Neuroprotective agents: Cannabinoids

Sánchez, Antonio; García‐Merino, Antonio

doi:10.1016/j.clim.2011.02.010

Cited by 99 publications

(73 citation statements)

References 141 publications

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“…Especially thanks to animal models of MS, i.e., experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a great deal of evidence has been a c c u m u l a t e d f o r a r o l e o f c a n n a b i n o i d s i n t h e immunopathogenesis of MS. To date, it is clear that not only the cannabinoid system is profoundly altered in MS patients (Centonze et al 2007;Maccarrone et al 2011;Chiurchiu et al 2013), but also that phyCBs and syCBs have the potential to exert a myriad of immunomodulatory and neuroprotective effects (Pryce and Baker 2012;Granja et al 2012;Jawahar et al 2013). These findings paved the way to multiple clinical trials with cannabinoids and, at present, the cannabinoid oral spray Nabiximol®, which is a 1:10 mixture of the two cannabinoids THC and CBD, is available in the UK, in some European and Asian countries, but not yet in the U.S.A. (Sanchez and Garcia-Merino 2012). Nabiximol® was developed by GW Pharmaceuticals, and is currently prescribed for the neuropathic pain and spasticity associated with MS.…”

Section: Cannabinoid-based Modulation Of Neuroinflammatory Diseasesmentioning

confidence: 88%

Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses

Chiurchiù

Leuti

Maccarrone

2015

J Neuroimmune Pharmacol

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The concept of the central nervous system (CNS) as an immune-privileged site, essentially due to the presence of the blood brain barrier, appears to be overly simplistic. Indeed, within healthy CNS immune activities are permitted and are required for neuronal function and host defense, not only due to the presence of the resident innate immune cells of the brain, but also by virtue of a complex cross-talk of the CNS with peripheral immune cells. Nonetheless, long-standing and persisting neuroinflammatory responses are most often detrimental and characterize several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that Cannabis sativa-derived phytocannabinoids, as well as synthetic cannabinoids, are endowed with significant immunoregulatory and anti-inflammatory properties, both in peripheral tissues and in the CNS, through the activation of cannabinoid receptors. In this review, the immunomodulatory effects of cannabinoid signaling on the most relevant brain immune cells will be discussed. In addition, the impact of cannabinoid regulation on the overall integration of the manifold brain immune responses will also be highlighted, along with the implication of these compounds as potential agents for the management of neuroinflammatory disorders.

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Section: Cannabinoid-based Modulation Of Neuroinflammatory Diseasesmentioning

confidence: 88%

Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses

Chiurchiù

Leuti

Maccarrone

2015

J Neuroimmune Pharmacol

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“…Cannabinoid type 2 (CB2) receptors, in particular, are up-regulated in activated microglia associated with Alzheimer's and multiple sclerosis plaques (31,32) and are thought to regulate microglial motility (33). Microglial/glial CB2 activation, however, is generally considered neuroprotective, and it has been associated with a reduction in neurotoxic factor release (34). Determining whether ABHD12 regulates 2-AG in primary microglia and how the loss of ABHD12 affects CB2-mediated microglial activity are fertile topics for future research.…”

Section: Discussionmentioning

confidence: 99%

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

Blankman

Long

Trauger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

167

279

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Advances in human genetics are leading to the discovery of new disease-causing mutations at a remarkable rate. Many such mutations, however, occur in genes that encode for proteins of unknown function, which limits our molecular understanding of, and ability to devise treatments for, human disease. Here, we use untargeted metabolomics combined with a genetic mouse model to determine that the poorly characterized serine hydrolase α/β-hydrolase domain-containing (ABHD)12, mutations in which cause the human neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract), is a principal lysophosphatidylserine (LPS) lipase in the mammalian brain. ABHD12 −/− mice display massive increases in a rare set of very long chain LPS lipids that have been previously reported as Toll-like receptor 2 activators. We confirm that recombinant ABHD12 protein exhibits robust LPS lipase activity, which is also substantially reduced in ABHD12 −/− brain tissue. Notably, elevations in brain LPS lipids in ABHD12 −/− mice occur early in life (2-6 mo) and are followed by age-dependent increases in microglial activation and auditory and motor defects that resemble the behavioral phenotypes of human PHARC patients. Taken together, our data provide a molecular model for PHARC, where disruption of ABHD12 causes deregulated LPS metabolism and the accumulation of proinflammatory lipids that promote microglial and neurobehavioral abnormalities.lipidomics | neuroinflammation G enome mapping and sequencing have facilitated determination of the genetic basis for over 3,500 inherited diseases in humans (1), with additional pathogenic mutations still being discovered. For many Mendelian disorders, however, the molecular and cellular mechanisms that link genotype to disease phenotype remain poorly understood. This problem is perhaps most apparent for diseases where the causative mutations occur in genes that encode for proteins with unannotated or poorly characterized functions. Here, we focus on one such disease -the neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract).PHARC [Mendelian Inheritance in Man (MIM) no. 612674; Online Mendelian Inheritance in Man database, http://omim.org] is a rare, autosomal recessive disorder that causes polymodal sensory and motor defects associated with demyelination of sensomotor neurons, retinal dystrophy, and cerebellar atrophy (2). PHARC symptoms are slowly progressive and begin in the childhood or teenage years; heterozygous carriers are unaffected (3). In 2010, PHARC was reported to be caused by homozygous mutations in ABHD12, which codes for the poorly characterized serine hydrolase enzyme α/β-hydrolase domain-containing (ABHD)12 (3). To date, five distinct ABHD12 mutations have been identified in patients with PHARC, all of which are expected to lead to complete loss of ABHD12 expression (3, 4). PHARC, therefore, likely represents a human ABHD12 null model.We demonstrated previously that ABHD12 is a membranebound e...

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“…Literature has shown that endocannabinoids may have a beneficial impact on neurodegenerative [12] and neuroinflammatory diseases [13], in addition to playing a neuroprotective role through the activation of the G-protein coupled receptors, cannabinoid 1 (CB1) receptor and cannabinoid 2 (CB2) receptor [14,15]. Though CB1 receptors are widely distributed in the nervous system and peripheral organs, density is greater in the central nervous system, specifically in the cerebral cortex and hippocampus [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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Neuroprotective agents: Cannabinoids

Cited by 99 publications

References 141 publications

Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses

Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

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

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