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Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival
Abstract
Therapeutic options for amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, remain limited. Emerging evidence from clinical studies and transgenic mouse models of ALS suggests that cannabinoids, the bioactive ingredients of marijuana (Cannabis sativa) might have some therapeutic benefit in this disease. However, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the predominant cannabinoid in marijuana, induces mind-altering effects and is partially addictive, compromising its clinical usefulness. We therefore tested whether cannabinol (CBN), a non-psychotropic cannabinoid, influences disease progression and survival in the SOD1 (G93A) mouse model of ALS. CBN was delivered via subcutaneously implanted osmotic mini-pumps (5 mg/kg/day) over a period of up to 12 weeks. We found that this treatment significantly delays disease onset by more than two weeks while survival was not affected. Further research is necessary to determine whether non-psychotropic cannabinoids might be useful in ameliorating symptoms in ALS.
... Aktif tedavi grubunda ciddi bir yan etki yoktu (132). Nabilone, fibromiyaljili 40 hastada ağrı yönetimi ve yaşam kalitesi için çalışıldı (133). Nabilone, plaseboya kıyasla 4 hafta boyunca günde 0.5 mg'dan 1 mg BID'ye kadar titre edilen dozlarda kullanıldı. ...
... Hastalar 2. ve 4. haftada ana sonuç olarak ağrı ve bir dizi hassas nokta için görsel analog skala (VAS) ile değerlendirildi; Fibromiyalji Etki Anketi (FIQ) ve ortalama hassas nokta ağrı eşiği ikincil son noktalardır. Bu çalışma, FIQ'nun yanı sıra nabilon ile tedavi edilen hastalarda VAS'ta bir düşüş gösterdi, sonlanım noktalarının geri kalanı anlamlı bir farklılık göstermedi (133). Diğerinde nabilone ile yapılan bir çalışmada, iskelet ve lokomotor sistemi kronik ağrısı olan hastalar, 14 haftalık çapraz geçiş döneminde (iki adet 4 haftalık ilaç aşaması ve arınma aşaması) nabilone ve plasebo ile tedavi edildi ve ardından çalışma ilaçlarını özgürce seçme hakkı. ...
... Magdelena ve arkadaşlarının yaptıkları yukarıda sunulmuş derlemede; aynı zamanda kannabinoidlerin çeşitli biyolojik etkileri, diyabet tedavisi ile ilgili olarak da çok yönlü (pleiotropik) etkiye sahip yeni bir ilaç grubunun piyasaya sürülmesi olasılığı için umut verici olduğunu bildirmişlerdir (128)(129)(130)35,131,132). Glikoz beyin için tek enerji kaynağı olduğundan, son yıllarda kannabinoidlerin etkileri ile merkezi sinir sisteminde glikoz tüketimi arasındaki olası bağlantıya daha fazla dikkat edilmiştir (133). Artan kanıtlar, aşırı aktif bir periferik ECS'nin diyabet ve insülin direnci geliştirme riskine yatkın olduğunu doğrulamaktadır ancak daha sağlam sonuçlara varmak için, daha uzun takip süreleri ve esrar kullanımı hakkında daha ayrıntılı bilgi içeren ileriye dönük çalışmalara ihtiyaç olduğu sonucuna varılmıştır (1). ...
... Aktif tedavi grubunda ciddi bir yan etki yoktu (132). Nabilone, fibromiyaljili 40 hastada ağrı yönetimi ve yaşam kalitesi için çalışıldı (133). Nabilone, plaseboya kıyasla 4 hafta boyunca günde 0.5 mg'dan 1 mg BID'ye kadar titre edilen dozlarda kullanıldı. ...
... Hastalar 2. ve 4. haftada ana sonuç olarak ağrı ve bir dizi hassas nokta için görsel analog skala (VAS) ile değerlendirildi; Fibromiyalji Etki Anketi (FIQ) ve ortalama hassas nokta ağrı eşiği ikincil son noktalardır. Bu çalışma, FIQ'nun yanı sıra nabilon ile tedavi edilen hastalarda VAS'ta bir düşüş gösterdi, sonlanım noktalarının geri kalanı anlamlı bir farklılık göstermedi (133). Diğerinde nabilone ile yapılan bir çalışmada, iskelet ve lokomotor sistemi kronik ağrısı olan hastalar, 14 haftalık çapraz geçiş döneminde (iki adet 4 haftalık ilaç aşaması ve arınma aşaması) nabilone ve plasebo ile tedavi edildi ve ardından çalışma ilaçlarını özgürce seçme hakkı. ...
