A pharmacological basis of herbal medicines for epilepsy.

Posted on September 6, 2015 by David

“Epilepsy is the most common chronic neurological disease, affecting about 1% of the world’s population during their lifetime. Most people with epilepsy can attain a seizure-free life upon treatment with antiepileptic drugs (AEDs).

Unfortunately, seizures in up to 30% do not respond to treatment. It is estimated that 90% of people with epilepsy live in developing countries, and most of them receive no drug treatment for the disease. This treatment gap has motivated investigations into the effects of plants that have been used by traditional healers all over the world to treat seizures.

Extracts of hundreds of plants have been shown to exhibit anticonvulsant activity in phenotypic screens performed in experimental animals.

Some of those extracts appear to exhibit anticonvulsant efficacy similar to that of synthetic AEDs.

Dozens of plant-derived chemical compounds have similarly been shown to act as anticonvulsants in various in vivo and in vitro assays.

To a significant degree, anticonvulsant effects of plant extracts can be attributed to widely distributed flavonoids, (furano)coumarins, phenylpropanoids, and terpenoids.

Flavonoids and coumarins have been shown to interact with the benzodiazepine site of the GABAA receptor and various voltage-gated ion channels, which are targets of synthetic AEDs.

Modulation of the activity of ligand-gated and voltage-gated ion channels provides an explanatory basis of the anticonvulsant effects of plant secondary metabolites.

Many complex extracts and single plant-derived compounds exhibit antiinflammatory, neuroprotective, and cognition-enhancing activities that may be beneficial in the treatment of epilepsy.

Thus, botanicals provide a base for target-oriented antiepileptic drug discovery and development.

In the future, preclinical work should focus on the characterization of the effects of plant extracts and plant-derived compounds on well-defined targets rather than on phenotypic screening using in vivo animal models of acute seizures. At the same time, available data provide ample justification for clinical studies with selected standardized botanical extracts and plant-derived compounds.”

http://www.ncbi.nlm.nih.gov/pubmed/26074183

http://www.thctotalhealthcare.com/category/epilepsy-2/

G protein-coupled receptor 18: A potential role for endocannabinoid signalling in metabolic dysfunction.

Posted on September 5, 2015 by David

“Endocannabinoids are products of dietary fatty acids that are modulated by an alteration in food intake levels.

Overweight and obese individuals have substantially higher circulating levels of the arachidonic acid-derived endocannabinoids, anandamide and 2-arachidonoyl glycerol, and show an altered pattern of cannabinoid receptor expression.

These cannabinoid receptors are part of a large family of G protein-coupled receptors (GPCRs).

GPCRs are major therapeutic targets for various diseases within the cardiovascular, neurological, gastrointestinal and endocrine systems, as well as metabolic disorders such as obesity and type 2 diabetes mellitus.

Obesity is considered a state of chronic low grade inflammation elicited by an immunological response.

Interestingly, the newly deorphanised G protein-coupled receptor GPR18, which is considered to be a putative cannabinoid receptor, is proposed to have an immunological function.

In this review, the current scientific knowledge on GPR18 is explored including its localisation, signalling pathways and pharmacology.

Importantly, the involvement of nutritional factors and potential dietary regulation of GPR18 and its (patho)physiological roles are described.

Further research on this receptor and its regulation will enable a better understanding of the complex mechanisms of GPR18 and its potential as a novel therapeutic target for treating metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26337420

Fatty acids, endocannabinoids and inflammation.

Posted on September 3, 2015 by David

“From their phylogenetic and pharmacological classification it might be inferred that cannabinoid receptors and their endogenous ligands constitute a rather specialised and biologically distinct signalling system.

However, the opposite is true and accumulating data underline how much the endocannabinoid system is intertwined with other lipid and non-lipid signalling systems.

Endocannabinoids per se have many structural congeners, and these molecules exist in dynamic equilibria with different other lipid-derived mediators, including eicosanoids and prostamides.

With multiple crossroads and shared targets, this creates a versatile system involved in fine-tuning different physiological and metabolic processes, including inflammation.

A key feature of this ‘expanded’ endocannabinoid system, or ‘endocannabinoidome’, is its subtle orchestration based on interactions between a relatively small number of receptors and multiple ligands with different but partly overlapping activities.

Following an update on the role of the ‘endocannabinoidome’ in inflammatory processes, this review continues with possible targets for intervention at the level of receptors or enzymes involved in formation or breakdown of endocannabinoids and their congeners.

Although its pleiotropic character poses scientific challenges, the ‘expanded’ endocannabinoid system offers several opportunities for prevention and therapy of chronic diseases.

In this respect, successes are more likely to come from ‘multiple-target’ than from ‘single-target’ strategies.”

http://www.ncbi.nlm.nih.gov/pubmed/26325095

Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow-Derived Monocytes/Macrophages in a CB1-Dependent Manner.

