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Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?

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Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic ap-proaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids.
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NEURAL REGENERATION RESEARCH
December 2016, Volume 11, Issue 12
1896
Can cannabinoids be a potential therapeutic tool in
amyotrophic lateral sclerosis?
Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is the most common
degenerative disease of the motor neuron system. e inci-
dence is about 13 cases per 100,000 population per year.
In Italy it is estimated that at least 3,500 patients and 1,000
new cases per year (http://www.osservatoriomalattierare.
it/sla). ALS is characterized by relentless progression of
muscle wasting and weakness until death ensues typically
due to respiratory muscle failure. Generally, ALS patients
present a number of clinical symptoms, including weak-
ness, spasticity, cachexia, dysarthria and drooling, and
pain secondary to immobility, among others (Zarei et al.,
2015).
The most abundant forms of ALS are sporadic (90%),
but the disease may be also familiar (10%), associated
with mutations in the superoxide dismutase-1 gene (SOD-
1), that encodes for a key antioxidant enzyme, and also in
TAR-DNA binding protein-43 (TDP-43) and FUS (fused
in sarcoma) which encode proteins involved in pre-mRNA
splicing, transport and stability (Hardiman et al., 2011).
Recently, mutation in non-coding hexanucleotide repeat
sequence (GGGGCC) in the C9orf72 gene was considered
as the most common genetic cause of ALS (Matamala et
al., 2016). The exact function of this protein remains un-
defined; however, it seems to play a major role in cellular
tracking, mainly in neurons (Williams et al., 2013). e
C9orf72 mutation was found also in frontotemporal de-
mentia (FTD) patients (Farg et al., 2014). Since 20% of ALS
patients develops dementia with a frontotemporal pheno-
type, this mutation may explain the link between familial
FTD and ALS (Farg et al., 2014).
Although the pathogenic mechanisms that underlie ALS
are yet unknown, it is believed that ALS could have a mul-
tifactorial etiology, where environmental factors can great-
ly contribute to pathology triggering. Moreover, several
mechanisms including mitochondrial dysfunction, protein
aggregation, oxidative stress, excessive glutamate activity, in-
ammation and apoptosis are involved in ALS pathogenesis
leading to motor neuron cell death in the brain and spinal
cord (Zarei et al., 2015).
To date, the only therapy available for ALS is the gluta-
mate-antagonist riluzole that was able to inhibit the presyn-
aptic release of glutamate, most likely by blockade of volt-
age-gated sodium channels. However, riluzole has limited
therapeutic ecacy and also it is able to moderately prolong
patient survival (Miller et al., 2007). erefore, new innova-
tive and safer therapeutic approaches are urgently needed, at
least aimed at delaying the neurodegenerative processes of
the ongoing disease.
Over the last years, a growing interest has been focused to
cannabinoids, the bioactive compounds of Cannabis sativa,
for their antioxidant, anti-inammatory and anti-excitotoxic
effects exhibited in preclinical models of central nervous
system disease (Croxford, 2003). Here, we provided an over-
view of the potential usefulness of cannabinoid agents in the
management of ALS.
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system.
Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic ap-
proaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown
antioxidant, anti-inammatory and neuroprotective eects in preclinical models of central nervous system
disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and
prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated
cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the
control of disease progression. e aim of this report was to provide a short but important overview of
evidences that are useful to better characterize the ecacy as well as the molecular pathways modulated by
cannabinoids.
Key Words: amyotrophic lateral sclerosis; cannabinoids; symptomatic ALS treatment; experimental ALS model;
clinical trials; mechanisms of neuroprotection
INVITED REVIEW
*Correspondence to:
Emanuela Mazzon, Ph.D.,
emazzon.irccs@gmail.com.
doi: 10.4103/1673-5374.197125
Accepted: 2016-12-10
Sabrina Giacoppo, Emanuela Mazzon*
IRCCS Centro Neurolesi “Bonino-Pulejo, Via Provinciale Palermo, Contrada Casazza, Messina, Italy
How to cite this article: Giacoppo S, Mazzon E (2016) Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?
Neural Regen Res 11(12):1896-1899.
Open access statement: is is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-
ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and
the new creations are licensed under the identical terms.
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Overview on Cannabinoids
The Cannabis plant, also known as marijuana, contains over
500 natural compounds and about 70 of these are classied as
cannabinoids (Fischedick et al., 2009). e discovery of Δ9-tet-
rahydrocannabinol (THC) as the major psychoactive principle
in Cannabis, as well as the identication of numerous non-psy-
choactive cannabinoids such as cannabidiol (CBD), cannab-
igerol (CBG), cannabinol (CBN), cannabichromene (CBC),
Δ9-tetrahydrocannabivarin (Δ9-THCV) and cannabidivarin
(CBDV), has led to a signicant growth in research aimed at
understanding the therapeutic eects of these compounds.
