“Changes in rhythmic activity can serve as early biomarkers of pathological alterations, but it remains unclear how different types of rhythmic activity are altered during neurodegenerative processes. Glutamatergic neurotoxicity, evoked by kainic acid (KA), causes hyperexcitation and acute seizures that result in delayed brain damage. We employed wide frequency range (0.1-300 Hz) local field potential recordings in guinea pigs to study the oscillatory activity of the hippocampus, entorhinal cortex, medial septum, and amygdala in healthy animals for three months after KA introduction. To clarify whether the activation of endocannabinoid (eCB) system can influence toxic KA action, AM404, an eCB reuptake inhibitor, and URB597, an inhibitor of fatty acid amide hydrolase, were applied. Our results demonstrate the protective potential of the eCB system during excitotoxic influences.” https://www.ncbi.nlm.nih.gov/pubmed/28192082]]>
Monthly Archives: February 2017
Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer’s disease.
“Despite efforts to understand the mechanism of neuronal cell death, finding effective therapies for neurodegenerative diseases is still a challenge. Cognitive deficits are often associated with neurodegenerative diseases.
Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer’s still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer’s disease may be addressed from two different points of view, neuroprotection or cognitive enhancement.
Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising.
In fact, G-protein-coupled receptors (GPCRs) remain the most common ‘druggable’ targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways.
Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer’s disease. GPCR-mediated modulation of mTOR may take advantage of different GPRCs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.”
Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer's disease.
“Despite efforts to understand the mechanism of neuronal cell death, finding effective therapies for neurodegenerative diseases is still a challenge. Cognitive deficits are often associated with neurodegenerative diseases. Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer’s still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer’s disease may be addressed from two different points of view, neuroprotection or cognitive enhancement. Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising. In fact, G-protein-coupled receptors (GPCRs) remain the most common ‘druggable’ targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways. Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer’s disease. GPCR-mediated modulation of mTOR may take advantage of different GPRCs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.” https://www.ncbi.nlm.nih.gov/pubmed/28189739]]>
Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis
“The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo. Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.” https://www.ncbi.nlm.nih.gov/pubmed/28189366]]>
Cannabinoids in treatment-resistant epilepsy: A review.
“Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day. This article is part of a Special Issue titled “Cannabinoids and Epilepsy”.” https://www.ncbi.nlm.nih.gov/pubmed/28188044]]>
Cannabinoids activate monoaminergic signaling to modulate key C. elegans behaviors.
“Cannabis or marijuana, a popular recreational drug, alters sensory perception and exerts a range of potential medicinal benefits. The present study demonstrates that the endogenous cannabinoid receptor agonists, 2-arachidonoylglycerol (2-AG) and anandamide (AEA) activate a canonical cannabinoid receptor in C. elegans and also modulate monoaminergic signaling at multiple levels. 2-AG or AEA inhibit nociception and feeding through a pathway requiring the cannabinoid-like receptor, NPR-19. 2-AG or AEA activate NPR-19 directly and cannabinoid-dependent inhibition can be rescued in npr-19 null animals by the expression of a human cannabinoid receptor, CB1, highlighting the orthology of the receptors. Cannabinoids also modulate nociception and locomotion through an NPR-19-independent pathway requiring an α2A-adrenergic-like octopamine receptor, OCTR-1, and a 5-HT1A-like receptor, SER-4, that involves a complex interaction among cannabinoid, octopaminergic and serotonergic signaling. 2-AG activates OCTR-1 directly. In contrast, 2-AG does not activate SER-4 directly, but appears to enhance SER-4-dependent serotonergic signaling by increasing endogenous 5-HT. This study defines a conserved cannabinoid signaling system in C. elegans, demonstrates the cannabinoid-dependent activation of monoaminergic signaling and highlights the advantages of studying cannabinoid signaling in a genetically-tractable whole animal model. SIGNIFICANCE STATEMENTCannabis sativa causes euphoria and exerts a wide range of medicinal benefits. For years, cannabinoids have been studied at the cellular level using tissue explants with conflicting results. To better understand cannabinoid signaling, we have used the C. elegans model to examine the effects of cannabinoids on behavior. The present study demonstrates that mammalian cannabinoid receptor ligands activate a conserved cannabinoid signaling system in C. elegans and also modulate monoaminergic signaling, potentially impacting an array of disorders, including anxiety and depression. This study highlights the potential role of cannabinoids in modulating monoaminergic signaling, and the advantages of studying cannabinoid signaling in a genetically-tractable, whole-animal model.” https://www.ncbi.nlm.nih.gov/pubmed/28188220]]>
Neuronal and Molecular Effects of Cannabidiol on the Mesolimbic Dopamine System: Implications for Novel Schizophrenia Treatments.
