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Cannabinoids control spasticity and tremor in a MS model

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Abstract

Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, delta9-tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis, and provides a means of evaluating more selective cannabinoids in the future.

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... Несмотря на разнородность химических структур, многие из производных морфолина обладают схожим спектром фармакологической активности. Для различных соединений в экспериментах на животных показана активность при таких заболеваниях нервной системы, как БА [18,19], БП [20,21,22], БАС [23], рассеянный склероз [24], хорея Гентингтона [25], ишемический инсульт [26] и когнитивные нарушения различной этиологии [27,28]. ...
... Еще одним нейродегенеративным заболеванием, эффективность в лечении которого продемонстрировал WIN 55,212-2, является рассеянный склероз [24]. У мышей с экспериментальным аллергическим энцефаломиелитом -общепринятой моделью РС [106] -WIN 55,212-2 уменьшал тремор и спастичность хвоста и конечностей спустя десять минут после внутрибрюшинного введения. ...
... У мышей с экспериментальным аллергическим энцефаломиелитом -общепринятой моделью РС [106] -WIN 55,212-2 уменьшал тремор и спастичность хвоста и конечностей спустя десять минут после внутрибрюшинного введения. На основании данных, полученных при превентивном введении мышам селективных антагонистов каннабиноидных рецепторов, авторы исследования предположили, что в данном случае ведущим механизмом действия WIN 55,212-2 является активация CB1-рецепторов [24]. ...
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Diseases of the nervous system, especially those of vascular, traumatic, and neurodegenerative nature, are characterized by high prevalence, disability and mortality rates, and therefore have a particularly big medical and social impact. Currently, pharmacotherapy options for these diseases are limited to a relatively small number of clinically proven drugs, which is largely due to the difficulties associated with the translation of preclinical studies results. This explains the essential importance of discovering and developing new drugs, both effective and safe, that could be used to reduce clinical manifestations of neurological disorders. The present review is aimed to give a detailed account of several biologically active derivatives of morpholine, a six-membered heterocyclic compound. As demonstrated by a number of in vitro and in vivo studies using cell and animal models, morpholine derivatives should be considered viable drug candidates for a broad range of neurological diseases.
... For example, tetrahydrocannabinol (THC) is used for the treatment of the symptoms of e.g. neurological diseases [3], multiple sclerosis [4] or cancer [5]. Other cannabinoids like cannabidiol (CBD), terpenes and phenolic compounds show further pharmacological effects, which make this plant a highly interesting pharmaceutical target [6]. ...
... The 3D animations of a drug-type (Additional file 3) and a fibre-type glandular trichome (Additional file 4) show that the C-H stretching signal of the essential oil (red and orange, respectively) is only dominant in the secretory cavities. The stalk is dominated by TPF of organic substances (grey). ...
Article
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Background Cannabis possesses a rich spectrum of phytochemicals i.e. cannabinoids, terpenes and phenolic compounds of industrial and medicinal interests. Most of these high-value plant products are synthesised in the disk cells and stored in the secretory cavity in glandular trichomes. Conventional trichome analysis was so far based on optical microscopy, electron microscopy or extraction based methods that are either limited to spatial or chemical information. Here we combine both information to obtain the spatial distribution of distinct secondary metabolites on a single-trichome level by applying Coherent anti-Stokes Raman scattering (CARS), a microspectroscopic technique, to trichomes derived from sepals of a drug- and a fibre-type. Results Hyperspectral CARS imaging in combination with a nonlinear unmixing method allows to identify and localise Δ⁹-tetrahydrocannabinolic acid (THCA) in the secretory cavity of drug-type trichomes and cannabidiolic acid (CBDA)/myrcene in the secretory cavity of fibre-type trichomes, thus enabling an easy discrimination between high-THCA and high-CBDA producers. A unique spectral fingerprint is found in the disk cells of drug-type trichomes, which is most similar to cannabigerolic acid (CBGA) and is not found in fibre-type trichomes. Furthermore, we differentiate between different cell types by a combination of CARS with simultaneously acquired two-photon fluorescence (TPF) of chlorophyll a from chloroplasts and organic fluorescence mainly arising from cell walls enabling 3D visualisation of the essential oil distribution and cellular structures. Conclusion Here we demonstrate a label-free and non-destructive method to analyse the distribution of secondary metabolites and distinguish between different cell and chemo-types with high spatial resolution on a single trichome. The record of chemical fingerprints of single trichomes offers the possibility to optimise growth conditions as well as guarantee a direct process control for industrially cultivated medicinal Cannabis plants. Moreover, this method is not limited to Cannabis related issues but can be widely implemented for optimising and monitoring all kinds of natural or biotechnological production processes with simultaneous spatial and chemical information. Electronic supplementary material The online version of this article (10.1186/s12870-018-1481-4) contains supplementary material, which is available to authorized users.
... Chronic administration of JWH-133 reduces sperm count. Young male mice at P7 were injected with JWH-133 (1.5 mg/kg) 10,14,15 or vehicle (see methods) and, at the end of 5 weeks, they were weighed and sacrificed. No differences between control and treated mice in body weight were detected at adulthood when they reached sexual maturity (Fig. 1A), while a significant reduction in testis weight of treated males was observed (Fig. 1B). ...
... Control group (n = 12) was injected with the vehicle phosphate-buffered saline (PBS). The dosage of administrations were based on previous studies 10,14,15,26,45 . At the end of treatment, control (n = 6/12) and JWH-133-treated mice (n = 6/12) were randomly selected and crossed with untreated and sexually mature CD-1 female (single male pared with single female, n = 3 total females for each male) in order to analyze fertility and offspring health. ...
Article
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The cannabinoid receptor type 2 (CB2) is the peripheral receptor for cannabinoids, involved in the homeostatic control of several physiological functions. Male mitotic germ cells express a high level of CB2, whose activation promotes their differentiation in both in vitro and in vivo experiments, controlling the correct progression of spermatogenesis. However, it remains elusive if CB2 activation in spermatogonia could affect reproductive success in terms of fertility and healthy pregnancy outcomes. In this study, we explored the effects of male CB2 activation on sperm number and quality and its influence on next generation health. We show that exposure of male mice to JWH-133, a selective CB2 agonist, decreased sperm count, impaired placental development and reduced offspring growth. These defects were associated with altered DNA methylation/hydroxymethylation levels at imprinted genes in sperm and conserved in placenta. Our findings reveal that paternal selective activation of CB2 alters the sperm epigenome and compromises offspring growth. This study demonstrates, for the first time, a new role of CB2 signaling in male gametes in causing epigenetic alterations that can be transmitted to the next generation by sperm, highlighting potential risks induced by recreational cannabinoid exposure.
... In this model, it was observed, in parallel with the entrance in the chronic phase, a profound neurodegeneration leading to hind-limb spasticity, elevated levels in the brain and spinal cord of AEA, its congener palmitoylethanolamide (3, PEA, Figure 3), and 2-AG, with respect to non-spastic EAE mice and healthy controls. [96,97,98,99,100] Interestingly, spasticity was rapidly increased after administration of a CB1R agonist, thus supporting the evidence that mitigation of hind limb spasticity is CB1R dependent and possibly derives from an endogenous compensatory mechanism mediated by the elevated ECs levels. [101,102] However, already three decades ago and even before EC description and categorization, the efficacy of Δ9-tetrahydrocannabinol (4, Δ9-THC, Figure 3), the psychoactive component of marijuana, to suppress EAE symptoms was reported [103] and, soon after, the efficacy of Δ8-THC (5, Figure 3), its less psychotropic analogue, was established in the same model. ...
... [101,102] However, already three decades ago and even before EC description and categorization, the efficacy of Δ9-tetrahydrocannabinol (4, Δ9-THC, Figure 3), the psychoactive component of marijuana, to suppress EAE symptoms was reported [103] and, soon after, the efficacy of Δ8-THC (5, Figure 3), its less psychotropic analogue, was established in the same model. [104] Later on, Baker and coworkers demonstrated that CBRs agonism using R-(+)-WIN 55,212 (6), Δ9-THC, methanandamide (7) and JWH-133 (8) (Figure 3) quantitatively ameliorated both tremor and spasticity in EAE mice thus providing a rationale for the therapeutic potential of cannabis in the control of the symptoms of MS. [105,96,106] The crucial role of ECs in neuroinflammation-derived neurodegeneration was also confirmed in CB1R-null mice, in which the rate of degeneration was increased with respect to wild-type EAE mice. In particular, these studies clearly indicate that the lack of CB1R is associated with an augmented caspase activation and with the loss of myelin proteins. ...
Article
Multiple sclerosis (MS) is a chronic, immune‐mediated disease of the central nervous system. At present, there is not a definitive cure and the few available disease‐modifying options display either poor efficacy or life‐threatening side effects. Currently, there is clear evidence that relapsing‐remitting clinical attacks in MS are driven by inflammatory demyelination and that the subsequent disease steps, being irresponsive to immunotherapy, result from neurodegeneration. The endocannabinoid system (ECS) stands halfway between three key patho‐mechanisms underlying MS, namely inflammation, neurodegeneration and oxidative stress, thus representing a kingpin for the identification of novel therapeutic targets in MS. This review aims at summarizing the current state of the art in the field of endocannabinoid metabolism modulators and their in vivo effects on relevant animal models. We also highlighted key molecular underpinnings of their therapeutic efficacy as well as the potential to turn them into promising clinical candidates.
... b, Intrathecal injection of a vehicle had no effect on harmaline-induced tremor. c, Area under the power spectra curve (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Each dot pair corresponds to one animal. ...
... e, Pretreatment with AM281 and subsequent intrathecal injection of a vehicle had no effect on tremor. f, Area under the power spectra curve (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Each dot pair corresponds to one animal. ...
Article
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Cannabinoids reduce tremor associated with motor disorders induced by injuries and neurodegenerative disease. Here we show that this effect is mediated by cannabinoid receptors on astrocytes in the ventral horn of the spinal cord, where alternating limb movements are initiated. We first demonstrate that tremor is reduced in a mouse model of essential tremor after intrathecal injection of the cannabinoid analog WIN55,212-2. We investigate the underlying mechanism using electrophysiological recordings in spinal cord slices and show that endocannabinoids released from depolarized interneurons activate astrocytic cannabinoid receptors, causing an increase in intracellular Ca2+, subsequent release of purines and inhibition of excitatory neurotransmission. Finally, we show that the anti-tremor action of WIN55,212-2 in the spinal cords of mice is suppressed after knocking out CB1 receptors in astrocytes. Our data suggest that cannabinoids reduce tremor via their action on spinal astrocytes. Astrocytes regulate synaptic transmission. Carlsen et al. report that spinal astrocytes activated by endocannabinoids inhibit excitatory synaptic transmission and, thereby, decrease tremor.