... Magdelena ve arkadaşlarının yaptıkları yukarıda sunulmuş derlemede; aynı zamanda kannabinoidlerin çeşitli biyolojik etkileri, diyabet tedavisi ile ilgili olarak da çok yönlü (pleiotropik) etkiye sahip yeni bir ilaç grubunun piyasaya sürülmesi olasılığı için umut verici olduğunu bildirmişlerdir (128)(129)(130)35,131,132). Glikoz beyin için tek enerji kaynağı olduğundan, son yıllarda kannabinoidlerin etkileri ile merkezi sinir sisteminde glikoz tüketimi arasındaki olası bağlantıya daha fazla dikkat edilmiştir (133). Artan kanıtlar, aşırı aktif bir periferik ECS'nin diyabet ve insülin direnci geliştirme riskine yatkın olduğunu doğrulamaktadır ancak daha sağlam sonuçlara varmak için, daha uzun takip süreleri ve esrar kullanımı hakkında daha ayrıntılı bilgi içeren ileriye dönük çalışmalara ihtiyaç olduğu sonucuna varılmıştır (1). ...
... As regards to the mechanisms that underlie these effects, the authors proposed a reduction in the oxidative stress and excitotoxic damage, they also found that Δ 9 -THC was effective in the reduction of both cytotoxic F I G U R E 2 Double immunostaining for the CB 2 receptor and markers of astrocytes and microglial cells supporting the up-regulatory response found in the CNS structures (spinal cord and primary motor cortex) lesioned in murine models of ALS (mSOD1(G93A) and TDP-43 (A315T) transgenic mice), dogs with ALS-like degeneration, and in post-mortem samples from ALS patients (scale bar = 10 μm) events in an in vitro study using spinal cord neuronal cultures (Raman et al., 2004). Similar results were reported with another phytocannabinoid cannabinol, which compared to Δ 9 -THC is significantly less psychotropic (Weydt et al., 2005), the non-selective cannabinoid agonist WIN55,212-2 (Bilsland et al., 2006;Shoemaker et al., 2007) and with the synthetic compounds that selectively activate the CB 2 receptor, for example AM-1241 (Kim et al., 2006;Shoemaker et al., 2007). However, a recent study also conducted in F I G U R E 3 Preservation of Nissl-stained motor neurons and reduced glial reactivity measured in the spinal cord, accompanied by improved rotarod performance, after the treatment with a selective agonist of CB 2 receptors in TDP-43 (A315T) transgenic mice (scale bar = 100 μm; *P < .05 vs. wild type, # P < .05 vs. ALS transgenic after data assessment with one-way ANOVA followed by the Bonferroni test) ...
... According to the research in cannabinoid-based neuroprotective therapies conducted in experimental ALS, potential clinical studies should investigate the relevance of CB 2 receptor activation on astrocyte trophic support, microglial reactivity and neuroinflammation. It also involves certain CB 1 receptor-mediated effects that might contribute to attenuate excitotoxic damage as well as the contribution of other mechanisms/ targets, for example those related to the cannabinoid receptorindependent effects (perhaps related to PPAR-γ signalling), which underlie the effects of some phytocannabinoids, for example Δ 9 -THC (Raman et al., 2004), cannabinol (Weydt et al., 2005) although, as mentioned above, this combination provided a poor neurological recovery and no changes in animal survival, suggesting the need for additional cannabinoid combinations that demonstrate to be effective in preclinical models and that may be translated to the clinical scenario. In this respect, a clinical trial (the EMERALD trial) aimed at evaluating the efficacy of a standardized cannabis extract (with high CBD/low Δ 9 -THC ratio) is presently in progress in Australia (Urbi et al., 2019). ...
