“Cannabinoids possess immunomodulatory activity, are neuroprotective in vivo and in vitro and can modify the production of inflammatory mediators… Cannabinoid-induced immunosuppression may have implications for the treatment of neurological disorders that are associated with excess immunological activity, such as multiple sclerosis and Alzheimer’s disease. There is anecdotal evidence that cannabis use improves the symptoms of multiple sclerosis, and studies with animal models are beginning to provide evidence for the mechanism of such effects. The development of nonpsychotropic cannabinoid analogues and modulators of the metabolism of endogenous cannabinoid ligands may lead to novel approaches to the treatment of neurodegenerative disorders.”
Tag Archives: cannabinoid
An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer’s disease.
“The endocannabinoids and their attending cannabinoid (CB)(1) receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear.
The results suggest that an Aβ(42)-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD.”
Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid.
Abstract
“Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Two of the primary hypotheses underlying motor neuron vulnerability are susceptibility to excitotoxicity and oxidative damage. There is rapidly emerging evidence that the cannabinoid receptor system has the potential to reduce both excitotoxic and oxidative cell damage. Here we report that treatment with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was effective if administered either before or after onset of signs in the ALS mouse model (hSOD(G93A) transgenic mice). Administration at the onset of tremors delayed motor impairment and prolonged survival in Delta(9)-THC treated mice when compared to vehicle controls. In addition, we present an improved method for the analysis of disease progression in the ALS mouse model. This logistic model provides an estimate of the age at which muscle endurance has declined by 50% with much greater accuracy than could be attained for any other measure of decline. In vitro, Delta(9)-THC was extremely effective at reducing oxidative damage in spinal cord cultures. Additionally, Delta(9)-THC is anti-excitotoxic in vitro. These cellular mechanisms may underlie the presumed neuroprotective effect in ALS. As Delta(9)-THC is well tolerated, it and other cannabinoids may prove to be novel therapeutic targets for the treatment of ALS.”
Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice.
“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motoneurons in the spinal cord, brain stem, and motor cortex. However, despite intensive research, an effective treatment for this disease remains elusive. In this study we show that treatment of postsymptomatic, 90-day-old SOD1G93A mice with a synthetic cannabinoid, WIN55,212-2, significantly delays disease progression…
Increasing evidence suggests that cannabinoids might have therapeutic potential in neurodegenerative conditions. In a variety of in vivo and in vitro models, cannabinoids exert neuroprotective effects under excitotoxic, ischemic, and inflammatory conditions. This combination of neuroprotective actions might be particularly relevant to ALS and suggests that cannabinoids might have a greater impact on disease progression than the established therapy that targets excitotoxicity alone.
… the neuroprotective effects observed following pharmacological and genetic augmentation of cannabinoid levels are not necessarily mediated by the CB1 receptor, and indeed inhibition of the CB1 receptor might actually be neuroprotective. Therefore, in contrast to previous studies that have suggested that cannabinoids exert neuroprotection via the CB1 receptor, the present results suggest that activation of CB2 receptors might underlie the beneficial effects of cannabinoids at least in SOD1G93A mice .”
Together these results show that cannabinoids have significant neuroprotective effects in this model of ALS and suggest that these beneficial effects may be mediated by non-CB1 receptor mechanisms.”
The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset.
“Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2-5 years of diagnosis. Currently, no effective pharmacological agents exist for the treatment of this devastating disease. Neuroinflammation may accelerate the progression of ALS. Cannabinoids produce anti-inflammatory actions via cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), and delay the progression of neuroinflammatory diseases…
…treatment with non-selective cannabinoid partial agonists prior to, or upon, symptom appearance minimally delays disease onset and prolongs survival through undefined mechanisms…
…Δ9-Tetrahydrocannabinol (Δ9-THC) is the main psychoactive constituent in the plant Cannabis sativa (marijuana) and produces its effects by activation of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) cannabinoid receptors. CB1 receptors are expressed throughout the CNS, while CB2 receptors are expressed predominantly in immune cells and non-neuronal tissues. Therapeutic agents which modulate the cann-abinoid system are effective in treating a wide variety of disorders characterized by inflammation. More specifically, drugs which activate CB2 receptors successfully improve the symptoms of several inflammatory diseases…
More importantly, daily injections of the selective CB2 agonist AM-1241, initiated at symptom onset, increase the survival interval after disease onset by 56%. Therefore, CB2 agonists may slow motor neuron degeneration and preserve motor function, and represent a novel therapeutic modality for treatment of ALS.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819701/
AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis.
“Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Motor neuron degeneration is the primary pathology in ALS; however non-neuronal cells contribute to the disease process. In particular, inflammatory processes have been shown to play an important role. AM1241 is a cannabinoid CB2 receptor selective agonist that has been shown to be effective in models of inflammation and hyperalgesia. Here we report that treatment with AM1241 was effective at slowing signs of disease progression when administered after onset of signs in an ALS mouse model (hSOD1(G93A) transgenic mice)…. As AM1241 was well tolerated by the animals, cannabinoid CB2 receptor-selective compounds may be the basis for developing new drugs for the treatment of ALS and other chronic neurodegenerative diseases.”
