Activation of the cannabinoid CB2 receptor increases renal perfusion.

Physiological Genomics 0 0 cover image

“Acute kidney injury (AKI) is an increasing problem clinically and is associated with chronic kidney disease progression.

Cannabinoid type 2 receptor activation has been shown to mitigate some of the deleterious tubular effects due to AKI, but its role on the renal vasculature has not been fully described.

In this study, we investigated the effects of our novel cannabinoid CB2 receptor agonist, SMM-295, on renal vasculature by assessing cortical perfusion using laser Doppler flowmetry and changes in luminal diameter using isolated afferent arterioles.

These data provide new insight into the potential benefit of SMM-295 by activating vascular and non-vascular CB2 receptors to promote renal vasodilation, and provide a new therapeutic target to treat renal injuries that impact renal blood flow dynamics.”

Is cannabidiol the ideal drug to treat non-motor Parkinson’s disease symptoms?

 “Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rest tremor, postural disturbances, and rigidity. PD is also characterized by non-motor symptoms such as sleep disturbances, cognitive deficits, and psychiatric disorders such as psychosis, depression, and anxiety. The pharmacological treatment for these symptoms is limited in efficacy and induce significant adverse reactions, highlighting the need for better treatment options.

Cannabidiol (CBD) is a phytocannabinoid devoid of the euphoriant and cognitive effects of tetrahydrocannabinol, and preclinical and preliminary clinical studies suggest that this compound has therapeutic effect in non-motor symptoms of PD.

In the present text, we review the clinical studies of cannabinoids in PD and the preclinical and clinical studies specifically on CBD.

We found four randomized controlled trials (RCTs) involving the administration of agonists/antagonists of the cannabinoid 1 receptor, showing that these compounds were well tolerated, but only one study found positive results (reductions on levodopa-induced dyskinesia).

We found seven preclinical models of PD using CBD, with six studies showing a neuroprotective effect of CBD.

We found three trials involving CBD and PD: an open-label study, a case series, and an RCT. CBD was well tolerated, and all three studies reported significant therapeutic effects in non-motor symptoms (psychosis, rapid eye movement sleep behaviour disorder, daily activities, and stigma). However, sample sizes were small and CBD treatment was short (up to 6 weeks). Large-scale RCTs are needed to try to replicate these results and to assess the long-term safety of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/30706171

https://link.springer.com/article/10.1007%2Fs00406-019-00982-6

Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer.

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Cannabinoid extracts may have anticancer properties, which can improve cancer treatment outcomes.

The aim of this review is to determine the potentially utility of cannabinoids in the treatment of pancreatic cancer.

Results: Cannabinol receptors have been identified in pancreatic cancer with several studies showing in vitroantiproliferative and proapoptotic effects. The main active substances found in cannabis plants are cannabidiol (CBD) and tetrahydrocannabinol (THC). There effects are predominately mediated through, but not limited to cannabinoid receptor-1, cannabinoid receptor-2, and G-protein-coupled receptor 55 pathways. In vitro studies consistently demonstrated tumor growth-inhibiting effects with CBD, THC, and synthetic derivatives. Synergistic treatment effects have been shown in two studies with the combination of CBD/synthetic cannabinoid receptor ligands and chemotherapy in xenograft and genetically modified spontaneous pancreatic cancer models. There are, however, no clinical studies to date showing treatment benefits in patients with pancreatic cancer.

Conclusions: Cannabinoids may be an effective adjunct for the treatment of pancreatic cancer. Data on the anticancer effectiveness of various cannabinoid formulations, treatment dosing, precise mode of action, and clinical studies are lacking.”

“Endogenous cannabinoids, synthetic or cannabis extracted from plants, can reduce tumor invasion and growth, induce tumor cell death, and inhibit tumor angiogenesis via cannabinoid receptor or receptor-independent pathways. Cannabinoid receptors appear to be highly expressed in pancreatic cancer compared with normal pancreatic tissue. CBD and THC appear to have antiproliferative and proapoptotic effects.”

Cannabinoids and Bone Regeneration.

 Publication Cover“Bone is a complex tissue of the with unique properties such as high strength and regeneration capabilities while carrying out multiple functions. Bone regeneration occurs both in physiological situations (bone turnover) and pathological situations (e.g. fractures), being performed by osteoblasts and osteoclasts. If this process is inadequate, fracture nonunion or aseptic loosening of implants occurs and requires a complex treatment.

Exogenous factors are currently used to increase bone regeneration process when needed, such as bisphosphonates and vitamin D, but limitations do exist. Cannabinoid system has been shown to have positive effects on bone metabolism. Cannabinoids at bone level mainly act on two receptors called CB-1 and CB-2, but GPR55, GPR119, TPRV1, TPRV4 receptors may also be involved. The CB-2 receptors are found in bone cells at higher levels compared to other receptors.

Endocannabinods represented by anandamide and 2-arachidonoylglycerol, can stimulate osteoblast formation, bone formation and osteoclast activity. CB-2 agonists including HU-308, HU-433, JWH133 and JWH015 can stimulate osteoblast proliferation and activity, while CB-2 antagonists such as AM630 and SR144528 can inhibit osteoclast differentiation and function. CB-1 antagonist AM251 has been shown to inhibit osteoclast differentiation and activity, while GPR55 antagonist cannabidiol increases osteoblast activity and decreases osteoclast function.

An optimal correlation of dose, duration, moment of action and affinity can lead to an increased bone regeneration capacity, with important benefits in many pathological situations which involve bone tissue. As adverse reactions of cannabinoids haven’t been described in patients under controlled medication, cannabinoids can represent future treatment for bone regeneration.”

https://www.ncbi.nlm.nih.gov/pubmed/30702341

https://www.tandfonline.com/doi/abs/10.1080/03602532.2019.1574303?journalCode=idmr20

Diet-Induced Obesity in Cannabinoid-2 Receptor Knockout Mice and Cannabinoid Receptor 1/2 Double-Knockout Mice.