Cannabinoids exert many of their activities by binding
cannabinoid (CB) receptors. To date, two types of receptors
have been identified to have different tissue distribution
and mechanisms of signaling. CB1 receptors are expressed
mainly on neurons and glial cells in various parts of the
brain, CB2 receptors are found predominantly in the cells of
immune system. Both CB1 and CB2 receptors belong to the
family of G-protein coupled receptors (GPCRs) that, aer
cannabinoid agonist binding and signaling, exert an inhib-
itory eect on adenylate cyclaseactivity, activation of mito-
gen-activated protein kinase, regulation of calcium and po-
tassium channels, and other signal transduction pathways
(Munro et al., 1993). Moreover, there is increasing evidence
supporting the existence of additional cannabinoid recep-
tors (no-CB1 and no-CB2) in both central and peripheral
system, identied in CB1 and CB2-knockout mice, involving
intracellular pathways that play a key role in neuronal phys-
iology. This kind of receptors includes transient receptor
potential vanilloid type 1 (TRPV1), G protein-coupled re-
ceptor 55 (GPR55), G protein-coupled receptor 18 (GPR18),
G protein-coupled receptor 119 (GPR119) and 5-hydroxy-
tryptamine receptor subtype 1A (5-HT1A) (Pertwee et al.,
2010). Δ9-THC, of which is well-known psychotropic eects,
is believed to perform the majority of itsactions in the CNS
binding CB1 and CB2 receptors. Non-psychotrophic phy-
tocannabinoids exert multiple pharmacological eects via
CB1/CB2 receptors as well as no-CB1 and no-CB2 receptors
(Pertwee et al., 2010).
Overall, recent studies showed that cannabinoids inhibit
the release of pro-inflammatory cytokines and chemokine
in neurological preclinical models suppressing in this way
the inflammatory response (Velayudhan et al., 2014). They
show also a potent action in inhibiting oxidative and nitro-
sative stress, modulating the expression of inducibile nitric
oxide synthase and reducing the production of reactive
oxygen species (ROS) (Velayudhan et al., 2014). Moreover,
cannabinoids were found to exert anti-glutamatergic action
by inhibiting glutamate release and enhancing the eect of
the inhibitory neurotransmitter gamma-aminobutyric acid
(GABA) (Croxford, 2003). Just about all these properties ex-
hibited by these compounds, have prompted researchers to
investigate their potential therapeutic eects in ALS, provid-
ing interesting results.
Neuroprotective Eects of Cannabinoids in
Experimental Model of ALS
Recent in vivo studies support that cannabinoids may be
Figure 1 Schematic illustration of the neuroprotective mechanisms of action of cannabinoids into ALS hSOD(G93A) mice.
Δ9-THC: Δ9 tetrahydrocannabinol; ALS: amyotrophic lateral sclerosis; CBD: cannabidiol; CB1R: cannabinoid 1 receptor; CBN: cannabinol.
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benecial as neuroprotective agents in ALS. e most com-
monly used murine model for human ALS is the hSOD
(G93A) transgenic mouse, which is genetically engineered to
develop clinical symptoms similar to those observed in hu-
mans with ALS.
Treatment with Δ9-THC in ALS hSOD(G93A) mice, either
before or aer signs onset, improves motor impairment and
increases survival by 5% probably via its anti-glutamatergic
and anti-oxidant activity (Raman et al., 2004). Moreover, it
was demonstrated that Δ9-THC attenuates oxidative stress in
ALS hSOD(G93A) mouse spinal cord primary cultures, that
were exposed to the oxidant tert-butyl hydroperoxide (TBH)
in the presence of Δ9-THC and SR141716A, the CB1 receptor
antagonist, as assessed by lactate dehydrogenase (LDH) and
SOD-1 release. Specifically, the antioxidant effect of Δ9-THC
was not CB1-receptor mediated; since the CB1 receptor an-
tagonist SR141716A did not diminish the antioxidant eect
(Raman et al., 2004). Δ9-THC was found also to protect
against excitotoxicity produced by kainic acid in primary
neuronal cultures, obtained from ALS hSOD(G93A) mouse
spinal cord, by activation of CB1 receptor. In this case, the
neuroprotective eect was blocked with the CB1 receptor an-
tagonist, SR141716A, indicating a receptor-mediated eect
(Raman et al., 2004). erefore, treatment with cannabinoids
may reduce elevated glutamate levels observed during ALS
by modulating excitotoxicity events.