Abnormal sensitivity of cannabinoid CB1 receptors in the striatum of mice with experimental amyotrophic lateral sclerosis.
“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons.
The sensitivity of cannabinoid CB1 receptors controlling both glutamate and GABA transmission was remarkably potentiated in ALS mice, indicating that adaptations of the endocannabinoid system might be involved in the pathophysiology of ALS. In conclusion, our data identify possible physiological correlates of striatal dysfunction in ALS mice, and suggest that cannabinoid CB1 receptors might be potential therapeutic targets for this dramatic disease.”
The (endo)cannabinoid system in multiple sclerosis and amyotrophic lateral sclerosis.
“Alterations of the endocannabinoid system (ECS) have been recently implicated in a number of neuroinflammatory and neurodegenerative conditions so that the pharmacological modulation of cannabinoid (CB) receptors and/or of the enzymes controlling synthesis, transport, and degradation of these substances has emerged as a valuable option to treat neurological diseases.
Here, we describe the current knowledge concerning the rearrangement of ECS in a primarily inflammatory disorder of the central nervous system such as multiple sclerosis (MS), and in a primarily degenerative condition such as amyotrophic lateral sclerosis (ALS).
Furthermore, the data supporting a therapeutic role of agents modulating CB receptors or endocannabinoid tone in these disorders will also be reviewed. Complex changes of ECS take place in both diseases, influencing crucial aspects of their pathophysiology and clinical manifestations. Neuroinflammation, microglial activation, oxidative stress, and excitotoxicity are variably combined in MS and in ALS and can be modulated by endocannabinoids or by drugs targeting the ECS.”
Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson’s disease
“Previous findings have indicated that a cannabinoid, such as Δ(9)-THCV, which has antioxidant properties and the ability to activate CB(2) receptors but to block CB(1) , might be a promising therapy for alleviating symptoms and delaying neurodegeneration in Parkinson’s disease (PD).
…Given its antioxidant properties and its ability to activate CB(2) but to block CB(1) receptors, Δ(9)-THCV has a promising pharmacological profile for delaying disease progression in PD and also for ameliorating parkinsonian symptoms…
Conclusion
In summary, given its antioxidant properties and its ability to activate CB2 but block CB1 receptors at a dose of 2 mg·kg−1, Δ9-THCV seems to have an interesting and therapeutically promising pharmacological profile. Thus, in contrast to other phytocannabinoids that have been investigated to date, it shows promise both for the treatment of disease progression in PD and for the relief of PD symptoms. This represents an important advance in the search for potential novel anti-parkinsonian agents, since Δ9-THCV administered alone or in combination with CBD may provide a much needed improved treatment for PD.”
Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures.
Abstract
“Cannabinoids derived from Cannabis sativa demonstrate neuroprotective properties in various cellular and animal models. Mitochondrial impairment and consecutive oxidative stress appear to be major molecular mechanisms of neurodegeneration. Therefore we studied some major cannabinoids, i.e. delta-9-tetrahydrocannabinolic acid (THCA), delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in mice mesencephalic cultures for their protective capacities against 1-methyl-4-phenyl pyridinium (MPP(+)) toxicity. MPP(+) is an established model compound in the research of parkinsonism that acts as a complex I inhibitor of the mitochondrial respiratory chain, resulting in excessive radical formation and cell degeneration. MPP(+) (10 μM) was administered for 48 h at the 9th DIV with or without concomitant cannabinoid treatment at concentrations ranging from 0.01 to 10 μM. All cannabinoids exhibited in vitro antioxidative action ranging from 669 ± 11.1 (THC), 16 ± 3.2 (THCA) to 356 ± 29.5 (CBD) μg Trolox (a vitamin E derivative)/mg substance in the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay. Cannabinoids were without effect on the morphology of dopaminergic cells stained by tyrosine hydroxylase (TH) immunoreaction. THC caused a dose-dependent increase of cell count up to 17.3% at 10 μM, whereas CBD only had an effect at highest concentrations (decrease of cell count by 10.1-20% at concentrations of 0.01-10 μM). It influenced the viability of the TH immunoreactive neurons significantly, whereas THCA exerts no influence on dopaminergic cell count. Exposure of cultures to 10 μM of MPP(+) for 48 h significantly decreased the number of TH immunoreactive neurons by 44.7%, and shrunken cell bodies and reduced neurite lengths could be observed. Concomitant treatment of cultures with cannabinoids rescued dopaminergic cells. Compared to MPP(+) treated cultures, THC counteracted toxic effects in a dose-dependent manner. THCA and CBD treatment at a concentration of 10 μM lead to significantly increased cell counts to 123% and 117%, respectively. Even though no significant preservation or recovery of neurite outgrowth to control values could be observed, our data show that cannabinoids THC and THCA protect dopaminergic neurons against MPP(+) induced cell death.”