“Cannabinoid receptors hold a core position in the brain and control memory, cognition, movement, and pain sensitivity. sn-2 arachidonoylglycerol (2-AG) activates neuronal cannabinoid receptors as a full agonist. The brain may rely on circulating arachidonic acid to synthesize endogenous cannabinoids. This Editorial highlights a study by Martin and coworkers in the current issue of the Journal of Neurochemistry in which the authors describe, for the first time, that liver acts as a pool of arachidonic acid that under certain conditions feeds the brain to produce endocannabinoids. Therapeutics affecting liver FABP1 levels should take into account that FABP1 represents a fatty acid reservoirs for the brain. Read the highlighted article “FABP-1 gene ablation impacts brain endocannabinoid system in male mice”” http://www.ncbi.nlm.nih.gov/pubmed/27329821
Tag Archives: agonists
The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells.
“Neuroendocrine (NE) differentiation represents a common feature of prostate cancer and is associated with accelerated disease progression and poor clinical outcome. Nowadays, there is no treatment for this aggressive form of prostate cancer.
The aim of this study was to determine the influence of the cannabinoid WIN 55,212-2 (WIN, a non-selective cannabinoid CB1 and CB2 receptor agonist) on the NE differentiation of prostate cancer cells.
Taken together, we demonstrate that PI3K/Akt/AMPK might be an important axis modulating NE differentiation of prostate cancer that is blocked by the cannabinoid WIN, pointing to a therapeutic potential of cannabinoids against NE prostate cancer.”
Pharmacological hypothermia: a potential for future stroke therapy?
“Mild physical hypothermia after stroke has been associated with positive outcomes.
Pharmacologically induced hypothermia has been explored as a possible treatment option following stroke in animal models.
Currently, there are eight classes of pharmacological agents/agonists with hypothermic effects affecting a multitude of systems including cannabinoid, opioid, transient receptor potential vanilloid 1 (TRPV1), neurotensin, thyroxine derivatives, dopamine, gas, and adenosine derivatives.
This review offers the opinion that these agents may be useful in combination therapies with physical hypothermia to achieve faster and more stable temperature control in hypothermia.”
Cannabinoid receptor agonism suppresses tremor, cognition disturbances and anxiety-like behaviors in a rat model of essential tremor.
“Cognitive and motor disturbances are serious consequences of tremor induced by motor disorders. Despite a lack of effective clinical treatment, some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of tremor.
In the current study, the effects of WIN55, 212-2 (WIN), a cannabinoid receptor (CBR) agonist, on harmaline-induced motor and cognitive impairments was studied.
The neuroprotective and anxiolytic effects of WIN demonstrated in the current study can be offered cannabinoid receptor (CBR) agonism as a potential neuroprotective agent in the treatment of patients with tremor that manifest mental dysfunctions.”
Inhibition of autophagy and enhancement of endoplasmic reticulum stress increase sensitivity of osteosarcoma Saos-2 cells to cannabinoid receptor agonist WIN55,212-2.
“WIN55,212-2, a cannabinoid receptor agonist, can activate cannabinoid receptors, which has proven anti-tumour effects in several tumour types. Studies showed that WIN can inhibit tumour cell proliferation and induce apoptosis in diverse cancers.
However, the role and mechanism of WIN in osteosarcoma are still unclear. In this study, we examined the effect of WIN55,212-2 on osteosarcoma cell line Saos-2 in terms of cell viability and apoptosis. Meanwhile, we further explored the role of endoplasmic reticulum stress and autophagy in apoptosis induced by WIN55,212-2.
Our results showed that the cell proliferation of Saos-2 was inhibited by WIN55,212-2 in a dose-dependent and time-dependent manner. WIN55,212-2-induced Saos-2 apoptosis through mitochondrial apoptosis pathway. Meanwhile, WIN55,212-2 can induce endoplasmic reticulum stress and autophagy in Saos-2 cells. Inhibition of autophagy and enhancement of endoplasmic reticulum stress increased apoptosis induced by WIN55,212-2 in Saos-2 cells.