Moreover, treatment with cannabinol (CBN), a non-psy-
chotropic cannabinoid, through its residual affinity to CB1
receptors, is able to delay signicantly disease onset in ALS
hSOD(G93A) mice subcutaneously implanted with osmotic
mini-pumps. However, the molecular mechanisms remain
undened. On the contrary, survival was not aected (Weydt
et al., 2005).
Likewise, a significant delay in disease progression was
found when CB1/CB2 receptor agonist WIN 55,212-2 was
intraperitoneally administered to ALS hSOD(G93A) mice
beginning after onset of motor impairment and tremor (at
90 days old), however, survival was not extended (Bilsland
et al., 2006). Genetic ablation of the fatty acid amide hydro-
lase (FAAH) enzyme, which results in raised levels of the
endocannabinoid anandamide, prevented the appearance
of disease signs in 90-day-old to ALS hSOD(G93A) mice.
However, elevation of cannabinoid levels with either WIN55,
212-2 or FAAH ablation had no eect on life span. On the
contrary, CB1 deletion had no eects on disease onset in ALS
hSOD(G93A) mice, but extend lifespan by 15 days, a 13%
increase in survival. erefore, the benecial eects exhibit-
ed by cannabinoids may be mediated by non-CB1 receptors,
but presumably by CB2 ones. Moreover, the neuroprotective
effects of cannabinoids were ascribed to a decrease of mi-
croglial activation, presynaptic glutamate release and forma-
tion of ROS (Bilsland et al., 2006).
Also, it was demonstrated that mRNA, receptor binding
and function of CB2, but not CB1, receptors are dramatical-
ly and selectively up-regulated in the spinal cords of ALS
hSOD(G93A) mice in a temporal pattern paralleling disease
progression (Shoemaker et al., 2007). It was found that daily
intraperitoneal administration of the selective CB2 agonist,
AM-1241, initiated aer disease onset in ALS hSOD(G93A)
mice, delayed motor impairment and increased survival by
56%. e benecial eects of cannabinoids could potentially
be mediated via CB2 receptor-mediated suppression of mi-
croglial/macrophage activation in the spinal cords of symp-
tomatic G93A mice and that CB2 receptors are selectively
up-regulated in spinal cords as a compensatory, protective
measure (Shoemaker et al., 2007).
Few years ago, the neuroprotective effects of a mixture
of two extracts in approximately a 1:1 ratio (2.7 mg of Δ9-
THC and 2.5 mg of CBD) commercially known as Sativex®
were investigated by using ALS hSOD(G93A) transgenic
mice (Moreno-Martet et al., 2014). Sativex® was found to
be eective in delaying ALS progression in the early stages
of disease and in animal survival, although the ecacy was
decreased during progression of disease. Also, it has been
demonstrated that changes occur in endocannabinoid sig-
naling, particularly a marked up-regulation of CB2 receptors
in SOD(G93A) transgenic mice together with an increase of
N-acyl phosphatidylethanolamine phospholipase D (NAPE-
PLD) enzyme, which is responsible for the generation of
anandamide (N-arachidonoylethanolamine), the ligand of
cannabinoid and vanilloid receptors (Moreno-Martet et
al., 2014). Therefore, the efficacy of cannabinoids in slow-
ing ALS progression, in extending life expectancy and in
reducing the overall gravity of the disease is mainly due to
activation of CB2 receptors. More specically, it was widely
demonstrated that drugs activating CB2 receptors, expressed
predominantly in immune cells and non-neuronal tissues,
successfully improve the symptoms of several inammatory
diseases (Walter and Stella, 2004). However, further studies
are necessary to assess the neuroprotective eects of canna-
binoids that target CB2 receptors. Molecular mechanisms
underlying cannabinoids-driven neuroprotective effects in
ALS hSOD(G93A) mice model are illustrated in Figure 1.
Potential erapeutic Eects of Cannabinoids
in Human ALS
e cannabinoid system seems to be involved in the patho-
genesis of ALS. Spinal cord from ALS patients demonstrate
motor neurons damages marked by CB2-positive microglia/
macrophages. Moreover, a recent study analyzing activated
microglia from spinal cord in human ALS patients demon-
strated a CB2 receptors increase. So all these data show how
editing CB2-mediated processes could change ALS progres-
sion and how much the endocannabinoid system is poten-
tially involved in reducing neuro-inflammation, excitotox-
icity, and oxidative cell damage (Yiangou et al., 2006). The
possibility that cannabinoids may provide therapeutic eects
in ALS has been also investigated at the clinical level. How-
ever, the small number of people with ALS that reported us-
ing Cannabis and the few studies performed on human ALS,
makes difficult the interpretation of the achieved results.
Nevertheless, it is believed that Cannabis could be useful in
the symptomatic treatment of ALS.