... It is being evaluated for tuberous sclerosis complex e Withdrawn from the global market because of its psychological side effects, including depression and suicidal impulses f In several states in USA, cannabis extracts are approved for post-traumatic stress disorder g Including pain, insomnia, stress, MS The administration of several cannabinoid receptor agonists (K i values are listed in Table 2) including Δ 9 -THC, WIN 55,212-2, JWH-133 (a more selective CB 2 agonist) and methanandamide (AEA analogue) was shown to lessen tremor and spasticity associated with this pathology in mouse models of MS. This action appeared to involve cannabinoid receptors because the use of specific antagonists of these receptors produced an exacerbation of symptoms that was more marked with CB 1 blockage [39]. Other authors have also identified the CB 1 receptor as primarily responsible for cannabinoid anti-spastic action because the spasticity reduction of CB 2 agonists was absent in CB 1 -deficient mice [40]. ...
Article
Cannabinoid receptors, endocannabinoids and the enzymes responsible for their biosynthesis and degradation constitute the endocannabinoid system. In recent decades, the endocannabinoid system has attracted considerable interest as a potential therapeutic target in numerous pathological conditions. Its involvement in several physiological processes is well known, such as in energy balance, appetite stimulation, blood pressure, pain modulation, embryogenesis, nausea and vomiting control, memory, learning and immune response, among others, as well as in pathological conditions where it exerts a protective role in the development of certain disorders. As a result, it has been reported that changes in endocannabinoid levels may be related to neurological diseases such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and multiple sclerosis, as well as anorexia and irritable bowel syndrome. Alterations in the endocannabinoid system have also been associated with cancer, affecting the growth, migration and invasion of some tumours. Cannabinoids have been tested in several cancer types, including brain, breast and prostate cancers. Cannabinoids have shown promise as analgesics for the treatment of both inflammatory and neuropathic pain. There is also evidence for a role of the endocannabinoid system in the control of emotional states, and cannabinoids could prove useful in decreasing and palliating post-traumatic stress disorder symptoms and anxiolytic disorders. The role of the endocannabinoid system in addictions has also been examined, and cannabinoids have been postulated as alternative and co-adjuvant treatments in some abuse syndromes, mainly in ethanol and opioid abuses. The expression of the endocannabinoid system in the eye suggests that it could be a potential therapeutic target for eye diseases. Considering the importance of the endocannabinoid system and the therapeutic potential of cannabinoids in this vast number of medical conditions, several clinical studies with cannabinoid-based medications are ongoing. In addition, some cannabinoid-based medications have already been approved in various countries, including nabilone and dronabinol capsules for the treatment of nausea and vomiting associated with chemotherapy, dronabinol capsules for anorexia, an oral solution of dronabinol for both vomiting associated with chemotherapy and anorexia, a Δ⁹-tetrahydrocannabinol/cannabidiol oromucosal spray for pain related to cancer and for spasticity and pain associated with multiple sclerosis, and an oral solution of cannabidiol for Dravet and Lennox–Gastaut syndromes. Here, we review the available efficacy, safety and tolerability data for cannabinoids in a range of medical conditions.
... Embora os compostos do vegetal produzam efeitos sobre um determinado número de órgãos, dentre os quais estão incluídos o sistema imunológico e reprodutivo, os efeitos terapêuticos apurados estão relacionados ao sistema nervoso central. Esses efeitos, em seres humanos correspondem à: analgesia (Brooks, 2002), mudança de humor, atua aumentando o apetite em pessoas tratados com quimioterapia (pacientes portadores de HIV e câncer) (Mechoulam, 1973), atividades psicomotoras com alteração, na percepção, na cognição, na memória, no controle da espasticidade em pacientes esclerótico (Baker et al., 2000). ...
... CBD, along with Δ9-tetrahydrocannabinol (THC), is a major phytocannabinoid and both are well described components of medicines. Unlike THC, CBD is not psychoactive and is now being used to treat epilepsy (O'Connell et al., 2017;Baker et al., 2000). A growing number of studies have demonstrated the anticancer properties of CBD, in both in vitro and in vivo models (Ramer and Hinz, 2017;Kis et al., 2019). ...
Article
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The cannabinoid, cannabidiol (CBD), is part of the plant's natural defense system that when given to animals has many useful medicinal properties, including activity against cancer cells, modulation of the immune system, and efficacy in epilepsy. Although there is no consensus on its precise mode of action as it affects many cellular targets, CBD does appear to influence mitochondrial function. This would suggest that there is a cross-kingdom ability to modulate stress resistance systems that enhance homeostasis. As NAD(P)H autofluorescence can be used as both a metabolic sensor and mitochondrial imaging modality, we assessed the potential of this technique to study the in vitro effects of CBD using 2-photon excitation and fluorescence lifetime imaging microscopy (2P-FLIM) of NAD(P)H against more traditional markers of mitochondrial morphology and cellular stress in MCF7 breast cancer cells. 2P-FLIM analysis revealed that the addition of CBD induced a dose-dependent decrease in bound NAD(P)H, with 20 µM treatments significantly decreased the contribution of bound NAD(P)H by 14.6% relative to the control (p < 0.001). CBD also increased mitochondrial concentrations of reactive oxygen species (ROS) (160 ± 53 vs. 97.6 ± 4.8%, 20 µM CBD vs. control, respectively, p < 0.001) and Ca 2+ (187 ± 78 vs. 105 ± 10%, 20 µM CBD vs. the control, respectively, p < 0.001); this was associated with a significantly decreased mitochondrial branch length and increased fission. These are all suggestive of mitochondrial stress. Our results support the use of NAD(P)H autofluorescence as an investigative tool and provide further evidence that CBD can modulate mitochondrial function and morphology in a dose-dependent manner, with clear evidence of it inducing oxidative stress at higher concentrations. This continues to support emerging data in the literature and may provide further insight into its overall mode of action, not only in cancer, but potentially its function in the plant and why it can act as a medicine.
... There is a need for new treatments for these conditions. Cannabinoids have long been used to alleviate muscular problems (Borgelt et al., 2013;Baker et al., 2000). In this study, we show that CBD reduces skeletal contraction in rat diaphragm muscle. ...
Article
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Cannabidiol (CBD) is the primary nonpsychotropic phytocannabinoid found in Cannabis sativa, which has been proposed to be therapeutic against many conditions, including muscle spasms. Among its putative targets are voltage-gated sodium channels (Navs), which have been implicated in many conditions. We investigated the effects of CBD on Nav1.4, the skeletal muscle Nav subtype. We explored direct effects, involving physical block of the Nav pore, as well as indirect effects, involving modulation of membrane elasticity that contributes to Nav inhibition. MD simulations revealed CBD’s localization inside the membrane and effects on bilayer properties. Nuclear magnetic resonance (NMR) confirmed these results, showing CBD localizing below membrane headgroups. To determine the functional implications of these findings, we used a gramicidin-based fluorescence assay to show that CBD alters membrane elasticity or thickness, which could alter Nav function through bilayer-mediated regulation. Site-directed mutagenesis in the vicinity of the Nav1.4 pore revealed that removing the local anesthetic binding site with F1586A reduces the block of INa by CBD. Altering the fenestrations in the bilayer-spanning domain with Nav1.4-WWWW blocked CBD access from the membrane into the Nav1.4 pore (as judged by MD). The stabilization of inactivation, however, persisted in WWWW, which we ascribe to CBD-induced changes in membrane elasticity. To investigate the potential therapeutic value of CBD against Nav1.4 channelopathies, we used a pathogenic Nav1.4 variant, P1158S, which causes myotonia and periodic paralysis. CBD reduces excitability in both wild-type and the P1158S variant. Our in vitro and in silico results suggest that CBD may have therapeutic value against Nav1.4 hyperexcitability.
... WIN-55,212-2 was reported to reduce inflammatory infiltrates in spinal cord and also induced apoptosis of encephalitogenic Tcell populations, partially via the CB2R in EAE model [548]. However, CB1R-related therapies cannot be disregarded since the CB1R has also been reported to treat various symptoms of MS, such as spasticity [549,550]. Interestingly, CB1Rs expressed on neuronal cells, but not on T cells, were also shown to have a critical role in cannabinoid-mediated attenuation of EAE pathology [551]. ...
Article
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The identification of the human cannabinoid receptors and their roles in health and disease, has been one of the most significant biochemical and pharmacological advancements to have occurred in the past few decades. In spite of the major strides made in furthering endocannabinoid research, therapeutic exploitation of the endocannabinoid system has often been a challenging task. An impaired endocannabinoid tone often manifests as changes in expression and/or functions of type 1 and/or type 2 cannabinoid receptors. It becomes important to understand how alterations in cannabinoid receptor cellular signaling can lead to disruptions in major physiological and biological functions, as they are often associated with the pathogenesis of several neurological, cardiovascular, metabolic, and inflammatory diseases. This review focusses mostly on the pathophysiological roles of type 1 and type 2 cannabinoid receptors, and it attempts to integrate both cellular and physiological functions of the cannabinoid receptors. Apart from an updated review of pre-clinical and clinical studies, the adequacy/inadequacy of cannabinoid-based therapeutics in various pathological conditions is also highlighted. Finally, alternative strategies to modulate endocannabinoid tone, and future directions are also emphasized.
... It has been reported that cannabinoid receptor agonists exert neuroprotective effects in mixed cortical cultures exposed to AMPA and NMDA, therefore reducing neuronal death Loría et al., 2010). Additionally, the CB1-mediated signaling is essential for tremor and spasticity control in animal model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) and EAE in CB1 knockout mice (Baker et al., 2000;Pryce and Baker, 2007). Besides, the dual activation of CB1 and CB2 by WIN 55,212-2, a cannabinoid agonist, improves the clinical score shown by animals, reduces inflammation and restores tolerance to selfmyelin antigen (Arevalo-Martin et al., 2012), while WOBE437, an inhibitor of eCB reuptake, reduces MS severity and infiltration of immune cells into the CNS (Reynoso-Moreno et al., 2021). ...
Article
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Historically, Cannabis is one of the first plants to be domesticated and used in medicine, though only in the last years the amount of Cannabis-based products or medicines has increased worldwide. Previous preclinical studies and few published clinical trials have demonstrated the efficacy and safety of Cannabis-based medicines in humans. Indeed, Cannabis-related medicines are used to treat multiple pathological conditions, including neurodegenerative disorders. In clinical practice, Cannabis products have already been introduced to treatment regimens of Alzheimer’s disease, Parkinson’s disease and Multiple Sclerosis’s patients, and the mechanisms of action behind the reported improvement in the clinical outcome and disease progression are associated with their anti-inflammatory, immunosuppressive, antioxidant, and neuroprotective properties, due to the modulation of the endocannabinoid system. In this review, we describe the role played by the endocannabinoid system in the physiopathology of Alzheimer, Parkinson, and Multiple Sclerosis, mainly at the neuroimmunological level. We also discuss the evidence for the correlation between phytocannabinoids and their therapeutic effects in these disorders, thus describing the main clinical studies carried out so far on the therapeutic performance of Cannabis-based medicines.
