An Agathokakological tale of ∆9 -THC: Exploration of Possible Biological Targets

“∆ 9 -Tetrahydrocannabinol (∆9 -THC), the active phytocannabinoid in cannabis, is virtually an adjunct to the endogenous endocannabinoid signaling system.

By interacting with G-protein-coupled receptors CB1 and CB2, ∆9 -THC affects peripheral and central circulation by lowering sympathetic activity, altering gene expression, cell proliferation, and differentiation, decreasing leukocyte migration, modulating neurotransmitter release thereby modulating cardiovascular functioning, tumorigenesis, immune responses, behavioral and locomotory activities respectively.

∆ 9 -THC is effective in suppressing chemotherapy-induced vomiting, retards malignant tumor growth, inhibits metastasis, and promotes apoptosis. Other mechanisms involved are targeting cell cycle at the G2-M phase in human breast cancer, downregulation of E2F transcription factor 1 (E2F1) in human glioblastoma multiforme, and stimulation of ER stress-induced autophagy.

∆ 9 -THC also plays a role in ameliorating neuroinflammation, excitotoxicity, neuroplasticity, trauma, and stroke and is associated with reliving childhood epilepsy, brain trauma, and neurodegenerative diseases.

∆9 -THC via CB1 receptors affects nociception, emotion, memory, and reduces neuronal excitability and excitotoxicity in epilepsy. It also increases renal blood flow, reduces intraocular pressure via a sympathetic pathway, and modulates hormonal release, thereby decreasing the reproductive function and increasing glucose metabolism.

Versatile medical marijuana has stimulated abundant research demonstrating substantial therapeutic promise, suggesting the possibilities of first-in-class drugs in diverse therapeutic segments. In this review, we represent the current pharmacological status of the phytocannabinoid, ∆ 9 -THC, and synthetic analogs in cancer, cardiovascular, and neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/33001012/

https://www.eurekaselect.com/186455/article

A Cannabinoid Type 2 (CB2) Receptor Agonist Augments NOS-Dependent Responses of Cerebral Arterioles during Type 1 Diabetes

Microvascular Research “While activation of cannabinoid (CB2) receptors has been shown to be neuroprotective, no studies have examined whether this neuroprotection is directed at cerebral arterioles and no studies have examined whether activation of CB2 receptors can rescue cerebrovascular dysfunction during a chronic disease state such as type 1 diabetes (T1D).

Our goal was to test the hypothesis that administration of a CB2 agonist (JWH-133) would improve impaired endothelial (eNOS)- and neuronal (nNOS)- dependent dilation of cerebral arterioles during T1D.

In vivo diameter of cerebral arterioles in nondiabetic and T1D rats was measured in response to an eNOS-dependent agonist (adenosine 5′-diphosphate; ADP), an nNOS-dependent agonist (N-methyl-D-aspartate; NMDA), and an NOS-independent agonist (nitroglycerin) before and 1 hour following JWH-133 (1 mg/kg IP). Dilation of cerebral arterioles to ADP and NMDA was greater in nondiabetic than in T1D rats.

Treatment with JWH-133 increased responses of cerebral arterioles to ADP and NMDA in both nondiabetic and T1D rats. Responses of cerebral arterioles to nitroglycerin were similar between nondiabetic and T1D rats, and JWH-133 did not influence responses to nitroglycerin in either group. The restoration in responses to the agonists by JWH-133 could be inhibited by treatment with a specific inhibitor of CB2 receptors (AM-630; 3 mg/kg IP).

