“Corticosteroid and endocannabinoid actions converge on prefrontocortical circuits associated with neuropsychiatric illnesses. Corticosteroids can also modulate forebrain synapses by using endocannabinoid effector systems…
Altogether, corticosteroids are unlikely to exert direct non-genomic presynaptic neuromodulation in the frontal cortex, but they may do so indirectly, via the stimulation of trans-synaptic endocannabinoid signaling.”
“Cannabinoid compounds usually produce biphasic effects in the modulation of emotional responses.
Low doses of the endocannabinoid anandamide (AEA) injected into the dorsolateral periaqueductal gray matter (dlPAG) induce anxiolytic-like effects via CB1 receptors activation.
However, at higher doses the drug loses this effect, in part by activating Transient Receptor Potential Vanilloid Type 1 (TRPV1).
Activation of these latter receptors could induce the formation of nitric oxide (NO). Thus, the present study tested the hypothesis that at high doses AEA loses it anxiolytic-like effect by facilitating, probably via TRPV1 receptor activation, the formation of NO.
…these results support the hypothesis that intra-dlPAG injections of high doses of AEA lose their anxiolytic effects by favoring TRPV1 receptors activity and consequent NO formation, which in turn could facilitate defensive responses.”
“Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in traditional and recreational medicine.
The plant and constituents were central in the discovery of the endocannabinoid system, the most new target for drug discovery.
The endocannabinoid system includes two G protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana’s psychoactive principle ∆(9)-tetrahydrocannabinol (∆9-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the proteins for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).
The endocannabinoid system has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer.
Targeting the CB1 receptors become a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzyme by phytocannabinoids obtained from non-cannabis plant lacking psychotropic adverse reactions has garnered interest in drug discovery.
These pCBs derived from plants beyond cannabis appear safe and effective with a wider access and availability.
In recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development in cancer therapeutics.
Several of them also target the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize, critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics.”
“Inflammation plays a pivotal role in the pathogenesis of many diseases in the central nervous system.
Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders.
2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and the true natural ligand for CB1 receptors, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in hippocampus.
In the present study, we discovered that 2-AG significantly protects CN neurons in culture against lipopolysaccharide (LPS)-induced inflammatory response.
Our study suggests the therapeutic potential of 2-AG for the treatment of some inflammation-induced neurological disorders and pain.”
“Homocysteine (Hcy) is a high risk factor for Alzheimer’s disease (AD). Caudate nucleus (CN), the major component of basal ganglia in the brain, is also involved in many neurological disorders.
2-Arachidonoylglycerol (2-AG), the true natural ligand for cannabinoid type-1 (CB1) receptors and the most abundant endogenous cannabinoid, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in the hippocampus and CN.
In the present work, we explored that 2-AG significantly protects CN neurons in culture against Hcy-induced response.
2-AG is capable of inhibiting elevation of Hcy-induced cyclooxygenase-2 expression associated with nuclear factor-kappaB/p38MAPK/ERK1/2 signaling pathway through CB1 receptors-dependent way in primary cultured CN neurons.
Our study reveals the therapeutic potential for 2-AG for the treatment of neurodegenerative diseases, such as AD.”
“Homocysteine (Hcy) is an important risk factor for Alzheimer’s disease (AD) and other neurodegenerative diseases. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders.
2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid, has been shown to exhibit neuroprotective effects from many stimuli in the central nervous system (CNS).
Furthermore, it has been reported that voltage-gated sodium channels (VGSCs) are the common targets of many neuronal damages and drugs.
However, it is still not clear whether VGSCs are involved in the neurotoxicity of Hcy and the neuroprotective effect of 2-AG in CN neurons. In the present study, whole-cell patch clamp recording was used to invest the action of Hcy on sodium currents in primary cultured rat CN neurons and its modulation by 2-AG.
The results showed that in cultured CN neurons, pathological concentration of Hcy (100 μM) significantly increased the voltage-gated sodium currents (I Na) and produced a hyperpolarizing shift in the activation-voltage curve of I Na.
The further data demonstrated 2-AG is capable of suppressing elevation of Hcy-induced increase in I Na and hyperpolarizing shift of activation curves most partly through CB1 receptor-dependent way.
Our study provides a better understanding of Hcy-associated neurological disorders and suggests the therapeutic potential for 2-AG for the treatment of these diseases.”
“Emerging evidence indicated that anandamide (AEA) stimulated vasorelaxation in both spontaneously hypertensive rats (SHRs) and L-NAME-induced hypertensive rats. Yet it remains unknown whether AEA modulates vasomotion of aorta in renovascular hypertensive (RVH) rats.
The aim of present study was to explore the effect of AEA on relaxation of thoracic aortas in two-kidney one-clip (2K1C)-induced RVH rats.
Taken together, the present study demonstrated that AEA enhanced endothelium-dependent aortic relaxation through activation of both CB1 and CB2 receptors and P-eNOS/NO pathway in 2K1C rats.”
“Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options.
Marijuana and its derivatives have been used in medicine for many centuries.
…cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture and in laboratory animals.
Indeed, we have recently demonstrated that the endocannabinoid anandamide (AEA) has antiproliferative effects on cholangiocarcinoma cell lines in vitro via a cannabinoid receptor-independent pathway involving the stabilization of lipid raft-membrane structures and the recruitment of death-receptor complexes into the lipid rafts.
Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment.
The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.
We propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA, would prove beneficial for the treatment of this devastating disease.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2604798/
“Cholangiocarcinomas are devastating cancers of intrahepatic and extrahepatic origin that are increasing in both their worldwide incidence and mortality rates.
Conventional chemotherapy and radiation therapy are not effective in prolonging long-term survival; therefore it is important to understand the cellular mechanisms of cholangiocarcinoma cell growth with a view to develop novel chemopreventive strategies.
We have recently demonstrated that the endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) exert opposing effects on cholangiocarcinoma cell growth in vitro via cannabinoid receptor-independent mechanisms.
AEA increased presenilin 1 expression and recruitment into the γ-secretase complex whereas 2-AG increased expression and recruitment of presenilin 2.
The development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.
We propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for the treatment of this devastating disease.”
“Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options…
Marijuana and its derivatives have been used in medicine for many centuries, and presently there is an emerging renaissance in the study of the therapeutic effects of cannabinoids…
In addition, cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture and in laboratory animals.
Modulation of the endocannabinoid system is being targeted to develop possible therapeutic strategies for a number of cancers; therefore, we evaluated the effects of the two major endocannabinoids, anandamide and 2-arachidonylglycerol, on numerous cholangiocarcinoma cell lines…
These findings suggest that modulation of the endocannabinoid system may be a target for the development of possible therapeutic strategies for the treatment of this devastating cancer.
Consistent with our observation that AEA has antiproliferative and proapoptotic properties, cannabinoids of various origins (endogenous, plant-derived, or synthetic analogues) have been shown to suppress cancer cell growth in vitro as well as in vivo.
In conclusion, we have clearly demonstrated opposing actions of the endocannabinoids AEA and 2-AG on cholangiocarcinoma cell proliferation and have shown that these actions are via a cannabinoid receptor-independent but lipid raft-mediated pathway. Furthermore we have shown that the antiproliferative/proapoptotic actions of AEA are mediated via an accumulation of ceramide and the recruitment of the Fas death receptor into the lipid rafts. Cholangiocarcinoma has a very poor prognosis and survival rate; therefore we propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA would prove beneficial for the treatment of this devastating disease.”