... First synthesised in 1999, JWH-133 is a THC analogue which is a highly selective, full agonist for CB 2 [73]. Excitingly, this synthetic cannabinoid has been shown to reduce spasticity in a murine model of multiple sclerosis [74], thus highlighting the therapeutic potential of selective synthetic cannabinoids. JWH-015 is also a selective CB 2 agonist which is widely used to date for CB 2 research [75,53]. ...
Article
Alzheimer's disease (AD) is a neurodegenerative disorder which accounts for 60-70% of the 50 million worldwide cases of dementia and is characterised by cognitive impairments, many of which have long been associated with dysfunction of the cholinergic system. Although the M1 muscarinic acetylcholine receptor (mAChR) is considered a promising drug target for AD, ligands targeting this receptor have so far been unsuccessful in clinical trials. As modulatory receptors to cholinergic transmission, the endocannabinoid system may be a promising drug target to allow fine tuning of the cholinergic system. Furthermore, disease-related changes have been found in the endocannabinoid system during AD progression and indeed targeting the endocannabinoid system at specific disease stages alleviates cognitive symptoms in numerous mouse models of AD. Here we review the role of the endocannabinoid system in AD, and its crosstalk with mAChRs as a potential drug target for cholinergic dysfunction.
... Cannabis was tried to manage persistent symptoms of MS such as tremor and spasticity. The anti-tremor effect of cannabis could involve the cholinergic, GABAergic, serotonergic, betaadrenergic, and cannabinoid systems [59,60]. Cannabis seemed to be beneficial for spasticity in MS. ...
Article
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Tremor is an important and common symptom in patients with multiple sclerosis (MS). It constituted one of the three core features of MS triad described by Charcot in the last century. Tremor could have a drastic impact on patients' quality of life. This paper provides an overview of tremor in MS and future perspectives with a particular emphasis on its epidemiology (prevalence: 25-58%), clinical characteristics (i.e., large amplitude 2.5-7 Hz predominantly postural or intention tremor vs. exaggerated physiological tremor vs. pseudo-rhythmic activity arising from cerebellar dysfunction vs. psychogenic tremor), pathophysiological mechanisms (potential implication of cerebellum, cerebello-thalamo-cortical pathways, basal ganglia, and brainstem), assessment modalities (e.g., tremor rating scales, Stewart-Holmes maneuver, visual tracking, digitized spirography and accelerometric techniques, accelerometry-electromyography coupling), and therapeutic options (i.e., including pharmacological agents, botulinum toxin A injections; deep brain stimulation or thalamotomy reserved for severe, disabling, or pharmaco-resistant tremors). Some suggestions are provided to help overcome the unmet needs and guide future therapeutic and diagnostic studies in this complex disorder.
... According to our literature research, there is no standard measure in rodents -especially in mice. Reports of clinical signs of spasticity such as a flexed elbow and forepaw are rare (Baker et al., 2000). Despite the genetic model, i.e., the spastic mice, characterized by a reduced muscle growth compared to wild type mice (Ziv et al., 1984), there are no reports in mice that investigated muscle spasms or increased muscle tone using force measurements and electromyographic recordings, as it has been reported in the well-established spastic rat tail model (Bennett et al., 1999). ...
Article
Although spasticity is one of the most common causes of motor disability worldwide, its precise definition and pathophysiology remain elusive, which to date renders its experimental targeting tricky. At least in part, this difficulty is caused by heterogeneous phenotypes of spasticity-causing neurological disorders, all causing spasticity by involving upper motor neurons. The most common clinical symptoms are a series of rapid muscle contractions (clonus), an increased muscle tone (hypertonia), and augmented tendon reflex activity (hyperreflexia). This muscle overactivity is due to disturbed inhibition of spinal reflexes following upper motor neuron dysfunction. Despite a range of physical and pharmacological therapies ameliorating the symptoms, their targeted application remains difficult. Therefore, to date, spasticity impacts rehabilitative therapy, and no therapy exists that reverses the pathology completely. In contrast to the incidence and importance of spasticity, only very little pre-clinical work in animal models exists, and this research is focused on the cat or the rat spastic tail model to decipher altered reflexes and excitability of the motor neurons in the spinal cord. Meanwhile, the characterization of spasticity in clinically more relevant mouse models of neurological disorders, such as stroke, remains understudied. Here, we provide a brief introduction into the clinical knowledge and therapy of spasticity and an in-depth review of pre-clinical studies of spasticity in mice including the current experimental challenges for clinical translation.
... Cannabinoids have long been used to alleviate muscular problems 59,60 . In this study, we show CBD reduces skeletal contraction in rat diaphragm muscle. ...
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Cannabis sativa contains active constituents called phytocannabinoids. Some phytocannabinoids are psychotropic and others are not. The primary non-psychotropic phytocannabinoid is cannabidiol (CBD), which is proposed to be therapeutic against many conditions, including muscle spasms. Mechanisms have been proposed for the action of CBD on different systems, involving multiple targets, including the voltage-gated sodium channel (Nav) family, which are heavily implicated in many of the conditions CBD has been reported to relieve. In this study, we investigated the modulatory mechanism of CBD on Nav1.4. Based on previous results, we tested the hypothesis that CBD mechanism of action involves: 1) modulation of membrane elasticity, which indirectly contributes to Nav inhibition; and 2) physical block of the Nav pore. We first performed molecular dynamic (MD) simulations to visualize CBD effects and localization inside the membrane, and then performed NMR to verify the MD results, showing CBD localizes below membrane headgroups. Then, we performed a gramicidin-based fluorescence (GFA) assay that showed CBD alters membrane elasticity. Next, we used site-directed mutagenesis in (F1586A) and around (WWWW) the Nav1.4 pore. Removing the local anesthetic binding site with F1586A reduced CBD block of INa. Occluding the fenestrations with WWWW blocked CBD access from the membrane into the Nav1.4 pore. However, stabilization of inactivation, via CBD-induced changes in membrane elasticity persisted, in WWWW. To investigate the potential therapeutic value of CBD against some Nav1.4 channelopathies, we used a pathogenic variant of Nav1.4, P1158S, known to cause myotonia and periodic paralysis. We found CBD reduces excitability in both wild-type and the mixed myotonia/periodic paralysis variant. Our in-vitro/in-silico results suggest that CBD may have therapeutic value against myotonia. Because Nav1.4 is crucial to skeletal muscle contraction, we used rat diaphragm myography and found the presence of saturating levels of CBD reduces skeletal muscle contraction. SUMMARY We used multidisciplinary approaches to show the mechanism and pathway by which CBD inhibits the skeletal muscle, Nav1.4. Our results suggest CBD modulates membrane elasticity and directly interacts with Nav1.4 within its pore.
... It acts on the function of neurotransmitters and transient receptor potential (TRP) channels [32]. It also has anti-inflammatory [33], analgesic [34], antispastic [35], antineoplastic [36] and antiemetic activity [37], it is also considered as a bronchodilator [38], a powerful antioxidant [39] and antipruritic agent [40]. Despite these potential beneficial effects on human health, THC may also have side effects in the human body such as anxiety, memory loss, and immunosuppression [31]. ...
Article
Cannabis sativa is a source of food, fiber and specialized metabolites such as cannabinoids, with psychoactive and pharmacological effects. Due to its expanding and increasingly-accepted use in medicine, cannabis cultivation is acquiring more importance and less social stigma. Humans initiated different domestication episodes whose later spread gave rise to a plethora of landrace cultivars. At present, breeders cross germplasms from different gene pools depending on their specific use. The fiber (hemp) and drug (marijuana) types of C. sativa differ in their cannabinoid chemical composition phenotype (chemotype) and also in the accumulation of terpenoid compounds that constitute a strain’s particular flavor and scent. Cannabinoids are isoprenylated polyketides among which cannabidiolic acid (CBDA) and (−)-trans-Δ⁹-tetrahydrocannabinol acid (THCA) have been well-documented for their many effects on humans. Here, we review the most studied specialized metabolic pathways in C. sativa, showing how terpenes and cannabinoids share both part of the isoprenoid pathway and the same biosynthetic compartmentalization (i.e. glandular trichomes of leaves and flowers). We enlist the several studies that have deciphered these pathways in this species including physical and genetic maps, QTL analyses and localization and enzymatic studies of cannabinoid and terpene synthases. In addition, new comparative modeling of cannabinoid synthases and phylogenetic trees are presented. We describe the genome sequencing initiatives of several accessions with the concomitant generation of next-generation genome maps and transcriptomic data. Very recently, proteomic characterizations and systems biology approaches such as those applying network theory or the integration of multi-omics data have increased the knowledge on gene function, enzyme diversity and metabolite content in C. sativa. In this revision we drift through the history, present and future of cannabis research and on how second- and third-generation sequencing technologies are bringing light to the field of cannabis specialized metabolism. We also discuss different biotechnological approaches for producing cannabinoids in engineered microorganisms. Cannabis sativa L. belongs to a genus of flowering plants with annual-growth and dioecious behaviour, native to Central and South Asia and with a long history of human use. Research in this species has grown exponentially in the last decade thanks to the unbanning of its cultivation in several world regions. This has permitted studying how the converging action of human- and nature-driven evolution of C. sativa has resulted in a plethora of valuable and complex specialized metabolites (SM). These are the center of attention of this review. Here, we cover how the emergence of genome-wide studies and the integration of big data analysis (i.e. systems biology, sysbio) is enabling us to comprehend the genetic regulation of cannabis secondary metabolism. Despite focusing on the outreach of genomic platforms and sysbio approaches, we also cover important aspects of cannabis history, effects of SM on human physiology and latest biotechnological approaches, all of which need to be acknowledged to understand the past, present and future of cannabis research.
... 10 With the different distribution of the two receptors, the CB2 receptor has unique physiological and pharmacological effects, such as immunosuppression, inhibition of tumor cell growth, bone formation, anti-fibrosis, and anti-neurological injury, while the CB1 receptor is involved in psychotropic or other CNS-related effects. [11][12][13][14][15][16] In terms of pain relief, antiinflammation, and inhibition of cough, 16,17 the CB2 receptor is almost non-addictive and non-tolerable, and hence targeting it will have a significant therapeutic value. A significant amount of research has been dedicated to the development of CB2 receptor ligands due to their high efficacy and high selectivity. ...
Article
The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonist with high efficacy and selectivity, a series of indole derivatives with N-ethyl morpholine moieties (Compound 1-56) were designed, synthesized and biologically evaluated. Compounds 1, 2, 3, 46 and 51 possessed high CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC50(CB1)/EC50(CB2) greater than 1000). The most active compound, Compound 2, was more potent than the standard drug GW405833 for in vitro agonistic action on the CB2 receptor. More importantly, in a rat model for CFA-induced inflammatory hyperalgesia, Compound 2 had a potent anti-inflammatory pain effect within 12 hours after administration. At the 1-h time point, Compoud 2 had a dose-dependent reversal for hyperalgesia with an estimated ED50 value of 1.097mg/kg. Moreover, Compound 2 significantly suppressed the pro-inflammatory cytokines (IL-1β,IL-6 and TNF-α) in CFA-induced lesions. These protective effects of Compound 2 on inflammatory pain was superior to GW405833, suggesting that Compound 2 may be a promising therapeutic that needs further validation.
