The role of cannabinoids and leptin in neurological diseases.

“Cannabinoids exert a neuroprotective influence on some neurological diseases, including Alzheimer’s, Parkinson’s, Huntington’s, multiple sclerosis and epilepsy.

Synthetic cannabinoid receptor agonists/antagonists or compounds can provide symptom relief or control the progression of neurological diseases. However, the molecular mechanism and the effectiveness of these agents in controlling the progression of most of these diseases remain unclear.

Cannabinoids may exert effects via a number of mechanisms and interactions with neurotransmitters, neurotropic factors and neuropeptides.

Leptin is a peptide hormone involved in the regulation of food intake and energy balance via its actions on specific hypothalamic nuclei. Leptin receptors are widely expressed throughout the brain, especially in the hippocampus, basal ganglia, cortex and cerebellum. Leptin has also shown neuroprotective properties in a number of neurological disorders, such as Parkinson’s and Alzheimer’s.

Therefore, cannabinoid and leptin hold therapeutic potential for neurological diseases.

Further elucidation of the molecular mechanisms underlying the effects on these agents may lead to the development of new therapeutic strategies for the treatment of neurological disorders.”

Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy.

“Oral cannabis extracts (OCEs) have been used in the treatment of epilepsy; however, no studies demonstrate clear efficacy. We report on a cohort of pediatric patients with epilepsy who were given OCE and followed in a single tertiary epilepsy center…

Seventy-five patients were identified of which 57% reported any improvement in seizure control and 33% reported a >50% reduction in seizures (responders).

Our retrospective study of OCE use in pediatric patients with epilepsy demonstrates that some families reported patient improvement with treatment;

We strongly support the need for controlled, blinded studies to evaluate the efficacy and safety of OCE for treatment of pediatric epilepsies using accurate seizure counts, formal neurocognitive assessments, as well as EEG as a biomarker.

This study provides Class III evidence that OCE is well tolerated by children and adolescents with epilepsy.”

http://www.ncbi.nlm.nih.gov/pubmed/25845492

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

 

Antiepileptic potential of cannabidiol analogs.

“In audiogenic seizure (AGS) susceptible rats, the acute (intraperitoneal and intravenous) dose-response effects of (–)-cannabidiol (CBD) for preventing AGS and for causing rototod neurotoxicity (ROT) were determined.

Also, the anti-AGS and ROT effects of 10 CBD analogs, given in intravenous doses equivalent to the AGS-ED50 (15 mg/kg) and ROT-ID50 (31 mg/kg) of CBD, were ascertained.

Compared to CBD, (–)-CBD diacetate and (–)-4-(2′-olivetyl)-alpha-pinene were equally effective whereas (–)-CBD monomethyl ether, (–)-CBD dimethyl ether, (–)-3′-acetyl-CBD monoacetate, (+)-4-(2′-olivetyl)-alpha-pinene, (–)-and (+)-4-(6′-olivetyl)-alpha-pinene, (+/-)-AF-11, and olivetol were less effective anticonvulsants. Except for (–)- and (+)-4-(2′-olivetyl)-alpha-pinene and olivetol, all analogs showed less ROT than CBD.

Also, CBD and all analogs were not active in tetrahydrocannabinol seizure-susceptible rabbits, the latter a putative model of cannabinoid psychoactivity in humans.

These data suggest anticonvulsant requirements of 2 free phenolic hydroxyl groups, exact positioning of the terpinoid moiety in the resorcinol system and correct stereochemistry.

Moreover, findings of separation of anticonvulsant from neurotoxic and psychoactive activities, notably with CBD diacetate, suggest that additional structural modifications of CBD may yield novel antiepileptic drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/7298873

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

Inhibition of monoacylglycerol lipase mediates a cannabinoid 1-receptor dependent delay of kindling progression in mice.

“Endocannabinoids, including 2-arachidonoylglycerol (2-AG), activate presynaptic cannabinoid type 1 receptors (CB1R) on inhibitory and excitatory neurons, resulting in a decreased release of neurotransmitters.

Event-specific activation of the endocannabinoid system by inhibition of the endocannabinoid degrading enzymes may offer a promising strategy to selectively activate CB1Rs at the site of excessive neuronal activation with the overall goal to prevent the development epilepsy.

The aim of this study was to investigate the impact of monoacylglycerol lipase (MAGL) inhibition on the development and progression of epileptic seizures in the kindling model of temporal lobe epilepsy.