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According to a single observational study of patients with
ALS only the 10% who admitted consuming Cannabis, re-
vealed moderate relief of several symptoms, including appe-
tite loss, depression, pain, and drooling was found (Carter
and Rosen, 2001; Amtmann et al., 2004).
In addition, spasticity is also major problem for ALS
patients, which reported that Cannabis can subjectively
improve spasticity (Amtmann et al., 2004). Moreover, a
randomized, double-blind crossover study investigating the
safety and tolerability of Δ9-THC in ALS patients revealed
that oral Δ9-THC administration was well tolerated, but a
non-significant attenuation of cramp frequency and inten-
sity were found. Other studies confirmed the same results,
demonstrating that Cannabis is remarkably safe with realisti-
cally no possibility of overdose.
ere are no clinical studies so far that have tried to prove
the potential of cannabinoids as disease-modifying therapies
as widely supported by experimental studies, so this hypoth-
esis remains a major challenge for future research.
Conclusion
In light of the above findings, there is a valid rationale to
propose the use of cannabinoid compounds in the pharma-
cological management of ALS patients. Cannabinoids in-
deed are able to delay ALS progression and prolong survival.
However, most of the studies that investigated the neuropro-
tective potential of these compounds in ALS were performed
in animal model, whereas the few clinical trials that investi-
gated cannabinoids-based medicines were focused only on
the alleviation of ALS-related symptoms, not on the control
of disease progression. This remains the major challenge
for the future and it may be facilitate by the recent approval
of the rst cannabinoid-based drug (Sativex®) available for
clinical use. In the last years, a growing interest is focused on
the combination drug approach with existing medications
in order to maximize the therapeutic ecacy and minimize
the adverse effects commonly observed with conventional
therapies. We strongly hope to have provided a short but
important overview of evidences that are useful to better
characterize the efficacy as well as the molecular pathways
modulated by cannabinoids. We hope that our studies could
be an alert to encourage the scientic community to further
studies to confirm the therapeutic use of cannabinoids in
this devastating disease.
Author contributions: SG wrote the manuscript. EM designed and re-
vised the manuscript. All authors approved the nal form for submission.
Conicts of interest: None declared.
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... Phytocannabinoids, such as cannabidiol (CBD), cannabivarin, delta-9-tetrahydrocannabinol (THC), cannabidivarin, and cannabigerol, have been widely studied for their involvement in endocannabinoid systems (Linge et al., 2016). CBD is one of the fascinating non-psychoactive phytocannabinoids with well-known anti-oxidant and anti-inflammatory properties (Giacoppo and Mazzon, 2016;Huestis et al., 2019). ...
... Amyotrophic lateral sclerosis (ALS) is a progressive and lethal neurodegenerative disease, which affects both lower and upper motor neurons, resulting in spasticity, weakness, and, lastly, death due to respiratory collapse (Hardiman et al., 2011;Miller et al., 2009). Although the pathobiology of ALS much remains unknown, like other NDDs, the pathogenic mechanisms, including OS, inflammation, excitotoxicity, mitochondrial dysfunction, and protein misfolding, are also known to be involved in ALS (Giacoppo and Mazzon, 2016;Zarei et al., 2015). Having antioxidant, anti-inflammatory, and neuroprotective potentials, CBD has shown to attenuate ALS pathology in various experimental evidence (Giacoppo and Mazzon, 2016;Raman et al., 2004). ...
... Although the pathobiology of ALS much remains unknown, like other NDDs, the pathogenic mechanisms, including OS, inflammation, excitotoxicity, mitochondrial dysfunction, and protein misfolding, are also known to be involved in ALS (Giacoppo and Mazzon, 2016;Zarei et al., 2015). Having antioxidant, anti-inflammatory, and neuroprotective potentials, CBD has shown to attenuate ALS pathology in various experimental evidence (Giacoppo and Mazzon, 2016;Raman et al., 2004). ...
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... In this review, we will concentrate on one of these chronic neurodegenerative disorders, ALS, which in recent years has become intensively focused on (Aymerich et al., 2018;Bilsland & Greensmith, 2008;De Lago et al., 2015;Giacoppo & Mazzon, 2016;Pryce & Baker, 2015;Urbi et al., 2019). First, we will describe the changes that take place in the different elements of endocannabinoid signalling in those CNS structures more affected (e.g. ...
... motor weakness) (Aymerich et al., 2018;Urbi et al., 2019; see Table 2 for a summary). Lastly, we will review the clinical evidence obtained so far, which is currently very limited, and also discuss the future perspectives for the necessary translational development of cannabinoid-based therapies (either for alleviating symptoms or for delaying disease progression) from the animal studies to ALS patients (Giacoppo & Mazzon, 2016;Pryce & Baker, 2015). ...