... EAE has also been used as an in vivo model for validating symptomatic treatments. Baker et al. demonstrated that the treatment with cannabinoids was able to control spasticity and tremor in EAE (51). Furthermore, bladder signs of MS could be mimicked in EAE and the utility of future drugs for neurogenic bladder impairment in MS could be tested in this model (52). ...
Article
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Immune-mediated inflammatory diseases of the central nervous system (CNS) are a group of neurological disorders in which inflammation and/or demyelination are induced by cellular and humoral immune responses specific to CNS antigens. They include diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), acute disseminated encephalomyelitis (ADEM) and anti-NMDA receptor encephalitis (NMDAR encephalitis). Over the years, many in vivo and in vitro models were used to study clinical, pathological, physiological and immunological features of these neuroimmunological disorders. Nevertheless, there are important aspects of human diseases that are not fully reproduced in the experimental models due to their technical limitations. In this review, we describe the preclinical models of neuroimmune disorders, and how they contributed to the understanding of these disorders and explore potential treatments. We also describe the purpose and limitation of each one, as well as the recent advances in this field.
... Different studies in MS mouse models have shown positive effects following the activation of CBRs [14]. In murine Theiler's encephalitis virus-induced demyelinating disease (TMEV-IDD) and chronic relapsing autoimmune encephalomyelitis (CREAE), treatment with CBR agonists revealed a beneficial impact on inflammation, improving tremor and spasticity [39,40]. Immunohistochemical analysis in post-mortem brains of MS patients showed an upregulation of microglia CB2Rs and increased amounts of FAAH metabolites [41]. ...
Article
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Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress and neuronal depletion. The broad-spectrum neuroprotective activity of the Mediterranean diet is widely documented, but it is not yet known whether its nutritional and caloric balance can induce a modulation of the endocannabinoid system. In recent decades, many studies have shown how endocannabinoid tone enhancement may be a promising new therapeutic strategy to counteract the main hallmarks of neurodegeneration. From a phylogenetic point of view, the human co-evolution between the endocannabinoid system and dietary habits could play a key role in the pro-homeostatic activity of the Mediterranean lifestyle: this adaptive balance among our ancestors has been compromised by the modern Western diet, resulting in a “clinical endocannabinoid deficiency syndrome”. This review aims to evaluate the evidence accumulated in the literature on the neuroprotective, immunomodulatory and antioxidant properties of the Mediterranean diet related to the modulation of the endocannabinoid system, suggesting new prospects for research and clinical interventions against neurodegenerative diseases in light of a nutraceutical paradigm.
... In patients who suffer from neuropathic pain, it could significantly reduce the intensity of chronic pain and also improve sleep. Cannabis also helps with involuntary muscle tightness and reduces muscle tremors and spasticity (Baker and others 2000;Borgelt and others 2013;Iannotti and others 2019;Pertwee 2008;Ware and others 2010;Wilsey and others 2013;Woodhams and others 2015). In addition to the plant-based phytocannabinoids, much effort has gone into studying the endogenous cannabinoids, 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide), which have important physiological implications (De Petrocellis and others 2011; Iannotti and others 2019). ...
Article
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Voltage-gated sodium (Nav) channels initiate action potentials in excitable tissues. Altering these channels’ function can lead to many pathophysiological conditions. Nav channels are composed of several functional and structural domains that could be targeted pharmacologically as potential therapeutic means against various neurological conditions. Mutations in Nav channels have been suggested to underlie various clinical syndromes in different tissues and in association with conditions ranging from epileptic to muscular problems. Treating those mutations that increase the excitability of Nav channels requires inhibitors that could effectively reduce channel firing. The main non-psychotropic constituent of the cannabis plant, cannabidiol (CBD), has recently gained interest as a viable compound to treat some of the conditions that are associated with Nav malfunctions. In this review, we discuss an overview of Nav channels followed by an in-depth description of the interactions of CBD and Nav channels. We conclude with some clinical implications of CBD use against Nav hyperexcitability based on a series of preclinical studies published to date, with a focus on Nav/CBD interactions.
... In addition, THC can act as an agonist of G-protein-coupled receptors (GPR55 and GPR18), the peroxisome proliferator-activated receptor (PPARγ), and transient receptor potential channels (TRPA1, TRPV2, TRPV3, and TRPV4), and as an antagonist of transient receptor potential channel TRPM8 and 5-HT3 receptor A, and can increase anandamide and adenosine levels [38,48]. Numerous studies have shown that CBD possesses analgesic [16,49], neuroprotective [40], anticonvulsant [11], antiemetic [50], spasmolytic [51], and anti-inflammatory [11,12,52] properties ( Figure 3). Unlike THC, CBD has a very low affinity for both CB1 and CB2 receptors, with K i of 4359 and 2860 nM, respectively [47]. ...
Article
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Cannabis (Cannabis sativa L.) plants from the family Cannabidaceae have been used since ancient times, to produce fibers, oil, and for medicinal purposes. Psychoactive delta-9-tetrahydrocannabinol (THC) and nonpsychoactive cannabidiol (CBD) are the main pharmacologically active compounds of Cannabis sativa. These compounds have, for a long time, been under extensive investigation, and their potent antioxidant and inflammatory properties have been reported, although the detailed mechanisms of their actions have not been fully clarified. CB1 receptors are suggested to be responsible for the analgesic effect of THC, while CB2 receptors may account for its immunomodulatory properties. Unlike THC, CBD has a very low affinity for both CB1 and CB2 receptors, and behaves as their negative allosteric modulator. CBD activity, as a CB2 receptor inverse agonist, could be important for CBD anti-inflammatory properties. In this review, we discuss the chemical properties and bioavailability of THC and CBD, their main mechanisms of action, and their role in oxidative stress and inflammation.
... In a report done by Baker et al., mice suffering from chronic relapsing EAE were treated with ∆ 9 -THC, methanandamide (analogue of AEA), WIN 55,212-2 (agonist of both CB1R and CB2R) and JWH-133 (agonist of CBR type 2). The treatment reduced motor symptoms, including limb spasticity, tremor and paralysis [203]. It was hypothesized that it could control clinical EAE symptoms through inhibition of synaptic transmission [204]. ...
Article
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Neurodegenerative diseases are an increasing cause of global morbidity and mortality. They occur in the central nervous system (CNS) and lead to functional and mental impairment due to loss of neurons. Recent evidence highlights the link between neurodegenerative and inflammatory diseases of the CNS. These are typically associated with several neurological disorders. These diseases have fundamental differences regarding their underlying physiology and clinical manifestations, although there are aspects that overlap. The endocannabinoid system (ECS) is comprised of receptors (type-1 (CB1R) and type-2 (CB2R) cannabinoid-receptors, as well as transient receptor potential vanilloid 1 (TRPV1)), endogenous ligands and enzymes that synthesize and degrade endocannabinoids (ECBs). Recent studies revealed the involvement of the ECS in different pathological aspects of these neurodegenerative disorders. The present review will explore the roles of cannabinoid receptors (CBRs) and pharmacological agents that modulate CBRs or ECS activity with reference to Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and multiple sclerosis (MS).
... Following THC treatment, some mouse models of MS showed improved spasticity and tremors [116]. In clinical trials of MS patients, THC exerted both decreased urinary incontinence and antispasticity effects [117]. Although THC has its therapeutical effects, it also has psychoactive properties; alternately, CBD is less toxic than THC to humans and has been recognised as a nonpsychoactive compound [115]. ...
Article
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Synthetic Cannabinoids (CBs) are a novel class of psychoactive substances that have rapidly evolved around the world with the addition of diverse structural modifications to existing molecules which produce new structural analogues that can be associated with serious adverse health effects. Synthetic CBs represent the largest class of drugs detected by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) with a total of 207 substances identified from 2008 to October 2020, and 9 compounds being reported for the first time. Synthetic CBs are sprayed on natural harmless herbs with an aim to mimic the euphoric effect of Cannabis. They are sold under different brand names including Black mamba, spice, K2, Bombay Blue, etc. As these synthetic CBs act as full agonists at the CB receptors, they are much more potent than natural Cannabis and have been increasingly associated with acute to chronic intoxications and death. Due to their potential toxicity and abuse, the US government has listed some synthetic CBs under schedule 1 classification. The present review aims to provide a focused overview of the literature concerning the development of synthetic CBs, their abuse, and potential toxicological effects including renal toxicity, respiratory depression, hyperemesis syndrome, cardiovascular effects, and a range of effects on brain function.
... Tetrahydrocannabinol is the main component of Cannabis sativa that can be used in the control of spasticity and tremor in MS because of its potential to rapidly cross the BBB and access the CNS (Baker et al., 2000;Zajicek et al., 2003). ...
Article
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Multiple sclerosis (MS) is a disease that has shown a considerable increase in prevalence in recent centuries. Current knowledge about its etiology is incomplete, and therefore it cannot be managed optimally utilizing targeted therapeutic regimens at each stage of the disease. MS progresses in different stages, beginning with a cascade of inflammation. The pivotal spark to initiate this cascade seems to be the migration of Th17 into the central nervous system across the blood–brain barrier (BBB) through the disrupted tight junctions. Coupling of interleukin (IL)‐17 and IL‐22 to their receptors in the BBB layer facilitates this migration. Subsequently, axon degeneration and the various manifestations of nerve–muscle disorders appear. Curcumin, a major component of turmeric, is derived from Curcuma longa, which belongs to the Zingiberaceae family. Numerous properties of curcumin have been identified recently, some of which can be effective in the treatment of MS, particularly the anti‐inflammatory properties via inhibition of secretion of proinflammatory cytokines. In this paper, we will review the various properties and key effects of curcumin for the treatment of MS.
... Additional reports have supported and extended these findings demonstrating that THC, but not CBD, ameliorated both tremor and spasticity and reduced the overall clinical severity of the disease [194,195]. ...
Article
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Although the medicinal properties of Cannabis species have been known for centuries, the interest on its main active secondary metabolites as therapeutic alternatives for several pathologies has grown in recent years. This potential use has been a revolution worldwide concerning public health, production, use and sale of cannabis, and has led inclusively to legislation changes in some countries. The scientific advances and concerns of the scientific community have allowed a better understanding of cannabis derivatives as pharmacological options in several conditions, such as appetite stimulation, pain treatment, skin pathologies, anticonvulsant therapy, neurodegenerative diseases, and infectious diseases. However, there is some controversy regarding the legal and ethical implications of their use and routes of administration, also concerning the adverse health consequences and deaths attributed to marijuana consumption, and these represent some of the complexities associated with the use of these compounds as therapeutic drugs. This review comprehends the main secondary metabolites of Cannabis, approaching their therapeutic potential and applications, as well as their potential risks, in order to differentiate the consumption as recreational drugs. There will be also a focus on the analytical methodologies for their analysis, in order to aid health professionals and toxicologists in cases where these compounds are present.
