“Sustained administration of cannabinoid agonists acting on neuronal CB1 receptors (CB1Rs) are proposed for treating spasticity and chronic pain…
Our data suggest that CB1Rs may control the circuit gateway regulating the inflow of sensory afferent inputs into the locomotor circuits, indicating a potential site of action for restricting peripheral signals disruptive for locomotor activity.”
“Nearly 30 years after the discovery in 1964 of the psychoactive ingredient of cannabis (Cannabis sativa), Δ9-tetrahydrocannabinol, its endogenous counterparts were discovered and collectively termed endocannabinoids (eCBs): N-arachidonoylethanolamine (anandamide) in 1992 and 2-arachidonoylglycerol in 1995.
Since then, intense research has identified additional eCBs and an ensemble of proteins that bind, synthesize and degrade them, the so-called eCB system.
Altogether, these new compounds have been recognized as key mediators of several aspects of human pathophysiology, and in particular of female fertility.
Here, the main features of the eCB system are presented, in order to put in a better perspective the relevance of eCB signaling in virtually all steps of human reproduction and to highlight emerging hopes that elements of this system might indeed become novel targets to combat fertility problems.”
“Alcohol use disorder represents a significant human health problem that leads to substantial loss of human life and financial cost to society. Currently available treatment options do not adequately address this human health problem, and thus, additional therapies are desperately needed.
The endocannabinoid system has been shown, using animal models, to modulate ethanol-motivated behavior, and it has also been demonstrated that chronic ethanol exposure can have potentially long-lasting effects on the endocannabinoid system.
For example, chronic exposure to ethanol, in either cell culture or preclinical rodent models, causes an increase in endocannabinoid levels that results in down-regulation of the cannabinoid receptor 1 (CB1) and uncoupling of this receptor from downstream G protein signaling pathways.
Using positron emission tomography (PET), similar down-regulation of CB1 has been noted in multiple regions of the brain in human alcoholic patients.
In rodents, treatment with the CB1 inverse agonist SR141716A (Rimonabant), or genetic deletion of CB1 leads to a reduction in voluntary ethanol drinking, ethanol-stimulated dopamine release in the nucleus accumbens, operant self-administration of ethanol, sensitization to the locomotor effects of ethanol, and reinstatement/relapse of ethanol-motivated behavior.
Although the clinical utility of Rimonabant or other antagonists/inverse agonists for CB1 is limited due to negative neuropsychiatric side effects, negative allosteric modulators of CB1 and inhibitors of endocannabinoid catabolism represent therapeutic targets worthy of additional examination.”
“Lung cancer is the major cause of cancer-related mortality worldwide.
Many of these over-express epidermal growth factor receptor (EGFR), and are usually highly aggressive and resistant to chemotherapy.
Recent studies have shown that Δ-9 Tetrahydrocannabinol (THC), the major component of Cannabis sativa, possess anti-tumor properties against various types of cancers.
However, not much is known about its effect on lung cancer. In this study, we sought to characterize the effect of THC on EGF-induced growth and metastasis of human non small lung cancer cell (NSCLC) lines A549 and SW-1573.
We demonstrate that these cell lines and primary tumor samples derived from lung cancer patients express cannabinoids receptors CB1 and CB2, the known targets for THC action.
We further show that THC inhibits EGF-induced growth in these cell lines.
In addition THC attenuated EGF-stimulated chemotaxis and chemoinvasion.
Next we characterized the effect of THC on in vivo lung cancer growth and metastasis in a murine model. A549 cells were implanted in SCID mice (n=6 per group) through subcutaneous and intravenous injections to generate subcutaneous and lung metastatic cancer, respectively. THC (5mg/kg body wt.) was administered once daily through intraperitoneal injections for 21 days. The mice were analyzed for tumor growth and lung metastasis.
A significant reduction (~50%) in tumor weight and volume were observed in THC treated animals compared to the vehicle treated animals.
THC treated animals also showed a significant (~60%) reduction in macroscopic lesions on the lung surface in comparison to vehicle treated control.
Immunohistochemical analysis of the tumor samples from THC treated animals revealed anti-proliferative and anti-angiogenic effects of THC with significant reduction in staining for Ki67, a proliferative marker and CD31, an endothelial marker indicative of vascularization. Investigation into the signaling events associated with reduced EGF-induced functional effects revealed that THC also inhibits EGF-induced Akt phosphorylation. Akt is a central signaling molecule of EGFR-mediated signaling pathways and it regulates a diverse array of cellular functions, including proliferation, angiogenesis, invasion and apoptosis.
