functional receptor using immunoaffinity chromatography. Using mass spectrometry-based bottom-up proteomic analysis of the hCB2R-AM1336 we identified a peptide with AM1336 attached to the cysteine C284(7.38) in H7. The hCB2R homology model in lipid bilayer accommodated covalent attachment of AM1336 to C284(7.38), supporting both biochemical and mass spectrometric data. This work consolidates proteomics data and in-silico modeling, and integrates with our ligand-assisted protein structure (LAPS) experimental paradigm to assist in structure-based design of cannabinoid antagonist/inverse agonists.” https://www.ncbi.nlm.nih.gov/pubmed/28374590

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