... The JWH family of synthetic cannabinoids have also been shown to be effective agonists of the cannabinoid receptors. Indeed, evidence indicates that JWH-133, a selective CB 2 agonist [161], ameliorates spasticity in murine MS [162] and prevents microglial cell activation and inflammation following exposure to -amyloid [163]. Finally, ACEA is a well described synthetic CB 1 agonist and analogue of AEA [164]. ...
Article
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Cannabidiol (CBD), one of the primary non-euphoric components in the Cannabis sativa L. plant, has undergone clinical development over the last number of years as a therapeutic for patients with Lennox-Gastaut syndrome and Dravet syndromes. This phytocannabinoid demonstrates functional and pharmacological diversity, and research data indicate that CBD is a comparable antioxidant to common antioxidants. This review gathers the latest knowledge regarding the impact of CBD on oxidative signalling, with focus on the proclivity of CBD to regulate antioxidants and control the production of reactive oxygen species. CBD is considered an attractive therapeutic agent for neuroimmune disorders, and a body of literature indicates that CBD can regulate redox function at multiple levels, with a range of downstream effects on cells and tissues. However, pro-oxidant capacity of CBD has also been reported, and hence caution must be applied when considering CBD from a therapeutic standpoint. Such pro- and antioxidant functions of CBD may be cell- and model-dependent, and may also be influenced by CBD dose, the duration of CBD treatment and the underlying pathology.
... Clinical studies assessing the therapeutic potential of cannabinoids and neurological disorders have been predominantly in epilepsy, MS and Parkinson's. In a human trial with MS patients, Δ 9 -THC ameliorated urinary incontinence, spasticity and tremors in MS, but no effect on disease progression was observed (Baker et al., 2000;Freeman et al., 2006;Zajicek et al., 2003). So far, CBD alone (Epidiolex, GW Pharmaceuticals, Cambridge, UK) and as a 1:1 formulation with Δ 9 -THC (Sativex, GW Pharmaceuticals, Cambridge, UK) are the only licenced cannabis-based medicines and are prescribed to treat Dravet syndrome and Lennox-Gastaut syndrome, both rare forms of childhood epilepsy. ...
Article
The blood brain barrier (BBB) is central to the neurovascular unit (NVU) where it creates a semi-permeable barrier between neuronal tissue and the vascular networks that feed the brain. In neurodegenerative conditions and ischaemic stroke, the BBB becomes compromised and as a result its permeability increases. This not only exacerbates neuronal damage at the site of injury but also causes unwanted extravasation of peripheral immune cells into the brain, fuelling the overactivation of the immune response. Endocannabinoids and phytocannabinoids have both displayed neuroprotective effects, attenuating damage in a range of models including Parkinson’s, Huntington’s, amyloid lateral sclerosis and ischaemic stroke. The current study aimed to investigate the neuroprotective properties of emerging phytocannabinoids; specifically focusing on the BBB and NVU in the context of ischaemic stroke pathophysiology. A four-cell blood brain barrier model was constructed consisting of; human brain microvascular endothelial cells (HBMECs), astrocytes, pericytes and neurons. Cells were cultured on collagen coated transwell inserts and permeability was assessed using transepithelial resistance (TEER). A systematic review was conducted to examine work on the neuroprotective properties of minor phytocannabinoids, aside from cannabidiol (CBD) and delta 9-tetrahydrocannabinol (Δ9-THC). Following on from this, in vitro experiments were conducted using minor phytocannabinoids with the most neuroprotective potential; cannabidivarin (CBDV), cannabigerol (CBG) and cannabidiolic acid (CBDA). Inserts or monocultures (four cell model and pericyte, HBMECs and neuronal monolayers) were subjected to either a 4 h oxygen-glucose deprivation (OGD) protocol or an 8 h OGD (astrocyte monocultures), to model ischaemic stroke in vitro. Media was analysed for various chemokines and cytokines using enzyme-linked immunoassays or multiplex assays. From the systematic review, emerging phytocannabinoids cannabidivarin (CBDV) and cannabigerol (CBG) were found to display efficacy in various neurogenerative conditions and of the limited available mechanistic data, were found to mediate some of their effects through peroxisome proliferator-activated receptor gamma (PPARy). Data showed CBDV (300 nM-10 µM) attenuated MCP-1 levels in HBMEC monolayers, as well as reducing IL-6 (30 nM, 1 µM and 10 µM; p<0.05) and VEGF (10 nM- 10 µM; p<0.01) levels in astrocyte monocultures post OGD. CBG (10 nM-3 µM; p<0.0001) also reduced levels of IL-6 secreted by astrocytes and decreased levels of DNA damage response proteins including Chk1, Chk2, H2A.X and p53 post OGD. Neither CBG, nor CBDV reduced levels of IL-6, VEG or IL-8 in pericytes compared to the vehicle control post OGD. Cannabidiolic acid (CBDA) was also investigated and was found to decrease IL-6 in pericyte monocultures which was mediated, at least in part, by 5-HT1A activation. In a four-cell model of the BBB, CBDA offset increases in permeability vs the vehicle control and offered direct protection to neurons, as shown by a lack of propidium iodide (PI) staining in CBDA treated cells, indicating live cells are present. Data presented in this thesis show minor phytocannabinoids CBDV, CBG and CBDA provide protection against OGD mediated damage, with CBDA also offering protection against increases in permeability of the BBB post OGD. These novel data warrant further investigation into the neuroprotective properties of phytocannabinoids, particularly in ischaemic stroke.
... This antihyperalgesia was abrogated by co-treatment with AM630, suggesting that CB2R activation on spinal dorsal horn neurons suppresses the hypersensitivity correlated with EAE. Baker et al. (2000) showed that JWH133 mitigated the tremors and spasticity in chronic relapsing EAE model mice. However, treatment with SR144528 exacerbated these symptoms, indicating that tonic CB2R activity may modulate tremor and spasticity. ...
Article
The pharmacological activation of cannabinoid type 2 receptors (CB2R) gained attention due to its ability to mitigate neuroinflammatory events without eliciting psychotropic activities, a limiting factor for the drugs targeting cannabinoid type 1 receptors (CB1R). Therefore, ligands activating CB2R are receiving enormous importance for therapeutic targeting in numerous diseases including neurodegenerative, neuropsychiatric and neurodevelopmental disorders as well as traumatic injuries and neuropathic pain where neuroinflammation is a common accompaniment. Since the characterization of CB2R, many CB2R selective synthetic ligands have been developed with high selectivity and functional activity. Among numerous ligands, JWH133 has been found one of the compounds with high selectivity for CB2R. JWH133 has been reported to exhibit numerous pharmacological activities including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, and immunomodulatory. Recent studies have showed that JWH133 possesses potent neuroprotective properties in several neurological disorders, including neuropathic pain, anxiety, epilepsy depression, alcoholism, psychosis, stroke, and neurodegeneration. Additionally, JWH133 protects neurons from oxidative damage and inflammation, promotes neuronal survival and neurogenesis, and serves as an immunomodulatory agent. The present review comprehensively examined neuropharmacological activities of JWH133 in neurological disorders including neurodegenerative, neurodevelopmental and neuropsychiatric using synoptic tables and elucidated pharmacological mechanisms based on reported observations. Considering the available data, JWH133 appears to be a promising CB2R agonist molecule for further evaluation and it can be a prototype agent for a unique class of drugs in drug discovery and development for neurotherapeutics and neuroprotection. Further, regulatory toxicology and pharmacokinetic studies are required to determine safety and proceed for clinical evaluation.
... Some of the resulting symptoms are spasticity, tremors, ataxia, bladder dysfunction and neuropathic pain, with a high impairment of the quality of life of the patient [378][379][380]. MS patients that consumed cannabis reported relief regarding several of these symptoms, highlighting a possible role for cannabinoids in MS [380][381][382][383][384][385]. Furthermore, the neuroprotective effects of these molecules in MS has been thoroughly described in the literature, since they are able to diminish oligodendrocyte death and increase remyelination whilst having an anti-inflammatory role [231,386,387]. ...
Article
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With the increase of life expectancy, neurodegenerative disorders are becoming not only a health but also a social burden worldwide. However, due to the multitude of pathophysiological disease states, current treatments fail to meet the desired outcomes. Therefore, there is a need for new therapeutic strategies focusing on more integrated, personalized and effective approaches. The prospect of using neural stem cells (NSC) as regenerative therapies is very promising, however several issues still need to be addressed. In particular, the potential actions of pharmacological agents used to modulate NSC activity are highly relevant. With the ongoing discussion of cannabinoid usage for medical purposes and reports drawing attention to the effects of cannabinoids on NSC regulation, there is an enormous, and yet, uncovered potential for cannabinoids as treatment options for several neurological disorders, specifically when combined with stem cell therapy. In this manuscript, we review in detail how cannabinoids act as potent regulators of NSC biology and their potential to modulate several neurogenic features in the context of pathophysiology.
... Baseline NRS score (mean ± SD) 7.3 ± 1. Moreover, the CB1 receptor seems to be involved in the control of spasticity both in EAE [25] and in patients with MS [11,24]. The probability of being late discontinuers was reduced in patients undergoing combined therapy compared to those treated with nabiximols alone confirming that a combined treatment may increase effectiveness on MS spasticity. ...
Article
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Background: Nabiximols (THC/CBD Oromucosal Spray, Sativex) is used as an add-on therapy to treat moderate to severe spasticity of Multiple Sclerosis (MS). Objectives: To examine the impact of physiotherapy (PT) programs on effectiveness and persistence of nabiximols treatment in people with MS-related spasticity. Methods: This is an observational multicenter study with a follow-up period of 12 weeks, conducted in routine care settings in Italy. Patients with moderate to severe MS-related spasticity who started nabiximols were included. Spasticity was evaluated by the patient-rated 0-10 numerical rating scale (NRS). Clinical data were collected at baseline (T0), 4 weeks (T1) and 12 weeks (T2) months after enrollment. Results: A total of 297 MS patients were selected, 290 completed the 3 months follow-up period. Mean NRS scores were 7.6 ± 1.1 at T0, 5.8 ± 1.4 at T1 and 5.5 ± 1.5 at T2. At T1, 77% of patients reached ≥20% improvement (initial response, IR); 22% reached ≥30% improvement (clinically relevant response, CRR). At T1, patients undergoing PT had a higher probability to reach CRR (Odds Ratio = 2.6 95% CI 1.3-5.6, p = 0.01). Nabiximols was discontinued in 30/290 (10.3%) patients at T1 (early discontinuers) and in 71/290 (24.5%) patients at T2 (late discontinuers). The probability of being late discontinuers was reduced in patients undergoing PT (Hazard Ratio = 0.41; 95% CI 0.23-0.69, p = 0.001). Conclusions: Our real-life study confirms nabiximols' effectiveness in MS-related spasticity and suggests that the association of a PT program may improve overall response and persistence to nabiximols treatment.