These findings indicated that WIN55,212-2 in combination with autophagic inhibitor or endoplasmic reticulum stress activator may shed new light on osteosarcoma treatment.”
CB2 Cannabinoid Receptor As Potential Target against Alzheimer’s Disease.
“The CB2 receptor is one of the components of the endogenous cannabinoid system, a complex network of signaling molecules and receptors involved in the homeostatic control of several physiological functions. Accumulated evidence suggests a role for CB2 receptors in Alzheimer’s disease (AD) and indicates their potential as a therapeutic target against this neurodegenerative disease.
Levels of CB2 receptors are significantly increased in post-mortem AD brains, mainly in microglia surrounding senile plaques, and their expression levels correlate with the amounts of Aβ42 and β-amyloid plaque deposition.
Moreover, several studies on animal models of AD have demonstrated that specific CB2 receptor agonists, which are devoid of psychoactive effects, reduce AD-like pathology, resulting in attenuation of the inflammation associated with the disease but also modulating Aβ and tau aberrant processing, among other effects.
CB2 receptor activation also improves cognitive impairment in animal models of AD.
This review discusses available data regarding the role of CB2 receptors in AD and the potential usefulness of specific agonists of these receptors against AD.”
Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning.
“Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported.
To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice.
Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition.
Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions.
Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear.”
Cannabinoid receptor 2 as anti-obesity target: inflammation, fat storage and browning modulation.
“Obesity is associated with a low-grade inflammatory state, and adipocyte hyperplasia/hypertrophy.
Obesity inhibits the “browning” of white adipose tissue.
Cannabinoid receptor 2 (CB2) agonists reduce food intake and induce anti-obesity effect in mice.
CB2 receptor is a novel pharmacological target that should be considered for obesity.”
Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2
“We have previously shown that cannabinoids induce growth inhibition and apoptosis in prostate cancer PC-3 cells, which express high levels of cannabinoid receptor types 1 and 2 (CB1 and CB2). In this study, we investigated the role of CB2 receptor in the anti-proliferative action of cannabinoids and the signal transduction triggered by receptor ligation.
This study defines the involvement of CB2-mediated signalling in the in vivo and in vitro growth inhibition of prostate cancer cells and suggests that CB2 agonists have potential therapeutic interest and deserve to be explored in the management of prostate cancer.
Cannabinoids, the active components of Cannabis sativa and their derivatives, exert a wide spectrum of modulatory actions and pharmacological activities in the brain as well as in the periphery, and therefore, the therapeutic potential of cannabinoids has gained much attention during the past few years. One of the most exciting areas of current research in the therapeutic potential of cannabinoids is cancer.
Recent evidence suggests that cannabinoids are powerful regulators of cell growth and differentiation. They have been shown to exert anti-tumoural effects by decreasing viability, proliferation, adhesion and migration on various cancer cells, thereby suggesting the potential use of cannabinoids in the treatment of gliomas, prostate and breast cancers and malignancies of immune origin.
Overall, our data show a role for the cannabinoid receptor CB2 in the anti-tumour effect of cannabinoids on prostate cells in vitroand in vivo. There is considerable interest in the application of selective CB2 receptor agonists, which are devoid of typical marijuana-like psychoactive properties of CB1 agonists, for future cannabinoid-based anticancer therapies. Therefore, our findings point to the potential application of cannabinoid receptor type 2 ligands as anti-tumour agents in prostate cancer.”
Activation of cannabinoid CB1 receptors in the ventral hippocampus improved stress-induced amnesia in rat.
“The ventral hippocampus (VH) has a high distribution of cannabinoid CB1 receptors which are important in modulating stress responses. Stress exposure activates the hypothalamic-pituitary-adrenal axis (HPA) which can impact hippocampal formation to change hippocampus-based memories.
The purpose of the present study was to determine the possible role of the VH cannabinoid CB1 receptors in stress-induced amnesia using a step-through passive avoidance procedure in male Wistar rats.
Taken together, it can be concluded that exposure to post-training inescapable stress impaired memory consolidation. The impairing effects of stress on memory retrieval may be mediated by the VH cannabinoid CB1 receptors.”