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... The final main effect is immunosuppression [135]. As reported by an article from Giacoppo and Mazzon, several studies have shownhow the application of cannabinoid receptor agonists in SOD1 G93A mouse models of ALS could be beneficial for the neuroprotective effects mediated by them [78]. Similarly, in 2019,Urbi et al. performeda meta-analysis on the studies regarding the application of cannabinoids in ALS murine models, highlighting the effective concordance in assessing that their application leads to a delay in disease progression [79]. ...
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Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy for its eradication, but still, no cure is available. The only two drugs approved for this pathology, Riluzole and Edaravone, are onlyable to slow down the inevitable disease progression. As assessed in the literature, drug targets such as protein kinases have already been extensively examined as potential drug targets for ALS, with some molecules already in clinical trials. Here, we focus on the involvement of another very important and studied class of biological entities, G protein-coupled receptors (GPCRs), in the onset and progression of ALS. This workaimsto give an overview of what has been already discovered on the topic, providing useful information and insights that can be used by scientists all around the world who are putting efforts into the fight against this very important neurodegenerating disease.
... Previous studies in animal models have shown that ALS is linked with some modifications in the endocannabinoid system, and its associated cannabinoid receptor agonists may decelerate the progression of the disease by slowing inflammation. Further, studies on mice involving an animal model of symptomatic ALS have highlighted that the levels of endogenous cannabinoids become high in the spinal cord [166]. CB2 receptors were up-regulated in G93A-SOD1 mutant mice, a mouse model of ALS [167]. ...
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Background Cannabis and its extracts are now being explored due to their huge health benefits. Although, the effect it elicits whether in humans or rodents may vary based on the age of the animal/subject and or the time in which the extract is administered. However, several debates exist concerning the various medical applications of these compounds. Nonetheless, their applicability as therapeutics should not be clouded based on their perceived negative biological actions. Methodology Articles from reliable databases such as Science Direct, PubMed, Google scholar, Scopus and Ovid were searched. Specific search methods were employed using multiple keywords: ‘‘Medicinal Cannabis; endocannabinoid system; cannabinoids receptors; cannabinoids and cognition; brain disorders; neurodegenerative diseases’’. For the inclusion/exclusion criteria, only relevant articles related to medicinal cannabis and its various compounds were considered. Result and conclusion The current review highlights the role, effects and involvement of cannabis; cannabinoids and endocannabinoids in preventing selected neurodegenerative diseases and possible amelioration of cognitive impairments. Also, cannabis utilization in many disease conditions such as Alzheimer’s and Parkinson’s disease among others. In conclusion, the usage of cannabis should be further explored as accumulating evidence suggests that it could be effective and somewhat safe especially when recommended dosage is adhered to. Furthermore, an in-depth studies should be conducted in order to unravel the specific mechanism underpinning the involvement of cannabinoids at the cellular level and their therapeutic applications.
... There is no evidence for these interventions as a disease-modifying therapy. A review of the available literature, however, has found it to be well-tolerated and has a tendency to reduce cramp frequency and intensity [46]. There are cannabinoid receptors in the dorsal spinal cord, basal ganglia, hippocampus, and cerebellum, which can modulate spasticity. ...
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Purpose of review Primary lateral sclerosis is a progressive neurodegenerative process that primarily affects upper motor neuron and presents with progressive stiffness and spasticity in all muscle groups. Given its rarity, diagnosis can be difficult and there has been limited research into what the best treatment is. This review will work to summarize the current available knowledge on the management of primary lateral sclerosis (PLS) including medications, nonpharmacologic interventions, diet, and exercise. Recent findings There have been no controlled studies of therapies in PLS. Management decisions are based on expert opinion from trials of other motor neuron diseases. The disease, while not curable, is treatable. A treatment plan will involve a mixture of medications, nonpharmacologic interventions, and exercise. The plan should be specific for each individual’s disabilities and not a one size fits all plan. Multidisciplinary centers with specialists trained in PLS can help to develop a plan. Research into the best practices and new treatments can have the potential to improve function. Summary While there is no cure for PLS, there are treatments for PLS. Therapy should involve an individualized care plan involving a mixture of treatment options developed and maintained through a multidisciplinary service and science hub model.
... This compound has entered Phase 3 trials for ALS in 2017, as it was observed in a Phase 2 trial that it could be of benefit to ALS patients as an add-on to Riluzole [123]. Regarding anti-inflammatory effects, it has to be noted that cannabinoids have also been proposed to be useful in the treatment of ALS due to their anti-inflammatory, anti-oxidant, and anti-excitotoxic properties [124,125]. However, a recent meta-analyses of the studies conducted so far on animal models has concluded that more standardized studies should be performed before supporting the treatment of ALS patients with these compounds [126]. ...