“Growing clinical and pre-clinical evidence points to a critical role for cannabidiol (CBD), the largest phytochemical component of cannabis, as a potential pharmacotherapy for various neuropsychiatric disorders. In contrast to delta-9-tetrahydrocannabinol (THC), which is associated with acute and neurodevelopmental pro-psychotic side-effects, CBD possesses no known psychoactive or dependence-producing properties. However, evidence has demonstrated that CBD strongly modulates the mesolimbic dopamine (DA) system and may possess promising anti-psychotic properties. Despite the psychotropic differences between CBD and THC, little is known regarding their molecular and neuronal effects on the mesolimbic DA system, nor how these differential effects may relate to their potential pro vs. anti-psychotic properties. This review summarizes clinical and pre-clinical evidence demonstrating CBD’s modulatory effects on DA activity states within the mesolimbic pathway, functional interactions with the serotonin 5-HT1A receptor system, and their downstream molecular signaling effects. Together with clinical evidence showing that CBD may normalize affective and cognitive deficits associated with schizophrenia, CBD may represent a promising treatment for schizophrenia, acting through novel molecular and neuronal mesolimbic substrates.” https://www.ncbi.nlm.nih.gov/pubmed/28185872]]>
Can Marijuana Cure Cancer? Pharmaceutical Company Developing Cannabis Medicine To Treat Brain Cancer
“Can Marijuana Cure Cancer? Pharmaceutical Company Developing Cannabis Medicine To Treat Brain Cancer” http://www.ibtimes.com/can-marijuana-cure-cancer-pharmaceutical-company-developing-cannabis-medicine-treat-2489282
“GW Pharmaceuticals Achieves Positive Results in Phase 2 Proof of Concept Study in Glioma” http://ir.gwpharm.com/releasedetail.cfm?ReleaseID=1010672
“Cannabinoid Drug Prolongs the Life of Brain Tumor Patients in Phase II Trials” http://labiotech.eu/gw-pharmaceuticals-brain-tumor/
“Drug Company Claims to Have Marijuana Treatment That Could Increase Lifespan of Brain Cancer Patients” http://www.complex.com/life/2017/02/gw-pharmaceuticals-claims-to-have-treatment-that-could-increase-lifespan-of-brain-cancer-patients
“GW Pharma’s cannabis-derived combo med helps brain cancer patients” http://www.fiercebiotech.com/biotech/gw-pharma-s-cannabis-derived-combo-med-helps-brain-cancer-patients
“GW pharmaceuticals to develop oncology portfolio after cannabis medication shows promising results” http://www.telegraph.co.uk/business/2017/02/07/gw-pharmaceuticals-develop-oncology-portfolio-cannabis-medication/
“GW Pharma is touting claims that a combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) produced positive survival benefits in a small study of 21 patients with recurrent glioblastoma multiforme, a common form of brain cancer.” https://endpts.com/gw-touts-positive-survival-benefit-in-small-brain-cancer-study-ablynx-files-for-ultra-rare-disease-drug-ok/
“GW Pharmaceuticals Is Set to Benefit as Cannabis Takes on Cancer” https://www.thestreet.com/story/13996559/1/gw-pharmaceuticals-is-set-to-benefit-as-cannabis-takes-on-cancer.html
“GW Pharmaceuticals Achieves Positive Results In Phase 2 Proof Of Concept Study In Glioma” https://www.clinicalleader.com/doc/gw-pharmaceuticals-phase-proof-of-concept-study-in-glioma-0001
“Here’s How Marijuana May Help Brain Cancer Patients Live Longer” http://www.menshealth.com/health/marijuana-drug-treats-brain-cancer?utm_source=facebook.com&utm_medium=social&utm_campaign=sharebutton
“New pharmaceutical drug uses marijuana to treat brain cancer” http://blog.sfgate.com/smellthetruth/2017/02/09/new-pharmaceutical-drug-uses-marijuana-to-treat-brain-cancer/
“Medicine’s Secret Weapon Against Brain Cancer Is Weed” https://www.inverse.com/article/27578-cancer-treatment-marijuana-gw-pharmaceuticals?utm_source=facebook.com&utm_medium=on_site&utm_campaign=desktop“The Next Big Brain Cancer Drug Could Come from Marijuana” http://fortune.com/2017/02/07/gw-pharmaceuticals-marijuana-brain-cancer/
“Can Weed Cure Cancer? Marijuana Helps Fight Glioblastoma Multiforme, One Of The Deadliest Forms Of Brain Cancer” http://www.medicaldaily.com/marijuana-just-might-help-cure-one-deadliest-forms-brain-cancer-410947 http://www.thctotalhealthcare.com/category/brain-cancer/Modulation of Human Peripheral Blood Mononuclear Cell Signaling by Medicinal Cannabinoids.
“Medical marijuana is increasingly prescribed as an analgesic for a growing number of indications, amongst which terminal cancer and multiple sclerosis.
In this study we aimed to investigate the immune-cell modulatory properties of medical cannabis.
Healthy volunteers were asked to ingest medical cannabis, and kinome profiling was used to generate comprehensive descriptions of the cannabis challenge on inflammatory signal transduction in the peripheral blood of these volunteers.
Results were related to both short term and long term effects in patients experimentally treated with a medical marijuana preparation for suffering from abdominal pain as a result of chronic pancreatitis or other causes.
The results reveal an immunosuppressive effect of cannabinoid preparations via deactivation of signaling through the pro-inflammatory p38 MAP kinase and mTOR pathways and a concomitant deactivation of the pro-mitogenic ERK pathway. However, long term cannabis exposure in two patients resulted in reversal of this effect.
While these data provide a powerful mechanistic rationale for the clinical use of medical marijuana in inflammatory and oncological disease, caution may be advised with sustained use of such preparations.”
https://www.ncbi.nlm.nih.gov/pubmed/28174520
http://journal.frontiersin.org/article/10.3389/fnmol.2017.00014/full
Cannabidiol: Swinging the Marijuana Pendulum From ‘Weed’ to Medication to Treat the Opioid Epidemic.
“Epidemics require a paradigm shift in thinking about all possible solutions. The rapidly changing sociopolitical marijuana landscape provides a foundation for the therapeutic development of medicinal cannabidiol to address the current opioid abuse crisis.”