... By contrast, studies conducted in the spinal cord of ALS patients reported apparent reductions in CB 1 receptors (Espejo-Porras et al., 2018).4 | TREATMENTS WITH CANNABINOIDS IN PRECLINICAL MODELS OF ALSAs mentioned above, the pharmacological evidence in support of the idea that cannabinoids may be a promising neuroprotective therapy in ALS was collected first in the classic transgenic mouse that overexpresses a mutated form (G93A) of SOD1(Bilsland et al., 2006;Kim et al., 2006;Raman et al., 2004;Rodríguez-Cueto et al., 2018;Shoemaker et al., 2007;Weydt et al., 2005; see Urbi et al., 2019, for a recent meta-analysis of these experimental studies), but recent studies have extended this evidence to the murine model based on the A315T mutation in TDP-43 protein (Espejo-Porras et al., 2019) (see ...
Cannabinoids form a singular group of plant‐derived compounds, endogenous lipids and synthetic derivatives with multiple therapeutic effects exerted by targeting different elements of the endocannabinoid system. One of their therapeutic applications is the preservation of neuronal integrity exerted by attenuating the multiple neurotoxic events that kill neurons in neurodegenerative disorders. In this review, we will address the potential of cannabinoids as neuroprotective agents in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder characterized by muscle denervation, atrophy and paralysis, and progressive deterioration in upper and/or lower motor neurons. The emphasis will be paid on the cannabinoid type 2 (CB2) receptor, whose activation limits glial reactivity, but the potential of additional endocannabinoid‐related targets will be also addressed. The evidence accumulated so far at the preclinical level supports the need to soon move towards the patients and initiate clinical trials to confirm the potential of cannabinoid‐based medicines as disease modifiers in ALS.
LINKED ARTICLES
This article is part of a themed issue on Recent advances in ALS pathogenesis and therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc
... TDP-43 transgenic mice; 19,20). In SOD1 G93A transgenic mice, pharmacological studies initiated in 2004 have demonstrated beneficial effects in animal survival, muscle strength improvement, preservation of motor neurons and/or reduction of glial reactivity and toxicity exerted by the phytocannabinoids Δ 9 -tetrahydrocannabinol (Δ 9 -THC) [21] and cannabinol (CBN) [22], the non-selective agonist WIN55,212-2 [23], the selective cannabinoid receptor type-2 (CB 2 ) agonist AM1241 [24,25], or through the genetic ablation of the fatty acid amide hydrolase (FAAH), one of the key enzymes in endocannabinoid inactivation [23]. More recently, our group has provided the first evidence of neuroprotective effects by activating the cannabinoid receptor type-1 (CB 1 ) receptor and, in particular, the CB 2 receptor in another experimental model of ALS based on overexpression of mutant TDP-43 (A315 mutation) in mice [20]. ...
... The studies in SOD1 G93A mutant mice have identified the activation of CB 2 receptors, the inhibition of the endocannabinoid inactivation, and/or the classic cannabinoid receptor-independent antioxidant properties of several cannabinoids, as the most probable mechanisms involved in the neuroprotective effects of the different cannabinoid compounds investigated to date [21][22][23][24][25]. However, the recent demonstration that certain cannabinoids may bind and activate nuclear receptors of the peroxisome proliferator-activated receptor (PPAR) family, in particular PPAR-γ type [26], as well as the fact that these receptors are involved in the regulation of inflammatory responses [27] and that non-cannabinoid PPAR-γ receptor activators (e.g. ...
... The hypothesis of the present study was to elucidate whether activation of PPAR-γ may be involved in the frequent neuroprotective effects found with different cannabinoids (e.g. Δ 9 -THC, CBN, WIN55,212-2, AM1241, etc) in the mutant SOD1 G93A mouse model of ALS [21][22][23][24][25]. In support of this possibility, treatment with non-cannabinoid compounds active at the PPAR-γ (e.g. ...