Article
Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system - known as the endocannabinoidome - that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.
Article
This review summarizes studies that examined the effectiveness of cannabinoids in treating spasticity, with a focus on understanding the relevance of the existing evidence to paediatric populations. MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched to identify studies that examined the use of cannabinoids in spasticity. We identified 32 studies in adult and paediatric populations. Results were summarized by condition, with adult and paediatric studies considered separately. There is evidence from randomized controlled clinical trials that cannabinoids are more effective than placebo in reducing symptoms of spasticity in adults with multiple sclerosis. Most positive effects were based on patient‐rated rather than clinician‐rated measures, were modest in size, and should be considered in the context of the narrow therapeutic index of cannabinoids for spasticity and adverse effects. There were comparatively few, and no large studies, of spasticity in conditions other than multiple sclerosis. Few studies have been conducted in paediatric populations. Paediatric studies of spasticity provide low quality evidence and are inadequate to inform clinical practice. • Cannabinoids have modest efficacy in reducing muscle spasticity in adults with multiple sclerosis. • There is limited evidence of efficacy for cannabinoid use in other conditions, particularly in paediatric populations. • Studies in paediatric populations have been of low quality and are insufficient to inform clinical practice.
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Resumo. A maconha é uma planta utilizada desde a Antiguidade com finalidade medicinal, atuando clinicamente como sedativo, analgésico e antiemético. O principal efeito colateral é a perturbação do sistema nervoso central, causando euforia e alucinações, levando a movimentação popular em favor da proibição, apesar de ser menos viciante e perigoso que etanol e derivados opioides. Em 1964, foi isolado o Δ9-tetrahidrocanabinol, principal psicoativo da maconha, levando a hipótese de que seu mecanismo de ação seria semelhante aos anestésicos gerais. Em 1988, foi descoberto os receptores canabinoides, dando inicio a exploração de seu sistema endógeno. Em 1992, a descoberta do primeiro mediador endógeno, denominado anandamida. Em 1994, é lançado o primeiro medicamento atuante no sistema de endocanabinoides, denominado rimonabanto, com a finalidade de inibir o apetite e tratar a obesidade. Em 2008, o rimonabanto é retirado do mercado por induzir a depressão e ansiedade e dispor de relação com a ocorrência de suicídio. Em 2019, a Agência Nacional de Vigilância Sanitária regulamentou os requisitos de fabricação, dispensação e receituário com a RDC 327/19. Atualmente, o sistema de canabinoides possui maior conhecimento e é possível estabelecer diversas aplicações clínicas, por exemplo, atuando na atenuação dos sintomas motores da Doença de Parkinson, na dor neuropática ou inflamatória, diminuição da pressão intraocular no glaucoma e como antiemetico durante a quimioterapia. O presente trabalho visa revisar os aspectos históricos da maconha no Brasil e o trajeto das
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Background: Kynurenine pathway metabolites and endocannabinoids both exert potent regulatory effects on the immune system, but the relationship between these molecules is unknown. The role of these immunobiological mediators in emotionality and personality traits is not previously characterized. Methods: Interleukin-6 (IL-6), 2-arachidonoylglycerol (2-AG) and picolinic acid (PIC) were measured in the plasma of physically healthy individuals who had history of mood, anxiety, and personality disorders (n = 96) or who had no history of any psychiatric disorder (n = 56) by DSM-5 Criteria. Dimensional assessments of personality were performed using the Eysenck Personality Questionnaire (EPQ) and the Tridimensional Personality Questionnaire (TPQ). Results: Plasma IL-6 levels were significantly associated with plasma 2-AG levels and plasma PIC levels across all subjects. PIC levels were also negatively associated with 2-AG levels across all subjects, independent of IL-6 levels. In our analysis of the biological determinants of personality factors, we identified significant associations between IL-6 and novelty seeking assessment, and between PIC and neuroticism assessment. Conclusions: These data provide evidence of a biological link between metabolites of the kynurenine pathway, the endocannabinoid system and IL-6 and suggest that these factors may influence personality traits.
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Introduction: : To investigate whether published systematic reviews of randomized controlled trials provide sufficient clarity to inform prescribing of cannabinoid products aimed for medicinal use, we examined their features and findings in two well-researched areas: chronic cancer/noncancer pain and multiple sclerosis (MS)-related symptoms. Areas covered: : Structured searches from January 2011 to 2 February 2021 identified 31 systematic reviews (with/without meta-analyses) that met the inclusion criteria. Support for the efficacy of cannabinoids was minimal in cancer pain, and somewhat stronger in noncancer (especially neuropathic) pain and MS spasticity. All systematic reviews and most meta-analyses grouped cannabinoid products together without appropriate consideration of their differential attributes (active constituent(s), concentration/strength, dosage forms, administration route), dosing regimens or treatment durations. Patient populations and efficacy outcome measures were inhomogeneous, particularly for studies in noncancer pain and MS. Separate results for specific cannabinoid formulations were rarely provided. Expert opinion: : The therapeutic effect of cannabinoids, as already demonstrated for some products, is not reflected clearly in the current range of systematic reviews and meta-analyses in chronic pain and MS. To truly inform evidence-based practice, future publications should aim to present results by individual product from well-conducted clinical trials using appropriate and homogeneous outcome measures in well-defined patient populations.
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Objective: Identify a coherent nomenclature of products containing cannabinoids (whether derived from Cannabis sativa L. or not). Design: Research undertaken in parallel to the three-year assessment of Cannabis derivatives by the World Health Organisation. The scope is limited to Cannabis products intended for human incorporation (internal and topical con- sumption). Primarily embedded in pharmacognosy, the study incorporates a wide range of scholarly and grey literature, folk knowledge, archives, pharmacopœias, international law, field pharmacy, clinical and herbal medicine data, under a philosophical scrutiny. Generic and Cannabis-specific nomenclatural frames are compared to determine the extent to which they coincide or conflict. Results: All lexica reviewed use weak, ambiguous, or inconsistent terms. There is insufficient scientific basis for terms and concepts related to Cannabis at all levels. No sound classification exists: current models conflict by adopting idiosyncratic, partial, outdated, or utilitarian schemes to arrange the extraordinarily numerous and diverse derivatives of the C. sativa plant. In law and policy, no clear or unequivocal boundary between herbal and non-herbal drugs, nor natural and synthetic cannabinoids was found; current nomenclatures used need updates. In science, the botanical Cannabis lexicon overlooks parthenocarpy, and wide disagreement remains as to the taxonomy and systematics of the plant; chemical research should address differences in kinds between synthetic cannabinoids; pharmacopœias include little information related to Cannabis, and disagree on broader classes of herbal medicines, virtually failing to embrace many known Cannabis medicines. Since existing products and compounds fail to be categorised in an evidence-based manner, confusions will likely increase as novel cannabinoid compounds, genetic and biotechnological modifications surge. Conclusions: The lack of clarity is comprehensive: for patients, physicians, and regulators. The study proposes an update of terms at several levels. It points at gaps in morphological descriptions in botany and pharmacognosy and a need for a metaphysical address of cannabinoids. Methods of obtention are identified as a common criterion to distinguish products; the way forward suggests a mutually exclusive nomenclatural pattern based on the smallest common denominator of obtention methods. In the context of a swelling number of Cannabis products being consumed (be it via medical prescription, adult-use, ‘hemp’ foodstuff and cosmetics, or other purposes), this study can assist research, contribute to transparent labelling of products, consumer safety and awareness, pharmacovigilance, medical standards of care, and an update of prevention and harm reduction approaches. It can also better inform regulatory policies surrounding C. sativa, its derivatives, and other cannabinoid-containing products. Original article available at: https://journals.sagepub.com/doi/full/10.1177/2050324520945797
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The emerging role of the endocannabinoid system (ECS) in the control of symptoms and disease progression in multiple sclerosis (MS) has been highlighted by recent studies. MS is a chronic, immune-mediated, and demyelinating disorder of the central nervous system with no cure so far. It is widely reported that cannabinoids might be used to control MS symptoms and that they also might exert neuroprotective effects and slow down disease progression. The aim of this chapter is to give an overview of the main endogenous and synthetic cannabinoids used for the symptomatic amelioration of MS and their beneficial outcomes, providing new possible perspectives for the treatment of this disease.
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The endocannabinoid system (ECS) is a complex physiological network involved in creating homeostasis and maintaining human health. Studies of the last 40 years have shown that endocannabinoids (ECs), a group of bioactive lipids, together with their set of receptors, function as one of the most important physiologic systems in human body. ECs and cannabinoid receptors (CBRs) are found throughout the body: in the brain tissues, immune cells, and in the peripheral organs and tissues as well. In recent years, ECs have emerged as key modulators of affect, neurotransmitter release, immune function, and several other physiological functions. This modulatory homoeostatic system operates in the regulation of brain activity and states of physical health and disease. In several research studies and patents the ECS has been recognised with neuro-protective properties thus it might be a target in neurodegenerative diseases. Most immune cells express these bioactive lipids and their receptors, recent data also highlight the immunomodulatory effects of endocannabinoids. Interplay of immune and nervous system has been recognized in past, recent studies suggest that ECS function as a bridge between neuronal and immune system. In several ongoing clinical trial studies, the ECS has also been placed in the anti-cancer drugs spotlight. This review summarizes the literature of cannabinoid ligands and their biosynthesis, cannabinoid receptors and their distribution, and the signaling pathways initiated by the binding of cannabinoid ligands to cannabinoid receptors. Further, this review highlights the functional role of cannabinoids and ECS in blood cell development, neuroimmune interactions and associated disorders. Moreover, we highlight the current state of knowledge of cannabinoid ligands as the mediators of neuroimmune interactions, which can be therapeutically effective for neuro-immune disorders and several diseases associated with neuroinflammation.
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It has been established that the endogenous cannabinoid (endocannabinoid) system plays key modulatory roles in a wide variety of pathological conditions. The endocannabinoid system comprises both cannabinoid receptors, their endogenous ligands including 2-arachidonoylglycerol (2-AG), N-arachidonylethanolamine (anandamide, AEA), and enzymes that regulate the synthesis and degradation of endogenous ligands which include diacylglycerol lipase alpha (DAGL-α), diacylglycerol lipase beta (DAGL-β), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α/β hydrolase domain 6 (ABHD6). As the endocannabinoid system exerts considerable involvement in the regulation of homeostasis and disease, much effort has been made towards understanding endocannabinoid-related mechanisms of action at cellular, physiological, and pathological levels as well as harnessing the various components of the endocannabinoid system to produce novel therapeutics. However, drug discovery efforts within the cannabinoid field have been slower than anticipated to reach satisfactory clinical endpoints and raises an important question into the validity of developing novel ligands that therapeutically target the endocannabinoid system. To answer this, we will first examine evidence that supports the existence of an endocannabinoid system role within inflammatory diseases, neurodegeneration, pain, substance use disorders, mood disorders, as well as metabolic diseases. Next, this review will discuss recent clinical studies, within the last 5 years, of cannabinoid compounds in context to these diseases. We will also address some of the challenges and considerations within the cannabinoid field that may be important in the advancement of therapeutics into the clinic.
