Tag Archives: neuroprotective

Endocannabinoids and Neurodegenerative Disorders: Parkinson’s Disease, Huntington’s Chorea, Alzheimer’s Disease, and Others.

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“This review focuses on the role of the endocannabinoid signaling system in controlling neuronal survival, an extremely important issue to be considered when developing new therapies for neurodegenerative disorders.

First, we will describe the cellular and molecular mechanisms, and the signaling pathways, underlying these neuroprotective properties, including the control of glutamate homeostasis, calcium influx, the toxicity of reactive oxygen species, glial activation and other inflammatory events; and the induction of autophagy.

We will then concentrate on the preclinical studies and the few clinical trials that have been carried out targeting endocannabinoid signaling in three important chronic progressive neurodegenerative disorders (Parkinson’s disease, Huntington’s chorea, and Alzheimer’s disease), as well as in other less well-studied disorders.

We will end by offering some ideas and proposals for future research that should be carried out to optimize endocannabinoid-based treatments for these disorders.

Such studies will strengthen the possibility that these therapies will be investigated in the clinical scenario and licensed for their use in specific disorders.”

A pharmacological basis of herbal medicines for epilepsy.

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“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/

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.

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“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.”

Cannabinoids and Schizophrenia: Risks and Therapeutic Potential.

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“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/

[Neuroprotective mechanisms of cannabinoids in brain ischemia and neurodegenerative disorders].

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“One of the most important causes of morbidity and mortality is neurologic dysfunction; its high incidence has led to an intense research of the mechanisms that protect the central nervous system from hypoxia and ischemia. The mayor challenge is to block the biochemical events leading to neuronal death.

This may be achieved by neuroprotective mechanisms that avoid the metabolic and immunologic cascades that follow a neurological damage. When it occurs, several pathophysiological events develop including cytokine release, oxidative stress and excitotoxicity.

Neuroprotective effects of cannabinoids to all those mechanisms have been reported in animal models of brain ischemia, excitotoxicity, brain trauma and neurodegenerative disorders.

Some endocannabinoid analogs are being tested in clinical studies (I-III phase) for acute disorders involving neuronal death (brain trauma and ischemia).

The study of the cannabinoid system may allow the discovery of effective neuroprotective drugs for the treatment of neurological disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26299059

Cannabinoid receptor type 1 agonist ACEA improves motor recovery and protects neurons in ischemic stroke in mice.

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“Brain ischemia produces neuronal cell death and the recruitment of pro-inflammatory cells.

In turn, the search for neuroprotection against this type of insult has rendered results involving a beneficial role of endocannabinoid receptor agonists in the Central Nervous System.

In this work, to further elucidate the mechanisms associated to this neuroprotective effect…

Motor tests showed a progressive deterioration in motor activity in ischemic animals, which only ACEA treatment was able to counteract.

Our results suggest that CB1R may be involved in neuronal survival and in the regulation of neuroprotection during focal cerebral ischemia in mice.”

http://www.ncbi.nlm.nih.gov/pubmed/26296704

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

Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release.

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“Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa, has therapeutic potential for certain psychiatric and neurological disorders.

Studies in laboratory animals and limited human trials indicate that CBD has anticonvulsant and neuroprotective properties.

Its effects against cocaine neurotoxicity, however, has remained unclear. Thus, the present study tested the hypothesis that CBD protects against cocaine-induced seizures and investigated the underlying mechanisms.

In conclusion, CBD protects against seizures in a model of cocaine intoxication.

CBD should be further investigated as a strategy for alleviating psychostimulant toxicity.”

http://www.ncbi.nlm.nih.gov/pubmed/26283212

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

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“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.”

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications.

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“Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems.

One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells.

These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells).

This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer’s disease, Parkinson’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis.

This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression…”

http://www.ncbi.nlm.nih.gov/pubmed/26260390

Endocannabinoid 2-arachidonylglycerol protects primary cultured neurons against LPS-induced impairments in rat caudate nucleus.

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“Inflammation plays a pivotal role in the pathogenesis of many diseases in the central nervous system.

Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders.

2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and the true natural ligand for CB1 receptors, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in hippocampus.

In the present study, we discovered that 2-AG significantly protects CN neurons in culture against lipopolysaccharide (LPS)-induced inflammatory response.

Our study suggests the therapeutic potential of 2-AG for the treatment of some inflammation-induced neurological disorders and pain.”

http://www.ncbi.nlm.nih.gov/pubmed/24510751