Antioxidant phytocannabinoids, synthetic compounds targeting the CB2 receptor, and inhibitors of the endocannabinoid inactivation afforded neuroprotection in SOD1G93A mutant mice, a model of ALS. These effects may involve the activation of PPAR-γ too. Here, we have investigated the neuroprotective effects in SOD1G93A mutant mice of the cannabigerol derivative VCE-003.2, which works as neuroprotectant by activating PPAR-γ. Mice were treated with VCE-003.2 from 60 days up to an advanced stage in disease progression (18 weeks), when they were euthanized and used for analysis of neuropathological signs. As expected, SOD1G93A transgenic mice experienced a progressive weight loss and neurological deterioration, which was associated with a marked loss of spinal cholinergic motor neurons, glial reactivity, and elevations in several biochemical markers (cytokines, glutamate transporters) that indirectly reflect the glial proliferation and activation in the spinal cord. The treatment with VCE-003.2 improved most of these neuropathological signs. It attenuated the weight loss and the anomalies in neurological parameters, preserved spinal cholinergic motor neurons, and reduced astroglial reactivity. VCE-003.2 also reduced the elevations in IL-1β and glial glutamate transporters. Lastly, VCE-003.2 attenuated the LPS-induced generation of TNF-α and IL-1β in cultured astrocytes obtained from SOD1G93A transgenic newborns, an effect also produced by rosiglitazone, then indicating a probable PPAR-γ activation as responsible of its neuroprotective effects. In summary, our results showed benefits with VCE-003.2 in SOD1G93A transgenic mice supporting PPAR-γ as an additional neuroprotective target available for cannabinoids in ALS. Such benefits would need to be validated in other ALS models prior to be translated to the clinical level.
... Recently cannabinoids have been shown to provide neuroprotection in ALS, specifically in the SOD-1 G93A transgenic mice (11,12), and the issue has reached the clinical scenario with the first trial with cannabinoid-based therapies in ALS (13). Neuroprotective effects have been found with D 9 -tetrahydrocannabinol (14), cannabinol (15), the synthetic agonist WIN55,212-2 (16), and the cannabinoid receptor type-2 (CB 2 ) agonist AM1241 (17,18). The fact that neuroprotective effects were reached with nonselective cannabinoids (14)(15)(16) suggests that different endocannabinoid mechanisms, for example, the cannabinoid receptor type-1 (CB 1 ) and also the CB 2 receptor, and even targets outside this system, may be involved (12). ...
... Neuroprotective effects have been found with D 9 -tetrahydrocannabinol (14), cannabinol (15), the synthetic agonist WIN55,212-2 (16), and the cannabinoid receptor type-2 (CB 2 ) agonist AM1241 (17,18). The fact that neuroprotective effects were reached with nonselective cannabinoids (14)(15)(16) suggests that different endocannabinoid mechanisms, for example, the cannabinoid receptor type-1 (CB 1 ) and also the CB 2 receptor, and even targets outside this system, may be involved (12). However, activating selectively the CB 2 receptor with AM1241 led to levels of neuroprotection (17,18) similar to treatments with nonselective agonists (14)(15)(16), which supports a major role for the CB 2 receptor. ...
... The fact that neuroprotective effects were reached with nonselective cannabinoids (14)(15)(16) suggests that different endocannabinoid mechanisms, for example, the cannabinoid receptor type-1 (CB 1 ) and also the CB 2 receptor, and even targets outside this system, may be involved (12). However, activating selectively the CB 2 receptor with AM1241 led to levels of neuroprotection (17,18) similar to treatments with nonselective agonists (14)(15)(16), which supports a major role for the CB 2 receptor. This may be facilitated by the CB 2 receptor up-regulation found in lesioned structures in neurodegenerative disorders (12,19,20). ...
Objective:
We have investigated the endocannabinoid system in the motor cortex of motor neuron disease (MND) patients.
Methods:
Post-mortem samples from MND patients and controls were used for immunostaining and/or Western blotting analysis of endocannabinoid elements.
Results:
We did not find any evidence of neuronal losses in the motor cortex of MND patients, but elevations in glial markers Iba-1 and GFAP were evident. We found no changes in FAAH and MAGL enzymes and in the CB1 receptor, which correlated with the lack of cortical neuron death. By contrast, the Western blotting analysis of CB2 receptors proved an increase in the motor cortex corroborated by immunostaining, correlating with the elevated gliosis in these patients. Double-labeling analyses revealed that this elevated CB2 receptor immunostaining was located in GFAP-labelled astroglial cells. However, we also found CB2 receptor labeling in cortical neurons confirmed with double immunofluorescence with the neuronal marker MAP-2. This was also found in the spinal cord, using double-labeling with the spinal motor neuron marker choline-acetyl transferase. This happened in both patients and controls, despite these neurons experienced an important degeneration in patients reflected in reduced Nissl staining, TDP-43 immunostaining and CB1 receptor levels measured by Western blotting.