Chapter
Multiple sclerosis is an autoimmune disease with underlying inflammatory and neurodegenerative processes. Future biomarker research is needed to increase our understanding of the pathophysiologic substrates of the disease and thereby enable prediction of disease course and response to immunomodulatory and neuroprotective therapy strategies. Recently developed ultra-sensitive analytic techniques (single molecule array (Simoa)) enable the reliable detection of low levels of protein that are released from the central nervous system (CNS) into the peripheral blood. However, peripheral sources of markers measured with the Simoa technique have to be taken into account, when interpreting CNS-disorders. In this chapter, we provide a detailed overview of the Simoa technique and present emerging and established markers of inflammatory and neurodegenerative processes of multiple sclerosis. We particularly highlight Neurofilament light chain (NfL), a biomarker for neurodegenerative processes in various neurological disorders.
Chapter
Multiple sclerosis (MS) can cause a range of disabling symptoms which may differ greatly from patient to patient and over the course of the disease. While numerous effective immunotherapies are available for MS patients, symptomatic treatment options are scarce. Randomized controlled trials examining symptomatic therapies are lacking and the current data basis is insufficient and inconsistent. This chapter will give an overview of potential pharmacological and nonpharmacological treatment strategies for the most common MS symptoms and present useful multimodal approaches for managing different symptoms in MS patients.
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In the last decades, cannabinoid receptor 2 (CB2R) has continued to receive attention as a key therapeutic target in neuroprotection. Indeed, several findings highlight the neuroprotective effects of CB2R through suppression of both neuronal excitability and reactive microglia. Additionally, CB2R seems to be a more promising target than cannabinoid receptor 1 (CB1R) thanks to the lack of central side effects, its lower expression levels in the central nervous system (CNS), and its inducibility, since its expression enhances quickly in the brain following pathological conditions. This review aims to provide a thorough overview of the main natural and synthetic selective CB2R modulators, their chemical classification and their potential therapeutic usefulness in neuroprotection, a crucial aspect for the treatment of neurodegenerative diseases.
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Medical benefi ts of cannabis and related compounds is widely known. Discovery of psychotropic plant cannabinoid Δ9-tetrahydrocannabinol have urged researchers to study more about the cannabinoid system and related therapeutics in the fi eld of neurology and medicine. Where activation of cannabinoid receptor type 1 (CB1R) yielded in unwanted and serious side eff ects, discovery of cannabinoid receptor type 2 (CB2R) and its ligands gave a new hope. Till now there is limited success in this fi eld because of complex expanded endocannabinoid system comprising of receptors, ligands and enzymes. In this review we will update about the role of endocannabinoidome relevant to neurological disorders.
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Nearly all FDA approved drugs and bioactive small molecules exert their effects by binding to and modulating proteins. Consequently, understanding how small molecules interact with proteins at an molecular level is a central challenge of modern chemical biology and drug development. Complementary to structure-guided approaches, chemoproteomics has emerged as a method capable of high-throughput identification of proteins covalently bound by small molecules. To profile noncovalent interactions, established chemoproteomic workflows typically incorporate photoreactive moieties into small molecule probes, which enable trapping of small molecule-protein interactions (SMPIs). This strategy, termed photoaffinity labelling (PAL), has been utilized to profile an array of small molecule interactions, including for drugs, lipids, metabolites, and cofactors. Herein we describe the discovery of photocrosslinking chemistries, including a comparison of the strengths and limitations of implementation of each chemotype in chemoproteomic workflows. In addition, we highlight key examples where photoaffinity labelling has enabled target deconvolution and interaction site mapping.
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We performed a structural study followed by a theoretical analysis of the chemical descriptors and the biological activity of a series of 5-thiophen-2-yl pyrazole derivatives as potent and selective Cannabinoid-1...
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Tremor is an involuntary, rhythmic movement disorder. Despite its prevalence, the underlying pathophysiology remains poorly understood and effective treatment options are limited. Animal models are essential in enhancing our understanding of the mechanisms of tremorogenesis and developing new therapeutic interventions. Although tremor is amenable to measurement by automated systems, visual observation is still the most prevalent method for recording tremor in animal studies. This review gives a brief summary of two behavioral methods that enable quantitative measurement of forelimb tremor (the press-while-licking task) and whole-body tremor (the force-plate actometer) in rodents. These methods utilize force transducer and computing technologies to generate high-resolution force-time waveforms for automated detection and characterization of tremor. The focus will be on the sensitive, precise, and quantitative measurement of tremors induced in rodents by low-dose pharmacological agents, brain lesion, physical training, and genetic mutations. The methods reviewed here provide new tools that can facilitate preclinical assessment of treatment strategies for tremor.
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Background Essential tremor is the most prevalent movement disorder and is thought to be caused by abnormalities in the cerebellar system; however, its underlying neural mechanism is poorly understood. In this study, we found that mice lacking netrin-G2, a cell adhesion molecule which is expressed in neural circuits related to the cerebellar system, exhibited a microtremor resembling an essential tremor. However, it was difficult to quantify microtremors in netrin-G2 KO mice. New Method We developed a new tremor detector which can quantify the intensity and frequency of a tremor. Results Using this system, we were able to characterize both the microtremors in netrin-G2 KO mice and low-dose harmaline-induced tremors which, to date, had been difficult to detect. Alcohol and anti-tremor drugs, which are effective in decreasing the symptoms of essential tremor in patients, were examined in netrin-G2 KO mice. We found that some drugs lowered the tremor frequency, but had little effect on tremor intensity. Forced swim as a stress stimulus in netrin-G2 KO mice dramatically enhanced tremor symptoms. Comparison with Existing Methods The detection performance even for tremors induced by low-dose harmaline was similar to that in previous studies or more sensitive than the others. Conclusions Microtremors in netrin-G2 KO mice are reliably and quantitatively detected by our new tremor detection system. We found different effects of medicines and factors between human essential tremors and microtremors in netrin-G2 KO mice, suggesting that the causations, mechanisms, and symptoms of tremors vary and are heterogeneous, and the objective analyses are required.
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The widely‐known claim of Voss and Clarke (1978) that much music is well modelled by “1/ƒ noise” is critically examined. Some new data are provided for classical music, yielding mainly negative conclusions. In the course of the investigation some of the problems of the statistical analysis of musical data are discussed.
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This paper introduces the use of magnetic field tomography (MFT), a noninvasive technique based on distributed source analysis of magnetoencephalography data, which makes possible the three-dimensional reconstruction of dynamic brain activity in humans. MFT has a temporal resolution better than 1 msec and a spatial accuracy of 2-5 mm at the cortical level, which deteriorates to 1-3 cm at depths of 6 cm or more. MFT is used here to visualize the origin of a spatiotemporally organized pattern of coherent 40-Hz electrical activity. This coherence, initially observed during auditory input, was proposed to be generated by recurrent corticothalamic oscillation. In support of this hypothesis, we illustrate well-defined 40-Hz coherence between cortical-subcortical sites with a time shift that is consistent with thalamocortical conduction times. Studies on Alzheimer patients indicate that, while a similar activity pattern is present, the cortical component is reduced in these subjects.
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The neural correlates of music perception were studied by measuring cerebral blood flow (CBF) changes with positron emission tomography (PET). Twelve volunteers were scanned using the bolus water method under four separate conditions: (1) listening to a sequence of noise bursts, (2) listening to unfamiliar tonal melodies, (3) comparing the pitch of the first two notes of the same set of melodies, and (4) comparing the pitch of the first and last notes of the melodies. The latter two conditions were designed to investigate short-term pitch retention under low or high memory load, respectively. Subtraction of the obtained PET images, superimposed on matched MRI scans, provides anatomical localization of CBF changes associated with specific cognitive functions. Listening to melodies, relative to acoustically matched noise sequences, resulted in CBF increases in the right superior temporal and right occipital cortices. Pitch judgments of the first two notes of each melody, relative to passive listening to the same stimuli, resulted in right frontal-lobe activation. Analysis of the high memory load condition relative to passive listening revealed the participation of a number of cortical and subcortical regions, notably in the right frontal and right temporal lobes, as well as in parietal and insular cortex. Both pitch judgment conditions also revealed CBF decreases within the left primary auditory cortex. We conclude that specialized neural systems in the right superior temporal cortex participate in perceptual analysis of melodies; pitch comparisons are effected via a neural network that includes right prefrontal cortex, but active retention of pitch involves the interaction of right temporal and frontal cortices.
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Steady-state magnetic responses to clicks presented at rates between 10 and 70 Hz have been recorded in healthy humans. The responses were highest in amplitude around 40 Hz. This amplitude enhancement is satisfactorily explained by summation of responses evoked by single clicks. The field maps suggest activation of the auditory cortex at all stimulus frequencies. Similar responses were obtained with gated noise bursts and by pauses in a series of clicks. The mean "apparent latency," determined from the phase lag at rates 30-70 Hz, was 54 ms. The physiological relevance of this quantity is shown to be questionable.
Marijuana is reported to decrease spasticity in patients with multiple sclerosis. This is a double blind, placebo controlled, crossover clinical trial of delta-9-THC in 13 subjects with clinical multiple sclerosis and spasticity. Subjects received escalating doses of THC in the range of 2.5-15 mg., five days of THC and five days of placebo in randomized order, divided by a two-day washout period. Subjective ratings of spasticity and side effects were completed and semiquantitative neurological examinations were performed. At doses greater than 7.5 mg there was significant improvement in patient ratings of spasticity compared to placebo. These positive findings in a treatment failure population suggest a role for THC in the treatment of spasticity in multiple sclerosis.
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Spasticity is a common neurologic condition in patients with multiple sclerosis, stroke, cerebral palsy or an injured spinal cord. Animal studies suggest that THC has an inhibitory effect on polysynaptic reflexes. Some spastic patients claim improvement after inhaling cannabis. We tested muscle tone, reflexes, strength and performed EMGs before and after double-blinded oral administration of either 10 or 5 mg THC or placebo. The blinded examiner correctly identified the trials in which the patients received THC in seven of nine cases. For the group, 10 mg THC significantly reduced spasticity by clinical measurement (P less than 0.01). Quadriceps EMG interference pattern was reduced in those four patients with primarily extensor spasticity. THC was administered to eight other patients with spasticity and other CNS lesions. Responses varied, but benefit was seen in three of three patients with "tonic spasms." No benefit was noted in patients with cerebellar disease.