Posted on September 1, 2015 by David

“Hepatic injury undergoes significant increases in endocannabinoids and infiltrations of macrophages, yet the concrete mechanisms of changes in endocannabinoids and the functions of macrophage-expressed cannabinoid receptors (CBs) are unclear…

In the chimeric murine model, we found that blockade of CB1 by administration of a CB1 antagonist inhibited the recruitment of Bone marrow-derived monocytes/macrophages (BMM) into injured liver using immunofluorescence staining and FACS, but it did not have effects on migration of T cells and dendritic cells without CB1 expression. Furthermore, activation of CB1 enhanced cytokine expression of BMM. In vivo, inhibition of CB1 attenuated the inflammatory cytokine level through real-time RT-PCR and cytometric bead array, ameliorating hepatic inflammation and fibrosis.

In this study, we identify inactivation of BMM-expressed CB1 as a therapeutic strategy for reducing hepatic inflammation and fibrosis.”

http://www.ncbi.nlm.nih.gov/pubmed/26320250

Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease.

Posted on August 29, 2015 by David

“Parkinson’s disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the progressive loss of dopaminergic neurons in the nigrostriatal region of the brain.

Symptomatic therapies are available but no treatment slows or prevents the loss of neurons.

Neuroinflammation has been implicated in its pathogenesis.

To this end, the present study utilises the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients.

Herein, the role of a potential regulator of an immune response, the endocannabinoid system (ECS), is investigated.

The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG) (3 and 5mg/kg), was added exogenously and its enzymatic degradation inhibited to provide protection against MPTP-induced cell death.

Furthermore, the addition of DFU (25mg/kg), a selective inhibitor of inflammatory mediator cyclooxygenase-2 (COX-2), potentiated these effects.

Levels of 2-AG were shown to be upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits.

The results expand the current understanding of the role that this signalling system has and its potential influence in PD.”

http://www.sciencedirect.com/science/article/pii/S0014488615300583

Cannabinoids and Schizophrenia: Risks and Therapeutic Potential.

Posted on August 28, 2015 by David

“The endocannabinoid system has been implicated in psychosis both related and unrelated to cannabis exposure, and studying this system holds potential to increase understanding of the pathophysiology of schizophrenia.

Anandamide signaling in the central nervous system may be particularly important.

Δ9-Tetrahydrocannabinol in cannabis can cause symptoms of schizophrenia when acutely administered, and cannabidiol (CBD), another compound in cannabis, can counter many of these effects.

CBD may have therapeutic potential for the treatment of psychosis following cannabis use, as well as schizophrenia, possibly with better tolerability than current antipsychotic treatments. CBD may also have anti-inflammatory and neuroprotective properties.

Establishing the role of CBD and other CBD-based compounds in treating psychotic disorders will require further human research.”

http://www.ncbi.nlm.nih.gov/pubmed/26311150

http://www.thctotalhealthcare.com/category/schizophrenia/

Monoacylglycerol Lipase Regulates Fever Response.

Posted on August 21, 2015 by David

“Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.”

http://www.ncbi.nlm.nih.gov/pubmed/26287872

Synthesis and biological evaluation of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist.

Posted on August 17, 2015 by David

“Cannabinoid receptor 2 (CB2) selective agonists and inverse agonists possess significant potential as therapeutic agents for regulating inflammation and immune function.

Although CB2 agonists have received the greatest attention, it is emerging that inverse agonists also manifest anti-inflammatory activity.

In process of designing new cannabinoid ligands we discovered that the 2,6-dihydroxy-biphenyl-aryl methanone scaffold imparts inverse agonist activity at CB2 receptor without functional activity at CB1. To further explore the scaffold we synthesized a series of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone analogs and evaluated the CB1 and CB2 affinity, potency, and efficacy.

The studies reveal that an aromatic C ring is required for inverse agonist activity and that substitution at the 4 position is optimum. The resorcinol moiety is required for optimum CB2 inverse agonist activity and selectivity. Antagonist studies against CP 55,940 demonstrate that the compounds 41 and 45 are noncompetitive antagonists at CB2.”

http://www.ncbi.nlm.nih.gov/pubmed/26275680

HU-444, A Novel, Potent Anti-Inflammatory, Non-Psychotropic Cannabinoid.

Posted on August 15, 2015 by David

“Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas.

In contrast to Δ9-tetrahydrocannabinol (Δ9-THC) it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of TNF-α, a proinflammatory cytokine, and was found to be an oral anti-arthritic therapeutic in murine collagen-induced arthritis in vivo.

However in acidic media it can cyclize to the psychoactive Δ9-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ9-THC-like compound.

In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-a production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ9-THC- like effects in mice.

We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26272937

Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer’s Disease.

Posted on August 15, 2015 by David

“Alzheimer’s disease (AD) is frequently associated with neuropsychiatric symptoms (NPS) such as agitation and aggression, especially in the moderate to severe stages of the illness. The limited efficacy and high-risk profiles of current pharmacotherapies for the management of agitation and aggression in AD have driven the search for safer pharmacological alternatives.

Over the past few years, there has been a growing interest in the therapeutic potential of medications that target the endocannabinoid system (ECS).

The behavioural effects of ECS medications, as well as their ability to modulate neuroinflammation and oxidative stress, make targeting this system potentially relevant in AD.

This article summarizes the literature to date supporting this rationale and evaluates clinical studies investigating cannabinoids for agitation and aggression in AD.

Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids-dronabinol or nabilone-on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies.

Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD.”

http://www.ncbi.nlm.nih.gov/pubmed/26271310

http://www.thctotalhealthcare.com/category/alzheimers-disease-ad/