Thus, activation of CB2 receptors can potentiate reactivity of cerebral arterioles during physiologic and pathophysiologic states. We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular diseases via a mechanism that can increase cerebral blood flow.”

https://pubmed.ncbi.nlm.nih.gov/32979391/

“Activation of CB2 receptors improves cerebral vascular function. Activation of CB2 receptors improves responses in type 1 diabetes. We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular disease that can contribute to the pathogenesis of stroke.”

https://www.sciencedirect.com/science/article/pii/S0026286220301370?via%3Dihub

Cannabidiol and Oxygen-Ozone Combination Induce Cytotoxicity in Human Pancreatic Ductal Adenocarcinoma Cell Lines

cancers-logo“Pancreatic cancer (PC) is related to lifestyle risks, chronic inflammation, and germline mutations in BRCA1/2ATMMLH1TP53, or CDKN2A. Surgical resection and adjuvant chemotherapy are the main therapeutic strategies but are less effective in patients with high-grade tumors.

Oxygen-ozone (O2/O3) therapy is an emerging alternative tool for the treatment of several clinical disorders. O2/O3 therapy has been found to ameliorate mechanisms promoting chronic pain and inflammation, including hypoxia, inflammatory mediators, and infection.

The advantages of using cannabinoids have been evaluated in vitro and in vivo models of several human cancers. Regarding PDAC, activation of cannabinoid receptors was found to induce pancreatic cancer cell apoptosis without affecting the normal pancreas cells.

In a murine model of PDAC, a combination of cannabidiol (CBD) and gemcitabine increased survival length by nearly three times. Herein, we evaluate the anticancer effect of CBD and O2/O3, alone or in combination, on two human PDAC cell lines, PANC-1 and MiaPaCa-2, examining expression profiles of 92 pancreatic adenocarcinoma associated genes, cytotoxicity, migration properties, and cell death. Finally, we assess the combination effects with gemcitabine and paclitaxel.

Summarizing, for the first time the antitumoral effect of combined therapy with CBD and oxygen-ozone therapy in PDAC is evidenced.”

https://pubmed.ncbi.nlm.nih.gov/32992648/

https://www.mdpi.com/2072-6694/12/10/2774

Δ 9 -Tetrahydrocannabinol promotes oligodendrocyte development and CNS myelination in vivo

“Δ9 -Tetrahydrocannabinol (THC), the main bioactive compound found in the plant Cannabis sativa, exerts its effects by activating cannabinoid receptors present in many neural cells.

Cannabinoid receptors are also physiologically engaged by endogenous cannabinoid compounds, the so-called endocannabinoids. Specifically, the endocannabinoid 2-arachidonoylglycerol has been highlighted as an important modulator of oligodendrocyte (OL) development at embryonic stages and in animal models of demyelination. However, the potential impact of THC exposure on OL lineage progression during the critical periods of postnatal myelination has never been explored.

Here, we show that acute THC administration at early postnatal ages in mice enhanced OL development and CNS myelination in the subcortical white matter by promoting oligodendrocyte precursor cell cycle exit and differentiation. Mechanistically, THC-induced-myelination was mediated by CB1 and CB2 cannabinoid receptors, as demonstrated by the blockade of THC actions by selective receptor antagonists. Moreover, the THC-mediated modulation of oligodendroglial differentiation relied on the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, as mTORC1 pharmacological inhibition prevented the THC effects.

Our study identifies THC as an effective pharmacological strategy to enhance oligodendrogenesis and CNS myelination in vivo.”

https://pubmed.ncbi.nlm.nih.gov/32956517/

“In summary, our findings identify THC as a novel pharmacological candidate to enhance OL development and CNS myelination in vivo.”

https://onlinelibrary.wiley.com/doi/10.1002/glia.23911

Activation of Cannabinoid Receptor 2 Prevents Colitis-Associated Colon Cancer through Myeloid Cell De-activation Upstream of IL-22 Production

iScience journal (@iScience_CP) | Twitter
” Here we show that delta-9-tetrahydrocannabinol (THC) attenuates colitis-associated colon cancer and colitis induced by anti-CD40.
 THC can prevent the development of colitis-associated colon cancer in mice.”