Conclusion:
We have confirmed that CB2 receptors are elevated in the motor cortex of MND patients associated with the reactive gliosis. This phenomenon is previous to neuronal losses. We also found CB2 receptors in cortical and spinal motor neurons. These observations support that targeting this receptor may serve for developing neuroprotective therapies in MNDs.
... CBN has shown several health benefits, such as neuroprotective effect by reducing increased intraocular pressure, inhibiting synaptic membrane ATPases, partially inhibiting adenylate cyclase activity, inhibiting amidase, delaying the onset of symptoms in SOD1 transgenic mice (Olmsted, 1976;Howlett, 1987;Watanabe et al., 1996;Weydt et al., 2005;Somvanshi et al., 2022), and modulating immune function through several mechanisms, including lymphocyte proliferation inhibition, NF-κB/Rel and IL-2 production by inhibition of IL-2 gene transcription (Herring et al., 1998;Herring and Kaminski, 1999;Jan and Kaminski, 2001). CBN exhibits a variety of pharmacological properties, including anticancer, antimicrobial, analgesic, and anti-inflammatory activities (Shammas, 2006;Wong and Cairns, 2019;Kolar et al., 2023;Mahadeo et al., 2023;Zaiachuk et al., 2023). ...
... In another study, CBN exhibited the ability to postpone the initiation of symptoms in SOD1 transgenic mice, which is a key factor in amyotrophic lateral sclerosis. The results also showed that CBN administration did not affect survival (Weydt et al., 2005). However, CBN administrated to cats caused a significant decrease in ocular tension, while administrated to rats, CBN caused conjunctival and erythema and hyperemia, leading authors to conclude that CBN produced both ocular and neural toxicity (Colasanti et al., 1984). ...
Cannabinol (CBN) is a non-psychoactive phytocannabinoid found in Cannabis sativa. Although overshadowed by its more well-known counterparts, such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), CBN has been gaining attention due to its potential therapeutic properties. This review aims to provide insight into the molecular mechanisms underlying the pharmacological actions of CBN. CBN interacts with the endocannabinoid system (ECS), primarily targeting the CB2 and CB1 cannabinoid receptors. It acts as a partial agonist for both receptors, modulating their activity and downstream signaling pathways. Through these interactions, CBN exhibits diverse effects on various physiological processes, including pain perception, inflammation, immune response, and neuroprotection. Moreover, CBN has been shown to affect non-cannabinoid receptors, including transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), and serotonin receptors. These interactions contribute to the modulation of pain, inflammation, and mood regulation. The molecular mechanisms of CBN also involve its antioxidant and anti-inflammatory properties. CBN has been found to reduce oxidative stress by scavenging reactive oxygen species (ROS) and inhibiting inflammatory mediators. This antioxidant activity potentially contributes to its neuroprotective effects and may have implications for the treatment of neurodegenerative disorders. Furthermore, CBN exhibits potential antimicrobial activity, acting 2 against various bacteria, fungi, and methicillin-resistant Staphylococcus aureus (MRSA) strains. The underlying mechanisms of this antimicrobial effect are still being elucidated, but may involve disruption of microbial cell membranes and interference with microbial biofilm formation. The molecular mechanisms underlying CBN's pharmacological actions involve its interactions with the ECS, modulation of non-cannabinoid receptors, anti-oxidant and anti-inflammatory properties, and potential antimicrobial activity. Further research is needed to fully understand the therapeutic potential of CBN and its role in various disease states, paving the way for the development of novel therapeutic interventions. Due to its multiple interests, the isolation and synthesis of CBN has been investigated by several approaches. CBN synthesis involves various approaches, including oxidative conversions, isomerization reactions, enzymatic transformations, and biotransformation techniques. Advancements in synthetic methodologies and innovative strategies continue to contribute to the efficient production of CBN. Further research and optimization are necessary to enhance yields, purity, and scalability of the synthesis processes.