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... В настоящее время возможность использования природных и синтетических каннабиноидов для оказания лекарственной помощи больным боковым амиотрофическим склерозом (БАС) является предметом обсуждения [99]. Наибольшее внимание исследователи уделяют способности соединений этой группы подавлять нейровоспалительные [100] и эксайтотоксические реакции [101], которые признаны важными звеньями патогенеза БАС [102]. ...
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The quinone derivative of the non-psychotropic cannabinoid cannabigerol (CBG), so-called VCE-003.2, has been recently investigated for its neuroprotective properties in inflammatory models of Parkinson’s disease (PD) in mice. Such potential derives from its activity at the peroxisome proliferator-activated receptor-γ (PPAR-γ). In the present study, we investigated the neuroprotective properties of VCE-003.2 against the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA), in comparison with two new CBG-related derivatives, the cannabigerolic acid quinone (CBGA-Q) and its sodium salt CBGA-Q-Salt, which, similarly to VCE-003.2, were found to be active at the PPAR-γ receptor, but not at the cannabinoid CB1 and CB2 receptors. First, we investigated their cytoprotective properties in vitro by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-003.2 at a concentration of 20 μM, which was not reversed by the blockade of PPAR-γ receptors with GW9662, supporting its activity at an alternative site (non-sensitive to classic antagonists) in this receptor. We also found CBGA-Q and CBGA-Q-Salt being cytoprotective in this cell assay, but their effects were completely eliminated by GW9662, thus indicating that they are active at the canonical site in the PPAR-γ receptor. Then, we moved to in vivo testing using mice unilaterally lesioned with 6-OHDA. Our data confirmed that VCE-003.2 administered orally (20 mg/kg) preserved tyrosine hydroxylase (TH)-positive nigral neurons against 6-OHDA-induced damage, whereas it completely attenuated the astroglial (GFAP) and microglial (CD68) reactivity found in the substantia nigra of lesioned mice. Such neuroprotective effects caused an important recovery in the motor deficiencies displayed by 6-OHDA-lesioned mice in the pole test and the cylinder rearing test. We also investigated CBGA-Q, given orally (20 mg/kg) or intraperitoneally (10 mg/kg, i.p.), having similar benefits compared to VCE-003.2 against the loss of TH-positive nigral neurons, glial reactivity and motor defects caused by 6-OHDA. Lastly, the sodium salt of CBGA-Q, given orally (40 mg/kg) to 6-OHDA-lesioned mice, also showed benefits at behavioral and histopathological levels, but to a lower extent compared to the other two compounds. In contrast, when given i.p., CBGA-Q-Salt (10 mg/kg) was poorly active. We also analyzed the concentrations of dopamine and its metabolite DOPAC in the striatum of 6-OHDA-lesioned mice after the treatment with the different compounds, but recovery in the contents of both dopamine and DOPAC was only found after the treatment with VCE-003.2. In summary, our data confirmed the neuroprotective potential of VCE-003.2 in 6-OHDA-lesioned mice, which adds to its previous activity found in an inflammatory model of PD (LPS-lesioned mice). Additional phytocannabinoid derivatives, CBGA-Q and CBGA-Q-Salt, also afforded neuroprotection in 6-OHDA-lesioned mice, but their effects were lower compared to VCE-003.2, in particular in the case of CBG-Q-Salt. In vitro studies confirmed the relevance of PPAR-γ receptors for these effects.
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Background The goals of this study were to determine whether serum concentrations of endocannabinoids (eCB) and related lipids predict disease status in patients with amyotrophic lateral sclerosis (ALS) relative to healthy controls, and whether concentrations correlate with disease duration and severity. Methods Serum concentrations of the eCBs 2‐arachidonoylglycerol (2‐AG) and N‐arachidonoylethanolamine (AEA), and related lipids palmitoylethanolamine (PEA), oleoylethanolamine (OEA), and 2‐oleoylglycerol (2‐OG), were measured in samples from 47 patients with ALS and 19 healthy adults. Hierarchical binary logistic and linear regression analyses assessed whether lipid concentrations predicted disease status (ALS or healthy control), duration, or severity. Results Binary logistic regression revealed that, after controlling for age and gender, 2‐AG, 2‐OG and AEA concentrations were unique predictors of the presence of ALS, demonstrating odds ratios of 0.86 (P = .039), 1.03 (P = .023), and 42.17 (P = .026), respectively. When all five lipids and covariates (age, sex, race, ethnicity, body mass index, presence of a feeding tube) were included, the resulting model had an overall classification accuracy of 92.9%. Hierarchical linear regression analyses indicated that in patients with ALS, AEA and OEA inversely correlated with disease duration (P = .030 and .031 respectively), while PEA demonstrated a positive relationship with disease duration (P = .013). None of the lipids examined predicted disease severity. Conclusions These findings support previous studies indicating significant alterations in concentrations of circulating lipids in patients with ALS. They suggest that arachidonic and oleic acid containing small lipids may serve as biomarkers for identifying the presence and duration of this disease.
