The case for cannabinoid CB1 receptors as a target for bronchodilator therapy for β-agonist resistant asthma.

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“Although b2-receceptor agonists are powerful bronchodilators and are at the forefront of asthma symptom relief, patients who use them frequently develop partial resistance to them. This can be a particularly serious problem during severe attacks, where high dose b2-agonist treatment is the front line therapy.

Alternative bronchodilators are urgently needed. In this article we review the evidence for the bronchodilator effects of the cannabinoid CB1 receptor tetrahydrocannabinol (THC) and suggest that the mechanism of action for these effects are sufficiently independent of the mechanisms of standard bronchodilators to warrant clinical investigation.

Specifically, clinical trials testing the bronchodilator effects of THC in b2 agonist resistant asthmatic patients would show whether THC could fill the role of rescue bronchodilator in cases of b2 agonist resistance.”

Selective modulator of cannabinoid receptor type 2 (CB2) against biochemical alterations and brain damage in chronic cerebral hypoperfusion induced vascular dementia.

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“Vascular dementia is the second most common cause of cognitive decline in aged people but the effectual therapeutic target is still missing.

Chronic cerebral hypoperfusion (CCH) has been widely found in vascular dementia (VaD) patients. CCH is thought to link with neurodegenerative disorders and their subsequent cognitive impairment.

The present study has been framed to investigate the role of selective agonist of CB2 receptor (1-phenylisatin) in CCH induced VaD.

These results indicate that 2VO induced CCH in rats, which was attenuated with the treatment of 1-phenylisatin.

Hence, it may be suggested that modulation in cannabinoid receptor may provide benefits in CCH as cognitive impairment and VaD.

Therefore, pharmacological positive modulation of CB2 receptors may be a potential research target for alleviation of VaD.”

Assay of Monoacylglycerol Lipase Activity.

“Monoacylglycerol lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). 2-AG is one of the main endogenous lipid agonists for cannabinoid receptors in the brain and elsewhere in the body. In the central nervous system (CNS), MGL is localized to presynaptic nerve terminals of both excitatory and inhibitory synapses, where it helps control the regulatory actions of 2-AG on synaptic transmission and plasticity. In this chapter, we describe an in vitro method to assess MGL activity by liquid chromatography/mass spectrometry (LC/MS)-based quantitation of the reaction product. This method may be used to determine the basal or altered MGL activity in various cells or animal tissues after pharmacological, genetic, or biological manipulations. In addition, this assay can be used for MGL inhibitor screening using purified recombinant enzyme or MGL-overexpressing cells.”

Phytocannabinoids and cannabimimetic drugs: recent patents in central nervous system disorders.

“Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs.

These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors.

Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases.

The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression.


Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.”

Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules.

“Adhesion molecules have been implicated in the development and progression of atherosclerosis. Cannabinoids have been reported to modulate the migration and adhesion molecules expression of various cell types.

Here we examined the effects of WIN55212-2, a cannabinoid receptor 1 (CB1-R)/cannabinoid receptor 2 (CB2-R) agonist on the development of atherosclerotic lesions…

WIN55212-2 seems to have direct anti-atherosclerotic effects in an animal model of atherosclerosis… these beneficial effects of WIN55212-2 may be mediated through the CB2 receptor.”

Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase.

“A putative endogenous cannabinoid ligand, arachidonylethanolamide (termed “anandamide”), was isolated recently from porcine brain.

Here we demonstrate that this compound is a specific cannabinoid agonist and exerts its action directly via the cannabinoid receptors.

Anandamide specifically binds to membranes from cells transiently (COS) or stably (Chinese hamster ovary) transfected with an expression plasmid carrying the cannabinoid receptor DNA but not to membranes from control nontransfected cells.

Moreover, anandamide inhibited the forskolin-stimulated adenylate cyclase in the transfected cells and in cells that naturally express cannabinoid receptors (N18TG2 neuroblastoma) but not in control nontransfected cells. As with exogenous cannabinoids…

These data indicate that anandamide is an endogenous agonist that may serve as a genuine neurotransmitter for the cannabinoid receptor.”

Peripheral, but not central effects of cannabidiol derivatives: mediation by CB(1) and unidentified receptors.

“Delta-9 tetrahydrocannabinol (Delta(9)-THC) and (-)-cannabidiol ((-)-CBD) are major constituents of the Cannabis sativa plant with different pharmacological profiles…

We tested a series of (+)- and (-)-CBD derivatives for central and peripheral effects in mice…

We suggest that (+)-CBD analogues have mixed agonist/antagonist activity in the brain.

Second, (-)-CBD analogues which are devoid of cannabinoid receptor affinity but which inhibit intestinal motility, suggest the existence of a non-CB(1), non-CB(2) receptor.

Therefore, such analogues should be further developed as antidiarrheal and/or antiinflammatory drugs.

We propose to study the therapeutic potential of (-)- and (+)-CBD derivatives for complex conditions such as inflammatory bowel disease and cystic fibrosis.”

The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain.

“The therapeutic effects of the cannabinoid anandamide and the putative CB2 agonist palmitoylethanolamide were tested in a model of persistent visceral pain (turpentine inflammation of the urinary bladder)…

The results confirm the analgesic potential of endogenous ligands at cannabinoid receptor sites.

The anti-nociceptive effect of the putative CB2 receptor agonist, palmitoylethanolamide, is particularly interesting since it is believed to be a peripherally mediated effect.

This observation might be exploited to separate central psychotropic effects from peripheral analgesic actions of the cannabinoids, under inflammatory conditions.”

Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder.

“To determined the localization of CB(1) and CB(2) receptors in rat bladder and investigate the effect of a mixed CB(1)/CB(2) receptor agonist, ajulemic acid (AJA), on chemically evoked release of the sensory neuropeptide calcitonin gene-related peptide (CGRP)…


CB(1) and CB(2) receptors are localized in the urothelium of rat bladder, and application of AJA inhibits the evoked release of CGRP by acting on CB(1) and CB(2) receptors.

These findings identify a potential new pathway for study in the evaluation and treatment of painful bladder syndrome/interstitial cystitis.”

Treatment with a Cannabinoid Receptor 2 Agonist Decreases Severity of Established Cystitis.

“We investigated whether treatment with the selective cannabinoid receptor 2 agonist… would ameliorate the severity of experimental cystitis…

Treatment with a selective cannabinoid receptor 2 agonist decreased severity of established acrolein induced cystitis and inhibited bladder inflammation associated increased referred mechanical sensitivity and increased bladder urinary frequency.

Our data indicate that cannabinoid receptor 2 is a potential therapeutic target for treatment of painful inflammatory bladder diseases.”