... In brief, they found that treatment with ∆ 9 -THC in SOD1 (G93A) transgenic mice prevented motor deficits and increased survival, whether administered before or after the onset of the disease [31]. One year later, Weydt et al. demonstrated that the phytocannabinoid CBN (cannabinol) also had significant benefits in delaying the onset of the disease in SOD1 (G93A) mice, although it did not extend their survival [32]. From these findings, numerous other studies have been conducted to explore whether or not cannabinoids, synthetic analogs, and modulators of the endocannabinoid system could potentially become new tools for complementary and alternative therapies in ALS, possibly through the identification of novel targets. ...
... The trial found that orally administered THC (5 mg) twice daily was ineffective in reducing cramp intensity and preventing fasciculation intensity. No effect of THC was found on the quality of life, sleep, appetite, or mood [32]. In 2019, Riva et al. conducted a phase 2 study (CANALS) that presented initial evidence of the effectiveness and safety of Nabiximols (THC and CBD in a 1:1 ratio) compared to a placebo in reducing spasticity in ALS patients [40]. ...
Neuromuscular disorders (NMDs) encompass a large heterogeneous group of hereditary and acquired diseases primarily affecting motor neurons, peripheral nerves, and the skeletal muscle system. The symptoms of NMDs may vary depending on the specific condition, but some of the most common ones include muscle weakness, pain, paresthesias, and hyporeflexia, as well as difficulties with swallowing and breathing. NMDs are currently untreatable. Therapeutic options include symptomatic and experimental medications aimed at delaying and alleviating symptoms, in some cases supplemented by surgical and physical interventions. To address this unmet medical need, ongoing research is being conducted on new treatments, including studies on medical cannabis, endocannabinoids, and related molecules with cannabimimetic properties. In this context, a significant amount of knowledge about the safety and effectiveness of cannabinoids in NMDs has been obtained from studies involving patients with multiple sclerosis experiencing pain and spasticity. In recent decades, numerous other preclinical and clinical studies have been conducted to determine the potential benefits of cannabinoids in NMDs. This review article aims to summarize and provide an unbiased point of view on the current knowledge about the use of cannabinoids, endocannabinoids, and synthetic analogs in NMDs, drawing from an array of compelling studies.
... After treatment with the phytocannabinoid D9-THC, motor degeneration is postponed and animal survival is increased in the SOD1G93A (the superoxide dismutase 1) transgenic mouse model of ALS [104]. Other plant-derived cannabinoids, like the less psychoactive cannabinoid cannabinol [105], WIN55,212-2, the non-selective cannabinoid receptor agonist [106], and AM1241, a selective CB2 agonist, have comparable effects [107,108]. The effectiveness of elements that target CB2 receptors corresponds with the findings that microglial cells in postmortem spinal cord samples from ALS patients exhibit overexpression of this receptor [109] or SOD1G93A transgenic mice [108], suggesting that this receptor is a promising target for the development of disease-modifying therapies in ALS [110,111]. ...
Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants. Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders. The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.
... There are other potentially therapeutic phytocannabinoids, which have been tested in pre-clinical studies, but not yet extensively in vivo and are represented by: ∆8-Tetrahydrocannabinol [51], Cannabinol [52], Cannabigerol [53], Cannabichromene [54], ∆9-Tetrahydrocannabivarin (∆ 9-THCV) [55] and Cannabidivarin (CBDV) [56]. ...
... Comparable effects to CBD were found in a rat maximal electroshock seizure model and a Scn1aRX/+ mouse model of Dravet syndrome hyperthermia, where treatment increased the temperature threshold required to induce tonic-clonic seizures [82,83]. Another minor cannabinoid, cannabidivarin (CBDV) also reduced seizure activity in multiple in vivo models of epilepsy, and improved neurobehavioral abnormalities in mouse models of Rett syndrome [84,85] Cannabinol (CBN) treatment delayed the progression of motor abnormalities in a model of amyotrophic lateral sclerosis [86]. ...
