“Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by neuroinflammation, extensive deposits of amyloid-β aggregates, and loss of memory and cognitive abilities. The brains of patients with AD show increased expression of cannabinoid receptor type 2 (CB2) receptors and glial markers. CB2 receptors act as a negative feedback regulator; when activated by a CB2agonist, they can help limit the extent of the neuroinflammatory response and the subsequent development of neuronal damage in the central nervous system. In a double transgenic APP/PS1 mice model of AD, we evaluated the effect of MDA7, a CB2 agonist, on several neuropathological conditions of AD including amyloid deposition, inflammatory reaction, Sox2 (sex-determining region Y-box 2) expression, and spatial memory. Activation of microglia CB2 receptors by MDA7 suppressed neuroinflammation, demonstrated by decreased immunosignal of Iba1 in the hippocampal CA1 and dentate gyrus (DG) areas, promoted clearance of amyloid plaques in the DG area, restored Sox2 expression, and promoted recovery of the neuronal synaptic plasticity in hippocampal CA1. In addition, treatment with MDA7 improved the behavioral performance in the Morris water maze in APP/PS1mice. Collectively, these findings suggest that MDA7 has a potential therapeutic effect in the setting of AD.” https://www.ncbi.nlm.nih.gov/pubmed/28551012 http://www.sciencedirect.com/science/article/pii/S0014299917303758]]>
Tag Archives: cannabinoid receptors
Activation of CB2 receptor system restores cognitive capacity and hippocampal Sox2 expression in a transgenic mouse model of Alzheimer’s disease.
“Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by neuroinflammation, extensive deposits of amyloid-β aggregates, and loss of memory and cognitive abilities. The brains of patients with AD show increased expression of cannabinoid receptor type 2 (CB2) receptors and glial markers. CB2 receptors act as a negative feedback regulator; when activated by a CB2agonist, they can help limit the extent of the neuroinflammatory response and the subsequent development of neuronal damage in the central nervous system. In a double transgenic APP/PS1 mice model of AD, we evaluated the effect of MDA7, a CB2 agonist, on several neuropathological conditions of AD including amyloid deposition, inflammatory reaction, Sox2 (sex-determining region Y-box 2) expression, and spatial memory. Activation of microglia CB2 receptors by MDA7 suppressed neuroinflammation, demonstrated by decreased immunosignal of Iba1 in the hippocampal CA1 and dentate gyrus (DG) areas, promoted clearance of amyloid plaques in the DG area, restored Sox2 expression, and promoted recovery of the neuronal synaptic plasticity in hippocampal CA1. In addition, treatment with MDA7 improved the behavioral performance in the Morris water maze in APP/PS1mice. Collectively, these findings suggest that MDA7 has a potential therapeutic effect in the setting of AD.”
https://www.ncbi.nlm.nih.gov/pubmed/28551012
http://www.sciencedirect.com/science/article/pii/S0014299917303758
Endocannabinoids modulate apoptosis in endometriosis and adenomyosis.
“Adenomyosis that is a form of endometriosis is the growth of ectopic endometrial tissue within the muscular wall of the uterus (myometrium), which may cause dysmenorrhea and infertility. Endocannabinoid mediated apoptotic mechanisms of endometriosis and adenomyosis are not known. We hypothesized that the down regulation of endocannabinoid receptors and/or alteration in their regulatory enzymes may have a direct role in the pathogenesis of endometriosis and adenomyosis through apoptosis. Endocannabinoid receptors CB1 and CB2, their synthesizing and catabolizing enzymes (FAAH, NAPE-PLD, DAGL, MAGL) and the apoptotic indexes were immunohistochemically assessed in endometriotic and adenomyotic tissues. Findings were compared to normal endometrium and myometrium. Endometrial adenocarcinoma (Ishikawa) and ovarian endometriosis cyst wall stromal (CRL-7566) cell lines were furthermore cultured with or without cannabinoid receptor agonists. The IC50 value for CB1 and CB2 receptor agonists was quantified. Cannabinoid agonists on cell death were investigated by Annexin-V/Propidium iodide labeling with flow cytometry. CB1 and CB2 receptor levels decreased in endometriotic and adenomyotic tissues compared to the control group (p=0,001 and p=0,001). FAAH, NAPE-PLD, MAGL and DAGL enzyme levels decreased in endometriotic and adenomyotic tissues compared to control (p=0,001, p=0,001, p=0,001 and p=0,002 respectively). Apoptotic cell indexes both in endometriotic and adenomyotic tissues also decreased significantly, compared to the control group (p=0,001 and p=0,001). CB1 and CB2 receptor agonist mediated dose dependent fast anti-proliferative and pro-apoptotic effects were detected in Ishikawa and ovarian endometriosis cyst wall stromal cell lines (CRL-7566). Endocannabinoids are suggested to increase apoptosis mechanisms in endometriosis and adenomyosis. CB1 and CB2 antagonists can be considered as potential medical therapeutic agents for endometriosis and adenomyosis.” https://www.ncbi.nlm.nih.gov/pubmed/28549792 http://www.sciencedirect.com/science/article/pii/S0065128116303154]]>
Activation of cannabinoid receptor type II by AM1241 protects adipose-derived mesenchymal stem cells from oxidative damage and enhances their therapeutic efficacy in myocardial infarction mice via Stat3 activation.
Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities.
“Cannabinoid pharmacology has been intensely studied because of cannabis’ pervasive medicinal and non-medicinal uses as well as for the therapeutic potential of cannabinoid-based drugs for the treatment of pain, anxiety, substance abuse, obesity, cancer and neurodegenerative disorders. The identification of allosteric modulators of the cannabinoid receptor 1 (CB1) has given a new direction to the development of cannabinoid-based therapeutics due to the many advantages offered by targeting allosteric site(s). Allosteric receptor modulators hold potential to develop subtype-specific and pathway-specific therapeutics. Here we briefly discuss the first-generation of allosteric modulators of CB1 receptor, their structure-activity relationships, signaling pathways and the allosteric binding site(s) on the CB1 receptor.” https://www.ncbi.nlm.nih.gov/pubmed/28527758 http://www.sciencedirect.com/science/article/pii/S0028390817302307]]>
Targeting cannabinoid signaling for peritoneal dialysis-induced oxidative stress and fibrosis.
“Long-term exposure to bioincompatible peritoneal dialysis (PD) solutions frequently results in peritoneal fibrosis and ultrafiltration failure, which limits the life-long use of and leads to the cessation of PD therapy. Therefore, it is important to elucidate the pathogenesis of peritoneal fibrosis in order to design therapeutic strategies to prevent its occurrence. Peritoneal fibrosis is associated with a chronic inflammatory status as well as an elevated oxidative stress (OS) status. Beyond uremia per se, OS also results from chronic exposure to high glucose load, glucose degradation products, advanced glycation end products, and hypertonic stress. Therapy targeting the cannabinoid (CB) signaling pathway has been reported in several chronic inflammatory diseases with elevated OS. We recently reported that the intra-peritoneal administration of CB receptor ligands, including CB1 receptor antagonists and CB2receptor agonists, ameliorated dialysis-related peritoneal fibrosis. As targeting the CB signaling pathway has been reported to be beneficial in attenuating the processes of several chronic inflammatory diseases, we reviewed the interaction among the cannabinoid system, inflammation, and OS, through which clinicians ultimately aim to prolong the peritoneal survival of PD patients.” https://www.ncbi.nlm.nih.gov/pubmed/28540200 http://www.wjgnet.com/2220-6124/full/v6/i3/111.htm]]>
Continuous Intrathecal Infusion of Cannabinoid Receptor Agonists Attenuates Nerve Ligation-Induced Pain in Rats.
“Cannabinoid receptors (CB1R/CB2R) are known to play important roles in pain transmission. In this study, we investigated the effects of continuous intrathecal infusion of CB1/2R agonists in the L5/6 spinal nerve ligation pain model.
Continuous intrathecal infusion of CB1/2R agonists elicits antinociception in the pain model.
The mechanisms might involve their actions on neurons and glial cells. CB2R, but not CB1R, seems to play an important role in the regulation of nerve injury-induced neuroinflammation.”
https://www.ncbi.nlm.nih.gov/pubmed/28492437]]>Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).
“Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy.
Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy.
The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models.
Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED50 164 mg/kg), mouse MES (ED50 83.5 mg/kg) and rat MES (ED50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses.
The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.” https://www.ncbi.nlm.nih.gov/pubmed/28478594