“Study reveals how cannabinoids may be useful to prevent colon cancer”   https://medicalxpress.com/news/2020-09-reveals-cannabinoids-colon-cancer.html

“Key cannabis chemical may help prevent colon cancer, researchers say”   https://www.heraldmailmedia.com/news/nation/key-cannabis-chemical-may-help-prevent-colon-cancer-researchers-say/article_7afd0a72-eead-57f0-a1d3-006be62b7469.html

“Treatment with a cannabinoid prevented the development of colon cancers in mice” https://www.news-medical.net/news/20200915/Treatment-with-a-cannabinoid-prevented-the-development-of-colon-cancers-in-mice.aspx

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Druggable Targets in Endocannabinoid Signaling

 “Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide.

Since the discovery of Δ9-tetrahydrocannabinol (THC) as the primary psychoactive component of cannabis over 50 years ago, substantial effort has been directed toward detection of endogenous mediators of cannabinoid activity. The discovery of anandamide and 2-arachidonoylglycerol as two endogenous lipid mediators of cannabinoid-like effects (endocannabinoids) has inspired exponential growth in our understanding of this essential pathway, as well as the pathological conditions that result from dysregulated endocannabinoid signaling.

This review examines current knowledge of the endocannabinoid system including metabolic enzymes involved in biosynthesis and degradation and their receptors, and evaluates potential druggable targets for therapeutic intervention.”

https://pubmed.ncbi.nlm.nih.gov/32894511/

https://link.springer.com/chapter/10.1007%2F978-3-030-50621-6_8

It Is Our Turn to Get Cannabis High: Put Cannabinoids in Food and Health Baskets

molecules-logo“Cannabis is an annual plant with a long history of use as food, feed, fiber, oil, medicine, and narcotics. Despite realizing its true value, it has not yet found its true place. Cannabis has had a long history with many ups and downs, and now it is our turn to promote it.

Cannabis contains approximately 600 identified and many yet unidentified potentially useful compounds. Cannabinoids, phenolic compounds, terpenoids, and alkaloids are some of the secondary metabolites present in cannabis. However, among a plethora of unique chemical compounds found in this plant, the most important ones are phytocannabinoids (PCs).

Over hundreds of 21-22-carbon compounds exclusively produce in cannabis glandular hairs through either polyketide and or deoxyxylulose phosphate/methylerythritol phosphate (DOXP/MEP) pathways. Trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are those that first come to mind while talking about cannabis. Nevertheless, despite the low concentration, cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabinodiol (CBND), and cannabinidiol (CBDL) may have potentially some medical effects.

PCs and endocannabinoids (ECs) mediate their effects mainly through CB1 and CB2 receptors. Despite all concerns regarding cannabis, nobody can ignore the use of cannabinoids as promising tonic, analgesic, antipyretic, antiemetic, anti-inflammatory, anti-epileptic, anticancer agents, which are effective for pain relief, depression, anxiety, sleep disorders, nausea and vomiting, multiple sclerosis, cardiovascular disorders, and appetite stimulation.

The scientific community and public society have now increasingly accepted cannabis specifically hemp as much more than a recreational drug. There are growing demands for cannabinoids, mainly CBD, with many diverse therapeutic and nutritional properties in veterinary or human medicine. The main objective of this review article is to historically summarize findings concerning cannabinoids, mainly THC and CBD, towards putting these valuable compounds into food, feed and health baskets and current and future trends in the consumption of products derived from cannabis.”

https://pubmed.ncbi.nlm.nih.gov/32899626/

https://www.mdpi.com/1420-3049/25/18/4036

Cannabidiol as a Novel Therapeutic for Immune Modulation

 “The immune-suppressive effects of cannabidiol (CBD) are attributed to the modulation of essential immunological signaling pathways and receptors. Mechanistic understanding of the pharmacological effects of CBD emphasizes the therapeutic potential of CBD as a novel immune modulator.