Chapter
Multiple Sclerosis and Cannabis – Benefits, Risks, and Special Considerations People with multiple sclerosis (MS) are interested in and use cannabis, and MS health professionals may be involved in the decision-making process about cannabis and provide care to those with MS who use cannabis. There is evidence that cannabis has therapeutic symptomatic effects in MS. Likewise, there is evidence that cannabis has side effects, drug interactions, and other potentially significant negative effects. People with MS and health professionals may not be knowledgeable about these potential beneficial and adverse effects and, as a result, in the MS community, informed decision-making may not be occurring. The aim of this chapter is to provide practical, MS-relevant information about the benefits and risks of cannabis so that, as with any medication, health professionals may effectively provide objective cannabis information, facilitate informed decision-making, and optimize safety and effectiveness in those patients who choose to use cannabis. The Evidence for Cannabis Use in Movement Disorders This chapter reviews the evidence for the efficacy and tolerability of cannabis in movement disorders. We present all the available preclinical and clinical studies of cannabis in Parkinson disease, Huntington’s disease, dystonia, Tourette syndrome, and other movement disorders. To date, there is not sufficient evidence to suggest that cannabis and its many derivative forms are effective and safe in any movement disorder. There is limited evidence for benefit of delta-9- tetrahydrocannabinol (Δ9-THC) and its synthetic analogs in Tourette syndrome and insufficient evidence to support its use in Parkinson disease, Huntington’s disease, and dystonia. There are no controlled clinical trials for the use of cannabis in essential tremor, restlessness legs syndrome, or rapid eye movement sleep behavior disorder. Overall, cannabidiol (CBD) was generally better tolerated than THC. Dizziness was one of the most common side effects of cannabinoids. Dizziness, falls, cognition, and liver function are common concerns posed by the elderly. Elderly persons and those with more advanced PD and HD should use cannabis cautiously. Cannabinoids in Neurosurgery This chapter will review the published literature for the treatment of neurosurgical conditions, including chronic low back and radicular pain, malignant gliomas, traumatic spinal cord and brain injury, and cerebrovascular hemorrhage. Summarizing the results, we have concluded that there is limited evidence to support or deny any benefits of the cannabinoid effectiveness for neurosurgery patients. Further epidemiological and clinical studies with rigorous study designs overcoming methodological limitations are needed to clarify contradictory findings. Therefore, the lack of conclusive scientific validation on short- and long-term safety, efficacy, and health risks should be the reason to limit the use of cannabinoids at the present time.
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The authors have identified that the image of internalised TrKB receptor control and siRNA (top panel) in Figure 5E was presented incorrectly. They provide here a new corrected image, which it can be seen is very similar to the incorrect image originally shown. The correct image clearly demonstrates a reduction in the intensity of internalized TrKB receptor in C9orf72-siRNA treated cells, as described. None of the conclusions were affected by this minor error as all quantification was performed using the correct blot. © The Author 2017. Published by Oxford University Press. All rights reserved.
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Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5-10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease.
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Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial Amyotrophic Lateral Sclerosis (ALS) and frontotemporal dementia (FTD). However, the cellular function of C9ORF72 protein remains unknown. Here we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 co-localized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical neurons and human spinal cord motor neurons, consistent with previous predictions that C9ORF72 bears Rab guanine exchange factor activity. Consistent with this notion, C9ORF72 was present in the extracellular space and as cytoplasmic vesicles. Depletion of C9ORF72 using siRNA inhibited transport of Shiga toxin from the plasma membrane to Golgi apparatus and the internalisation of TrkB receptor, and altered the ratio of autophagosome marker LC3II:LC3I, indicating that C9ORF72 regulates endocytosis and autophagy. C9ORF72 also co-localised with ubiquilin-2 and LC3-positive vesicles, and co-migrated with lysosome-stained vesicles in neuronal cell lines, providing further evidence that C9ORF72 regulates autophagy. Investigation of proteins interacting with C9ORF72 using mass spectrometry identified other proteins implicated in ALS; ubiquilin-2 and heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 and hnRNPA1, and actin. Treatment of cells over-expressing C9ORF72 with proteasome inhibitors induced the formation of stress granules positive for hnRNPA1 and hnRNPA2/B1. Immunohistochemistry of C9ORF72 ALS patient motor neurons revealed increased co-localisation between C9ORF72 and Rab7 and Rab11 compared to controls, suggesting possible dysregulation of trafficking in patients bearing the C9ORF72 repeat expansion. Hence this study identifies a role for C9ORF72 in Rab mediated cellular trafficking.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.