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“Evidence suggests that cannabinoid-1 receptor (CB1R) activation is associated with increased food intake and body weight gain. Human epidemiological studies, however, show decreased prevalence of obesity in cannabis users.

Given the overlapping and complementary functions of the cannabinoid receptors (CB1R and CB2R), mice lacking CB2R and mice lacking both CB1R and CB2R were studied.

These results indicate that lacking both CB1R and CB2R protected mice from diet-induced obesity, possibly through the prominent role of CB1R in obesity or through an interactive effect of both receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/30699233

https://onlinelibrary.wiley.com/doi/abs/10.1002/oby.22403

Cannabinoid Ligands Targeting TRP Channels.

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“Many diseases involve Transient receptor potential (TRP) channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be “ionotropic cannabinoid receptors.””

https://www.ncbi.nlm.nih.gov/pubmed/30697147

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00487/full

[Endogenous Cannabinoid System of the Brain as the Target for Influences at Neurodegenerate Diseases]

“The review represents the analysis of works about role of endogenous cannabinoid (EC) system in the neuro- degenerate diseases (ND), in which the cellular death and disturbances of neuronal functions of the hippo- campus, neocortex and striatum are observed. Here, the diseases.ofAlzheimer, of Parkinson, of Hangtington, and the temporal lobe epilepsy are considered. In recent years the fundamental role of EC system in regu- lation of neuroexcitability, energy metabolism, inflammatory and many other processes has been opened in ND pathogenesis. It points to possibility of development of therapeutic approaches which use the prepara- tions for activation of EC system. In the review various mechanisms of cellular survival and their reparations provided to EC system during action of pathological factors are stated.”

https://www.ncbi.nlm.nih.gov/pubmed/30695519

Dark Classics in Chemical Neuroscience: Δ9-Tetrahydrocannabinol.

 ACS Chemical Neuroscience

“Cannabis (Cannabis sativa) is the most widely used illicit drug in the world, with an estimated 192 million users globally.

The main psychoactive component of cannabis is (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), a molecule with a diverse range of pharmacological actions. The unique and distinctive intoxication caused by Δ9-THC primarily reflects partial agonist action at central cannabinoid type 1 (CB1) receptors.

Δ9-THC is an approved therapeutic treatment for a range of conditions, including chronic pain, chemotherapy-induced nausea and vomiting, and is being investigated in indications such as anorexia nervosa, agitation in dementia, and Tourette’s syndrome.

It is available as a regulated pharmaceutical in products such as Marinol®, Sativex®, and Namisol®, as well as in an ever-increasing range of unregistered medicinal and recreational cannabis products.

While cannabis is an ancient medicament, contemporary use is embroiled in legal, scientific, and social controversy, much of which relates to the potential hazards and benefits of Δ9-THC itself.

Robust contemporary debate surrounds the therapeutic value of Δ9-THC in different diseases, its capacity to produce psychosis and cognitive impairment, and the addictive and “gateway” potential of the drug.

This review will provide a profile of the chemistry, pharmacology, toxicology, and recreational and therapeutic uses of Δ9-THC, as well as the historical and societal importance of this unique, distinctive, and ubiquitous psychoactive substance.”

https://www.ncbi.nlm.nih.gov/pubmed/30689342

https://pubs.acs.org/doi/10.1021/acschemneuro.8b00651

Targeting CB1 and GPR55 Endocannabinoid Receptors as a Potential Neuroprotective Approach for Parkinson’s Disease.

 “Cannabinoid CB1 receptors (CB1R) and the GPR55 receptor are expressed in striatum and are potential targets in the therapy of Parkinson’s disease (PD), one of the most prevalent neurodegenerative diseases in developed countries.

The aim of this paper was to address the potential of ligands acting on those receptors to prevent the action of a neurotoxic agent, MPP+, that specifically affects neurons of the substantia nigra due to uptake via the dopamine DAT transporter.

These results show that neurons expressing heteromers are more resistant to cell death but question the real usefulness of CB1R, GPR55, and their heteromers as targets to afford PD-related neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/30687889

https://link.springer.com/article/10.1007%2Fs12035-019-1495-4

Indazolylketones as new multitarget cannabinoid drugs.

European Journal of Medicinal Chemistry

“Multitarget cannabinoids could be a promising therapeutic strategic to fight against Alzheimer’s disease.

In this sense, our group has developed a new family of indazolylketones with multitarget profile including cannabinoids, cholinesterase and BACE-1 activity. A medicinal chemistry program that includes computational design, synthesis and in vitro and cellular evaluation has allowed to us to achieve lead compounds.

In this work, the synthesis and evaluation of a new class of indazolylketones have been performed. Pharmacological evaluation includes functional activity for cannabinoid receptors on isolated tissue. In addition, in vitro inhibitory assays in AChE/BuChE enzymes and BACE-1 have been carried out. Furthermore, studies of neuroprotective effects in human neuroblastoma SH-SY5Y cells and studies of the mechanisms of survival/death in lymphoblasts of patients with Alzheimer’s disease have been achieved.

The results of pharmacological tests have revealed that some of these derivatives (5, 6) behave as CB2 cannabinoid agonists and simultaneously show BuChE and/or BACE-1 inhibition.”

https://www.ncbi.nlm.nih.gov/pubmed/30685536

https://www.sciencedirect.com/science/article/pii/S0223523419300406?via%3Dihub