Cumulatively, these studies indicate that THC has anti-tumorigenic and anti-metastatic effects against lung cancer. Novel therapies against EGFR overexpressing, aggressive and chemotherapy resistant lung cancers may include targeting the cannabinoids receptors.”
http://cancerres.aacrjournals.org/content/67/9_Supplement/4749.short
“The global pandemic of HIV infection currently afflicts 34 million individuals, has killed over 25 million people since 1981, and is the cause of death in an estimated 1.8 million people per year.
Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients…
Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes.
Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model…
These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety of ways, acting principally through the CB2 receptors and microglia.
Overall, this study confirms that gp120 is capable of damaging human dopaminergic neurons, that this damage involves human microglia, and that synthetic cannabinoids can alleviate this damage through mechanisms involving human microglia.
Thus, the results of these experiments set the stage for further studies designed to tease out the role human microglia have in the mechanisms underlying the toxic effects of HIV-1 on human dopaminergic neurons and understanding the microglial-centered mechanisms underlying the protective effects of selected synthetic cannabinoids.”
“In our previous studies, we found that a single ultralow dose of tetrahydrocannabinol (THC)… protects the brain from different insults that cause cognitive deficits.
Because various insults may trigger a neuroinflammatory response that leads to secondary damage to the brain, the current study tested whether this extremely low dose of THC could protect the brain from inflammation-induced cognitive deficits…
Our results suggest that an ultralow dose of THC that lacks any psychotrophic activity protects the brain from neuroinflammation-induced cognitive damage and might be used as an effective drug for the treatment of neuroinflammatory conditions, including neurodegenerative diseases.”
“Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of Δ9-tetrahydrocannabinol (Δ9-THC) inhibited viral replication and intestinal inflammation and slowed disease progression…
These results support a role for differential miRNA induction in THC-mediated suppression of intestinal inflammation. Whether similar miRNA modulation occurs in other tissues requires further investigation.
Gastrointestinal (GI) tract disease/inflammation is a hallmark of HIV/SIV infection.
Previously, we showed that chronic treatment of SIV-infected macaques with Δ9-tetrahydrocannabinol (Δ9-THC) increased survival and decreased viral replication and infection-induced gastrointestinal inflammation.
Here, we show that chronic THC administration to SIV-infected macaques induced an anti-inflammatory microRNA expression profile in the intestine…
Overall, our results show that selective upregulation of anti-inflammatory miRNA expression contributes to THC-mediated suppression of gastrointestinal inflammation and maintenance of intestinal homeostasis.”
“Somatostatin (SST), a growth hormone inhibitory peptide, is expressed in different parts of the brain and functions as a neurotransmitter and neuromodulator. In the central nervous system (CNS), SST inhibits Ca2+ influx and regulates neuronal excitability in the hippocampus, the brain region which plays a major role in seizure, as well as cognitive and memory function.
Much like SST, cannabinoid receptor 1 (CB1 receptor) is also widely distributed in the CNS, associated with memory function ad exerts inhibitory effects on seizure.
It is unknown whether overlapping functional activities of SST and CB1 receptor are also associated with coexpression in the hippocampus.
In the present study, we determined the colocalization between SST and CB1 receptor in adult rat brain hippocampus. In the CNS, the majority of SST positive interneurons coexpress neuronal nitric oxide synthase (nNOS). Accordingly, colocalization studies were also performed to determine whether nNOS positive neurons display comparable colocalization with CB1 receptor.
The findings suggested that SST and nNOS are expressed in most interneurons whereas CB1 receptor is present in both interneurons and projection neurons in hippocampal regions. The distinct neuronal populations either expressing CB1 receptor, SST and nNOS alone or colocalization were observed in a region specific manner.
Taken together, the observations described here anticipate the possibility of crosstalk between somatostatin subtypes and CB1 receptor in regulation of physiological activities in the hippocampus.”
“Activation of cannabinoid receptor-2 (CB2) results in β-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception.
Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists.”
“Cannabinoids appear to be of therapeutic value as antiemetics, antispasmodics, analgesics and appetite stimulants and may have potential uses in epilepsy, glaucoma and asthma.
This paper reviews the clinical trials which have been carried out with cannabinoids including Δ⁹-tetrahydrocannabinol (THC) and synthetic cannabinoids such as nabilone and levonantradol, and discusses the advantages and adverse effects of cannabinoids in clinical use.
The place of cannabinoids in modern medicine remains to be properly evaluated, but present evidence suggests that they could be valuable, particularly as adjuvants, for symptom control in a range of conditions for which standard drugs are not fully satisfactory.”