The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation—Evidence from In Vivo Studies (original) (raw)
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Neuroprotective Properties of Cannabinoids in Cellular and Animal Models: Hypotheses and Facts
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Progressive neuronal loss is a typical characteristic of neurodegenerative diseases. In Parkinson’s disease, the loss of dopaminergic neurons in the basal ganglia results in impaired mobility and flawed muscle control. The loss of cholinergic neurons largely in the basal forebrain contributes to memory and attention deficits and the overall cognitive impairment in Alzheimer’s disease. This being said, neuroprotective drugs should be expected to preserve and/or restore the functions affected by neuronal loss, and substantially prevent cell death. The endocannabinoid system, comprising lipid mediators able to bind to and activate cannabinoid receptors, has emerged as a therapeutic target of potential interest in a variety of central nervous system diseases. Palmitoylethanolamide (PEA) is one of the most important endocannabinoids, which has a key role in modulating oxidative stress and inflammatory response with neuroprotective potential in neurological disorders. Neurodegenerative di...
The dual neuroprotective-neurotoxic profile of cannabinoid drugs
British Journal of Pharmacology, 2011
Extensive in vitro and in vivo studies have shown that cannabinoid drugs have neuroprotective properties and suggested that the endocannabinoid system may be involved in endogenous neuroprotective mechanisms. On the other hand, neurotoxic effects of cannabinoids in vitro and in vivo were also described. Several possible explanations for these dual, opposite effects of cannabinoids on cellular fate were suggested, and it is conceivable that various factors may determine the final outcome of the cannabinoid effect in vivo. In the current review, we focus on one of the possible reasons for the dual neuroprotective/ neurotoxic effects of cannabinoids in vivo, namely, the opposite effects of low versus high doses of cannabinoids. While many studies reported neuroprotective effects of the conventional doses of cannabinoids in various experimental models for acute brain injuries, we have shown that a single administration of an extremely low dose of D 9-tetrahydrocannabinol (THC) (3-4 orders of magnitude lower than the conventional doses) to mice induced long-lasting mild cognitive deficits that affected various aspects of memory and learning. These findings led to the idea that this low dose of THC, which induces minor damage to the brain, may activate preconditioning and/or postconditioning mechanisms and thus will protect the brain from more severe insults. Indeed, our recent findings support this assumption and show that a pre-or a postconditioning treatment with extremely low doses of THC, several days before or after brain injury, provides effective long-term cognitive neuroprotection. The future therapeutical potential of these findings is discussed.
Behavioural Neurology
Cannabidiol (CBD), derived from Cannabis sativa, has gained remarkable attention for its potential therapeutic applications. This thorough analysis explores the increasing significance of CBD in treating neurological conditions including epilepsy, multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease, which present major healthcare concerns on a worldwide scale. Despite the lack of available therapies, CBD has been shown to possess a variety of pharmacological effects in preclinical and clinical studies, making it an intriguing competitor. This review brings together the most recent findings on the endocannabinoid and neurotransmitter systems, as well as anti-inflammatory pathways, that underlie CBD’s modes of action. Synthesized efficacy and safety assessments for a range of neurological illnesses are included, covering human trials, in vitro studies, and animal models. The investigation includes how CBD could protect neurons, control neuroinflammation, fend off oxidativ...
Possibilities of therapeutic action of cannabinoids in neurodegenerative diseases
Pharmacotherapy in Psychiatry and Neurology
important of which is anandamide and enzymes for the synthesis and biodegradation of endocannabinoids. Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), which define the progressive activity associated with the further loss of specific subpopulation of neurons and disorders of multiple brain neurotransmitters. These diseases also include pathological protein accumulation (such as tau proteins), impairment of the lysosomal system, excitotoxicity, oxidative stress, and inflammatory features of the nervous system. The endocannabinoid system can modulate phenomena with neurodegeneration. It is caused by the action of cannabinoid receptors-CB1, causing the normalization of glutamatergic transmission and autophagy, activation of CB2 receptors, limiting the weakening of action, and lowering the level of emission reduction-the independence of cannabinoid receptors. The article presents data on the beneficial effects of cannabinoids on the symptoms of neurodegenerative diseases obtained in experimental studies in animal models (AD, PD, HD, ALS), as well as in clinical studies (AD, PD, HD). Conclusions. The results of research, mainly experimental and clinical, may indicate a beneficial effect of cannabinoids, reducing some of the symptoms of neurodegenerative diseases. These results are promising prerequisites for further research.
British Journal of …, 2012
Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with D 9 -tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like D 9 -tetrahydrocannabinol, i.e. CB1 and CB2 receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB 2 receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels.
Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2009
Recognition of the importance of the endocannabinoid system in both homeostasis and pathologic responses raised interest recently in the development of therapeutic agents based on this system. The CB(2) receptor, a component of the endocannabinoid system, has significant influence on immune function and inflammatory responses. Inflammatory responses are major contributors to central nervous system (CNS) injury in a variety of diseases. In this report, we present evidence that activation of CB(2) receptors, by selective CB(2) agonists, reduces inflammatory responses that contribute to CNS injury. The studies demonstrate neuroprotective effects in experimental autoimmune encephalomyelitis, a model of multiple sclerosis, and in a murine model of cerebral ischemia/reperfusion injury. In both cases, CB(2) receptor activation results in reduced white cell rolling and adhesion to cerebral microvessels, a reduction in immune cell invasion, and improved neurologic function after insult. In a...
Modulation of the endocannabinoid system: Neuroprotection or neurotoxicity
Experimental Neurology, 2010
There is now a large volume of data indicating that compounds activating cannabinoid CB1 receptors, either directly or indirectly by preventing the breakdown of endogenous cannabinoids, can protect against neuronal damage produced by a variety of neuronal “insults”. Given that such neurodegenerative stimuli result in increased endocannabinoid levels and that animals with genetic deletions of CB1 receptors are more susceptible to the deleterious effects of such stimuli, a case can be made for an endogenous neuroprotective role of endocannabinoids. However, this is an oversimplification of the current literature, since (a) compounds released together with the endocannabinoids can contribute to the neuroprotective effect; (b) other proteins, such as TASK-1 and PPARα, are involved; (c) the CB1 receptor antagonist/inverse agonist rimonabant has also been reported to have neuroprotective properties in a number of animal models of neurodegenerative disorders. Furthermore, the CB2 receptor located on peripheral immune cells and activated microglia are potential targets for novel therapies. In terms of the clinical usefulness of targeting the endocannabinoid system for the treatment of neurodegenerative disorders, data are emerging, but important factors to be considered are windows of opportunity (for acute situations such as trauma and ischemia) and the functionality of the target receptors (for chronic neurodegenerative disorders such as Alzheimer's disease).