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Electromyographic (EMG) studies were carried out with the genetically spastic mouse (spa, autosomal recessive), obtained from matings of B6C3a/a, spa/+ heterozygotes. Spastic homozygotes exhibited high amplitude repetitive EMG bursts during spontaneous activity. Following an electrical stimulus to hindlimb or forelimb, high amplitude stereotyped EMG bursts were recorded from contralateral limbs in spastic mice, but were not observed in phenotypically unaffected littermates or normal C57BL/6J mice. The timing and latency of this stereotyped response to an electrical stimulus was consistent with the participation of spinal cord neuronal pathways. In normal C57BL/6J mice the administration of strychnine (0.65 mg/kg), but not picrotoxinin (up to convulsant doses), reproduced all of the behavioral and EMG features observed in spastic homozygotes. We hypothesize that the symptoms in the spastic mutant may result from a deficiency of strychnine-sensitive (presumably glycinergic) inhibition in the spinal cord.
Transient and steady-state auditory evoked fields (AEFs) to brief tone pips were recorded over the left hemisphere at 7 different stimulus rates (0.125-39 Hz) using a 37-channel biomagnetometer. Previous observations of transient auditory gamma band response (GBR) activity were replicated. Similar rate characteristics and equivalent dipole locations supported the suggestion that the steady-state response (SSR) at about 40 Hz represents the summation of successive overlapping (10 Hz) middle latency responses (MLRs). On the other hand, differences in equivalent dipole locations and habituation effects suggest that the magnetically recorded GBR is a separate phenomenon which occurs primarily at low stimulus rates and is unrelated to either the magnetically recorded MRL or SSR.
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Steady-state responses (SSRs) or steady-state fields (SSFs) show maximum amplitude when tone pulses are presented at repetition rates near 40 Hz. This result has led to the hypothesis that the SSR/SSF consists of superimposed transient 'middle latency' responses which display wave periods near 40 Hz and summate with one another when phase locked by 40 Hz steady-state stimulation. We evaluated this hypothesis by comparing the cortical sources of the 40 Hz auditory SSF with sources of the middle latency Pa wave which is prominent in electrical and magnetic recordings, and with the cortical sources of the familiar N1 wave, at different carrier frequencies between 250 and 4000 Hz. SSF sources determined for the different carrier frequencies were found to display a 'medial' tendency tonotopy resembling that of the N1m (sources for the higher frequencies represented more deeply within the supratemporal sulcus), opposite the 'lateral' tendency tonotopy of the middle latency Pam (sources for the higher frequencies situated more laterally). A medial SSF tonotopy was observed in each of the subjects investigated, including three subjects for whom Pam and N1m maps were also available. These findings suggest that the 40 Hz SSF may not consist of summated or entrained middle latency responses, as has previously been proposed. Alternative mechanisms for the SSR are discussed.
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Fifty-three UK and 59 USA people with multiple sclerosis (MS) answered anonymously the first questionnaire on cannabis use and MS. From 97 to 30% of the subjects reported cannabis improved (in descending rank order): spasticity, chronic pain of extremities, acute paroxysmal phenomenon, tremor, emotional dysfunction, anorexia/weight loss, fatigue states, double vision, sexual dysfunction, bowel and bladder dysfunctions, vision dimness, dysfunctions of walking and balance, and memory loss. The MS subjects surveyed have specific therapeutic reasons for smoking cannabis. The survey findings will aid in the design of a clinical trial of cannabis or cannabinoid administration to MS patients or to other patients with similar signs or symptoms.
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There are at least two types of cannabinoid receptors, CB1 and CB2, both coupled to G-proteins. CB1 receptors are present in the central nervous system and CB1 and CB2 receptors in certain peripheral tissues. The existence of endogenous cannabinoid receptor agonists has also been demonstrated. These discoveries have led to the development of selective cannabinoid CB1 and CB2 receptor ligands. This review focuses on the classification, binding properties, effector systems and distribution of cannabinoid receptors. It also describes the various cannabinoid receptor agonists and antagonists now available and considers the main in vivo and in vitro bioassay methods that are generally used.
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The effects of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4- benzoxazin-yl]-(1-napthalenyl)methanone mesylate (WIN 55,212-2) and N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR141716A) on guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding to membranes isolated from human cannabinoid CB1 receptor-transfected Chinese hamster ovary (CHO) cells were examined. WIN 55,212-2 stimulated [35S]GTPgammaS binding 76.3% above basal levels whereas SR141716A produced a 22.3% decrease in basal [35S]GTPgammaS binding. These findings demonstrate that WIN 55,212-2 is an agonist and SR141716A is an inverse agonist in this system.
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To explore the relationship between the processing of melodic and rhythmic patterns in speech and music, we tested the prosodic and musical discrimination abilities of two "amusic" subjects who suffered from music perception deficits secondary to bilateral brain damage. Prosodic discrimination was assessed with sentence pairs where members of a pair differed by intonation or rhythm, and musical discrimination was tested using musical-phrase pairs derived from the prosody of the sentence pairs. This novel technique was chosen to make task demands as comparable as possible across domains. One amusic subject showed good performance on both linguistic and musical discrimination tasks, while the other had difficulty with both tasks. In both subjects, level of performance was statistically similar across domains, suggesting shared neural resource for prosody and music. Further tests suggested that prosody and music may overlap in the processes used to maintain auditory patterns in working memory.
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The potent analgesic effects of cannabis-like drugs and the presence of CB1-type cannabinoid receptors in pain-processing areas of the brain and spinal cord indicate that endogenous cannabinoids such as anandamide may contribute to the control of pain transmission within the central nervous system (CNS). Here we show that anandamide attenuates the pain behaviour produced by chemical damage to cutaneous tissue by interacting with CB1-like cannabinoid receptors located outside the CNS. Palmitylethanolamide (PEA), which is released together with anandamide from a common phospholipid precursor, exerts a similar effect by activating peripheral CB2-like receptors. When administered together, the two compounds act synergistically, reducing pain responses 100-fold more potently than does each compound alone. Gas-chromatography/mass-spectrometry measurements indicate that the levels of anandamide and PEA in the skin are enough to cause a tonic activation of local cannabinoid receptors. In agreement with this possibility, the CB1 antagonist SR141716A and the CB2 antagonist SR144528 prolong and enhance the pain behaviour produced by tissue damage. These results indicate that peripheral CB1-like and CB2-like receptors participate in the intrinsic control of pain initiation and that locally generated anandamide and PEA may mediate this effect.
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Unprecedented developments in cannabinoid research within the past decade include discovery of a brain (CB1) and peripheral (CB2) receptor; endogenous ligands, anandamide, and 2-arachidonylglycerol; cannabinoid drug-induced partial and inverse agonism at CB1 receptors, antagonism of NMDA receptors and glutamate, and antioxidant activity; and preferential CB1 receptor localization in areas subserving spasticity, pain, abnormal involuntary movements, seizures, and amnesia. These endogenous structures and chemicals and mechanisms are potentially new pathophysiologic substrates, and targets for novel cannabinoid treatments, of several neurological disorders.
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The effects of the primary psychoactive constituent of marijuana, delta 9-tetrahydrocannabinol, are mediated by cannabinoid receptors, CB1 and CB2. The CB1 receptors display a unique central nervous system (CNS) distribution and are present in mammalian brain at higher levels than most other known G-protein-coupled receptors. The highest levels occur in several areas involved in motor control and hippocampus. Cannabinoid effects on CNS activities, including movement, memory, nociception, endocrine regulation, thermoregulation, sensory perception, cognitive functions, and mood, correlate with the regional distribution of cannabinoid receptors and their activation of specific G-protein-mediated signal transduction systems in various brain regions.
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In binocular rivalry, the observer views two incongruent images, one through each eye, but is conscious of only one image at a time. The image that is perceptually dominant alternates every few seconds. We used this phenomenon to investigate neural correlates of conscious perception. We presented a red vertical grating to one eye and a blue horizontal grating to the other eye, with each grating continuously flickering at a distinct frequency (the frequency tag for that stimulus). Steady-state magnetic fields were recorded with a 148 sensor whole-head magnetometer while the subjects reported which grating was perceived. The power of the steady-state magnetic field at the frequency associated with a grating typically increased at multiple sensors when the grating was perceived. Changes in power related to perceptual dominance, presumably reflecting local neural synchronization, reached statistical significance at several sensors, including some positioned over occipital, temporal, and frontal cortices. To identify changes in synchronization between distinct brain areas that were related to perceptual dominance, we analyzed coherence between pairs of widely separated sensors. The results showed that when the stimulus was perceived there was a marked increase in both interhemispheric and intrahemispheric coherence at the stimulus frequency. This study demonstrates a direct correlation between the conscious perception of a visual stimulus and the synchronous activity of large populations of neocortical neurons as reflected by stimulus-evoked steady-state neuromagnetic fields.
Article
Steady-state auditory evoked fields were recorded from 15 subjects using a whole head MEG system. Stimuli were 800 ms trains of binaural clicks with constant stimulus onset asynchrony (SOA). Seven different SOA settings (19, 21, 23, 25, 27, 29 and 31 ms) were used to give click rates near 40 Hz. Transient responses to each click were reconstructed using a new algorithm that deconvoluted the averaged responses to the different trains. Spatio-temporal multiple dipole modelling in relation to 3D MRI scans revealed two overlapping source components in both the left and right auditory cortex. The primary sources in the medial part of Heschl's gyrus exhibited a N19-P30-N40 m pattern. The secondary, weaker sources at more lateral sites on Heschl's gyrus showed a N24-P36-N46 m pattern. When applied to transient middle latency auditory evoked fields (MAEFs) recorded at SOAs of 95-135 ms, the primary sources imaged activities similar to the deconvoluted steady-state responses, but the secondary source activities were inconsistent. Linear summation of the deconvoluted source waveforms accounted for more than 96% of the steady-state variance. This indicates that the primary activity of the auditory cortex remains constant up to high stimulation rates and is not specifically enhanced around 40 Hz.
Article
Mammalian tissues contain at least two types of cannabinoid receptor, CB1 and CB2, both coupled to G proteins. CB1 receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB2 receptors occur in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this endogenous cannabinoid system has been paralleled by a renewed interest in possible therapeutic applications of cannabinoids, for example in the management of pain and in the suppression of muscle spasticity/spasm associated with multiple sclerosis or spinal cord injury. It has also prompted the development of a range of novel cannabinoid receptor ligands, including several that show marked selectivity for CB1 or CB2 receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB1 and CB2 receptor ligands. Particular attention is paid to the binding properties of these ligands, to the efficacies of cannabinoid receptor agonists, as determined using cyclic AMP or [35S]GTPgammaS binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectively oppose the actions of CB1 or CB2 receptor agonists are also described. When administered by themselves, some of these ligands produce effects in certain tissue preparations that are opposite in direction to those produced by cannabinoid receptor agonists and the possibility that the ligands producing such inverse cannabimimetic effects are inverse agonists rather than pure antagonists is discussed.
3-(1′,1′-Dimethylbutyl)-1-deoxy-Δ9-THC and related compounds: synthesis of selective ligands for the CB2 receptor
  • J W Huffman
  • JW Huffman
Huffman, J. W. et al. 3-(19,19-Dimethylbutyl)-1-deoxy-D 9 -THC and related compounds: synthesis of selective ligands for the CB2 receptor. Bioorg. Med. Chem. 7, 2905±2914 (1999).