Studies have observed that the antagonists of CB1 and CB2 receptors and transient receptor potential vanilloid 1 reverse the immunomodulatory effects of CBD. CBD also inhibits critical activators of the Janus kinase/signal transducer and activator of transcription signaling pathway, as well as the nucleotide-binding oligomerization domain-like receptor signaling pathway, in turn decreasing pro-inflammatory cytokine production. Furthermore, CBD protects against cellular damage incurred during immune responses by modulating adenosine signaling.

Ultimately, the data overwhelmingly support the immunosuppressive effects of CBD and this timely review draws attention to the prospective development of CBD as an effective immune modulatory therapeutic.”

https://pubmed.ncbi.nlm.nih.gov/32903924/

https://www.dovepress.com/cannabidiol-as-a-novel-therapeutic-for-immune-modulation-peer-reviewed-article-ITT

Endocannabinoid-Epigenetic Cross-Talk: A Bridge toward Stress Coping

ijms-logo“There is no argument with regard to the physical and psychological stress-related nature of neuropsychiatric disorders. Yet, the mechanisms that facilitate disease onset starting from molecular stress responses are elusive.

Environmental stress challenges individuals’ equilibrium, enhancing homeostatic request in the attempt to steer down arousal-instrumental molecular pathways that underlie hypervigilance and anxiety.

A relevant homeostatic pathway is the endocannabinoid system (ECS).

In this review, we summarize recent discoveries unambiguously listing ECS as a stress coping mechanism.

As stress evokes huge excitatory responses in emotional-relevant limbic areas, the ECS limits glutamate release via 2-arachydonilglycerol (2-AG) stress-induced synthesis and retrograde cannabinoid 1 (CB1)-receptor activation at the synapse. However, ECS shows intrinsic vulnerability as 2-AG overstimulation by chronic stress rapidly leads to CB1-receptor desensitization.

In this review, we emphasize the protective role of 2-AG in stress-response termination and stress resiliency. Interestingly, we discuss ECS regulation with a further nuclear homeostatic system whose nature is exquisitely epigenetic, orchestrated by Lysine Specific Demethylase 1.

We here emphasize a remarkable example of stress-coping network where transcriptional homeostasis subserves synaptic and behavioral adaptation, aiming at reducing psychiatric effects of traumatic experiences.”

https://pubmed.ncbi.nlm.nih.gov/32872402/

https://www.mdpi.com/1422-0067/21/17/6252

Distinctive Evidence Involved in the Role of Endocannabinoid Signalling in Parkinson’s Disease: A Perspective on Associated Therapeutic Interventions

ijms-logo“Current pharmacotherapy of Parkinson’s disease (PD) is symptomatic and palliative, with levodopa/carbidopa therapy remaining the prime treatment, and nevertheless, being unable to modulate the progression of the neurodegeneration. No available treatment for PD can enhance the patient’s life-quality by regressing this diseased state.

Various studies have encouraged the enrichment of treatment possibilities by discovering the association of the effects of the endocannabinoid system (ECS) in PD.

These reviews delineate the reported evidence from the literature on the neuromodulatory role of the endocannabinoid system and expression of cannabinoid receptors in symptomatology, cause, and treatment of PD progression, wherein cannabinoid (CB) signalling experiences alterations of biphasic pattern during PD progression.

Endocannabinoids regulate the basal ganglia neuronal circuit pathways, synaptic plasticity, and motor functions via communication with dopaminergic, glutamatergic, and GABAergic signalling systems bidirectionally in PD.

Further, gripping preclinical and clinical studies demonstrate the context regarding the cannabinoid compounds, which is supported by various evidence (neuroprotection, suppression of excitotoxicity, oxidative stress, glial activation, and additional benefits) provided by cannabinoid-like compounds (much research addresses the direct regulation of cannabinoids with dopamine transmission and other signalling pathways in PD).

More data related to endocannabinoids efficacy, safety, and pharmacokinetic profiles need to be explored, providing better insights into their potential to ameliorate or even regress PD.”

https://pubmed.ncbi.nlm.nih.gov/32872273/

https://www.mdpi.com/1422-0067/21/17/6235