In conclusion, the data demonstrate that indirect CB1R agonism delays the development of generalized epileptic seizures, but has no relevant acute anticonvulsive effects.

Furthermore, we confirmed that the effects of JZL184 on kindling progression are CB1R mediated.

Thus, the data indicate that the endocannabinoid 2-AG might be a promising target for an anti-epileptogenic approach.”

Attenuation of kainic acid-induced status epilepticus by inhibition of endocannabinoid transport and degradation in guinea pigs.

“Status epilepticus (SE) is a medical emergency associated with a high rate of mortality if not treated promptly.

Exogenous and endogenous cannabinoids have been shown to possess anticonvulsant properties both in vivo and in vitro.

Here we study the influence of endocannabinoid metabolism on the development of kainic acid-induced SE in guinea pigs.

The present study provides electrophysiologic and behavioral evidences that inhibition of endocannabinoid metabolism plays a protective role against kainic acid-induced SE and may be employed for therapeutic purposes.”

http://www.ncbi.nlm.nih.gov/pubmed/25769371

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

Marijuana: A Time-Honored but Untested Treatment for Epilepsy.

Image result for marijuana

“The biology of the endocannabinoid system in the brain provides a possible basis for a beneficial pharmacological effect of marijuana on seizures.

However, evidence for efficacy of cannabis treatment of epilepsy is anecdotal because no acceptable randomized controlled trials have been done.

Proper dosage and means of administration remain unknown.

Cannabis is safer than other controlled substances, including tobacco or alcohol, and appears to be relatively safe compared with most pharmaceuticals used to treat epilepsy.”

 http://www.ncbi.nlm.nih.gov/pubmed/25715711

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

Fatty Acid Binding Proteins (FABPs) are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD).

Image result for fatty acid binding proteins

“Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex.

Recent reports suggest that CBD and THC elevates the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance.

Fatty acid binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH).

By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and we demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs.

Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption.

Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD.

Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids.

These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy towards epilepsy and other neurological disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/25666611

Phytocannabinoids and epilepsy.

“Antiepileptic drugs often produce serious adverse effects, and many patients do not respond to them properly.

Phytocannabinoids produce anticonvulsant effects in preclinical and preliminary human studies, and appear to produce fewer adverse effects than available antiepileptic drugs.

The present review summarizes studies on the anticonvulsant properties of phytocannabinoids.

Preclinical studies suggest that phytocannabinoids, especially cannabidiol and cannabidivarin, have potent anticonvulsant effects which are mediated by the endocannabinoid system. Human studies are limited in number and quality, but suggest that cannabidiol has anticonvulsant effects in adult and infantile epilepsy and is well tolerated after prolonged administration…

 

Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects.”

http://www.ncbi.nlm.nih.gov/pubmed/25475762

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

Cannabidiol: promise and pitfalls.

“Over the past few years, increasing public and political pressure has supported legalization of medical marijuana.

One of the main thrusts in this effort has related to the treatment of refractory epilepsy-especially in children with Dravet syndrome-using cannabidiol (CBD).

Despite initiatives in numerous states to at least legalize possession of CBD oil for treating epilepsy, little published evidence is available to prove or disprove the efficacy and safety of CBD in patients with epilepsy. This review highlights some of the basic science theory behind the use of CBD, summarizes published data on clinical use of CBD for epilepsy, and highlights issues related to the use of currently available CBD products.

Cannabidiol is the major nonpsychoactive component of Cannabis sativa.

Over the centuries, a number of medicinal preparations derived from C. sativa have been employed for a variety of disorders, including gout, rheumatism, malaria, pain, and fever.

These preparations were widely employed as analgesics by Western medical practitioners in the 19(th) century.

More recently, there is clinical evidence suggesting efficacy in HIV-associated neuropathic pain, as well as spasms associated with multiple sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/25346628

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

Seizing an opportunity for the endocannabinoid system.

“Exogenous cannabinoids can limit seizures and neurodegeneration, and their actions are largely mimicked by endogenous cannabinoids (endocannabinoids).

Endocannabinoids are mobilized by epileptiform activity and in turn influence this activity by inhibiting synaptic transmission; both excitatory and some inhibitory synapses can be suppressed, leading to potentially complex outcomes.

Moreover, the endocannabinoid system is not a fixed entity, and its strength can be enhanced or reduced.

Endocannabinoids and their receptors are altered by epileptic seizures in ways that can reduce the efficacy of both exogenous and endogenous cannabinoids in sometimes unexpected ways.”

http://www.ncbi.nlm.nih.gov/pubmed/25346637

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