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There are at least two types of cannabinoid receptors (CB(1) and CB(2)). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ(9)-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB(1), non-CB(2) established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB(1) and/or CB(2) receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB(3)" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB(1), non-CB(2) pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB(3) receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB(1) receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB(1)/CB(2) receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB(1), non-CB(2) cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.
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The discovery of the C9orf72 hexanucleotide repeat expansion heralded significant advancement in the understanding of amyotrophic lateral sclerosis (ALS).1 ,2 Critically, the C9orf72 mutation represents the most common genetic cause of ALS (up to 50% of familial and 20% of sporadic ALS), responsible for the majority of motor and cognitive manifestations across the ALS–frontotemporal dementia (FTD) continuum.3–5 Pathologically, the C9orf72 mutation is associated with TDP-43 protein aggregation, the hallmark of ALS cases and is also present in 50% of FTD. The exact function of the normal C9orf72 protein remains undefined; however, it seems to play a major role in cellular trafficking, specifically in neurons. The loss of function …
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Cannabis (marijuana) has been proposed as treatment for a widening spectrum of medical conditions and has many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). This study is the first, anonymous survey of persons with ALS regarding the use of cannabis. There were 131 respondents, 13 of whom reported using cannabis in the last 12 months. Although the small number of people with ALS that reported using cannabis limits the interpretation of the survey findings, the results indicate that cannabis may be moderately effective at reducing symptoms of appetite loss, depression, pain, spasticity, and drooling. Cannabis was reported ineffective in reducing difficulties with speech and swallowing, and sexual dysfunction. The longest relief was reported for depression (approximately two to three hours).
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Cannabinoids afford neuroprotection in SOD1(G93A) mutant mice, an experimental model of amyotrophic lateral sclerosis (ALS). However, these mice have been poorly studied to identify alterations in those elements of the endocannabinoid system targeted by these treatments. Moreover, we studied the neuroprotective effect of the phytocannabinoid-based medicine Sativex(®) in these mice. First, we analyzed the endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice at a late stage of the disease. Second, 10-week-old transgenic mice were daily treated with an equimolecular combination of Δ(9) -tetrahydrocannabinol- and cannabidiol-enriched botanical extracts (20 mg/kg for each phytocannabinoid). We found a significant increase of CB2 receptors and NAPE-PLD enzyme in SOD1(G93A) transgenic males and only CB2 receptors in females. Pharmacological experiments demonstrated that the treatment of these mice with the Sativex(®) -like combination of phytocannabinoids only produced weak improvements in the progression of neurological deficits and in the animal survival, particularly in females. Our results demonstrated changes in endocannabinoid signaling, in particular a marked up-regulation of CB2 receptors, in SOD1(G93A) transgenic mice, and provide support that Sativex(®) may serve as a novel disease-modifying therapy in ALS.
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Objective Expansions of a hexanucleotide repeat in C9ORF72 are a common cause of familial amyotrophic lateral sclerosis (ALS) and a small proportion of sporadic ALS cases. We sought to examine clinical and neurophysiological features of familial and sporadic ALS with C9ORF72 expansions. Methods C9ORF72 was screened for expansions in familial and sporadic ALS. Clinical features of expansion positive cases are described. Cortical excitability studies used novel threshold tracking transcranal magnetic stimulation techniques with motor evoked responses recorded over the abductor pollicis brevis. Results and conclusions Analysis of large clinical cohorts identified C9ORF72 expansions in 38.5% (72/187) of ALS families and 3.5% (21/606) of sporadic ALS cases. Two expansion positive families were known to carry reported ANG mutations, possibly implicating an oligogenic model of ALS. 6% of familial ALS cases with C9ORF72 expansions were also diagnosed with dementia. The penetrance of ALS was 50% at age 58 years in male subjects and 63 years in female subjects. 100% penetrance of ALS was observed in male subjects by 86 years, while 6% of female subjects remained asymptomatic at age 82 years. Gender specific differences in age of onset were evident, with male subjects significantly more likely to develop ALS at a younger age. Importantly, features of cortical hyperexcitability were apparent in C9ORF72-linked familial ALS as demonstrated by significant reduction in short interval intracortical inhibition and cortical silent period duration along with an increase in intracortical facilitation and motor evoked potential amplitude, indicating that cortical hyperexcitability is an intrinsic process in C9ORF72-linked ALS.