Traumatic brain injury is common, and often results in debilitating consequences. Even mild traumatic brain injury leaves approximately 20% of patients with symptoms that persist for months. Despite great clinical need there are currently no approved pharmaceutical interventions that improve outcomes after traumatic brain injury. Increased understanding of the endocannabinoid system in health and disease has accompanied growing evidence for therapeutic benefits of Cannabis sativa. This has driven research of Cannabis’ active chemical constituents (phytocannabinoids), alongside endogenous and synthetic counterparts, collectively known as cannabinoids. Also of therapeutic interest are other Cannabis constituents, such as terpenes. Cannabinoids interact with neurons, microglia, and astrocytes, and exert anti-inflammatory and neuroprotective effects which are highly desirable for the management of traumatic brain injury. In this review, we comprehensively appraised the relevant scientific literature, where major and minor phytocannabinoids, terpenes, synthetic cannabinoids, and endogenous cannabinoids were assessed in TBI, or other neurological conditions with pathology and symptomology relevant to TBI, as well as recent studies in preclinical TBI models and clinical TBI populations.
... Similarly, CBN, a non-psychoactive cannabinoid from marijuana that acts as CB1R and CB2R agonist, delayed disease onset without affecting survival when applied for 12 weeks in G93A-SOD1 mice [244]. In TDP-43 transgenic mice, WIN 55,212-2 showed only trends towards improved motor performance in the rotarod test, recovery of spinal motor neurons, and reduced astrocytic and microglial reactivity, and these effects were partially mediated by CB2R. ...
Some of the most prevalent neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease, are proteinopathies characterized by the accumulation of specific protein aggregates in the brain. Such misfolded protein aggregates can trigger modulation of the innate and adaptive immune systems and subsequently lead to chronic neuroinflammation that drives the onset and progression of neurodegenerative diseases. Since there is still no effective disease-modifying treatment, new therapeutic targets for neurodegenerative proteinopathies have been sought. The endocannabinoid system, and in particular the cannabinoid CB2 receptors, have been extensively studied, due to their important role in neuroinflammation, especially in microglial cells. Several studies have shown promising effects of CB2 receptor activation on reducing protein aggregation-based pathology as well as on attenuating inflammation and several dementia-related symptoms. In this review, we discuss the available data on the role of CB2 receptors in neuroinflammation and the potential benefits and limitations of specific agonists of these receptors in the therapy of neurodegenerative proteinopathies.
... Its popularity is increasing as commercial preparations are becoming available to the public, particularly as an alternative sleep aid to over-the-counter (OTC) or prescription drugs. Cannabinoids including CBN have been shown in rodent studies to delay symptoms in amyotrophic lateral sclerosis (mice) (Weydt et al. 2005), to reduce myofascial pain (rats) (Wong and Cairns 2019), to act as an anticonvulsant (mice) (Karler et al. 1973) alternative treatment for mood disorders and anxiety (rodent and human) (Ferber et al. 2020), and to be a potential treatment for sleep disorders (rodent and human) (Murillo- Rodriguez et al. 2020;Kaufmann 2021a). The wide variety of applications for cannabinoids are possibly due in part to their activity at transient receptor potential vanilloid (TRPV) channels [reviewed in (Muller et al. 2018)] as well as cannabinoid (CB) receptors CB-1 and CB-2. ...
Background
Cannabinol (CBN) is one of the many cannabinoids present in Cannabis sativa and has been explored as a potential treatment for sleeplessness. The purpose of this study was to determine the physiological and behavioral effects of subacute exposure to therapeutic and low pharmacological levels of a mechanically formed, stabilized water-soluble cannabinol nano-emulsion (CBNight™).
Methods
Sixty-two male mice were randomly assigned to one of six treatment groups given CBNight™ at dosages designed to deliver 0mg (control) to 4 mg/kg of CBN daily via oral gavage for 14 days. In-cage behavior was observed at 30 minutes and at 2, 4, 8, and 16 hours after each dose. After 14 days, the mice were sacrificed and necropsied. Organs were weighed and inspected for gross abnormalities, and blood was collected via cardiac puncture for clinical chemistry.
Results
No dosage-dependent adverse effects on behavior, body mass, or blood chemistry were observed, except that the highest doses of CBNight™ were associated with significantly lower eosinophil counts.
Conclusions
The commercially available, water-soluble CBN compound employed in this study does not appear to cause adverse effects in mice; rather, it appears to be well tolerated at pharmacological levels. The findings of eosinopenia at higher doses of CBN and lack of hepatotoxicity at any dosage employed in this study have not been reported to date.
... Another prominent cannabinoid is cannabinol (CBN), which is a degradation product of THC that occurs during storing, aging, or heating of cannabis products. CBN has gained interest lately as it is also proved to play a significant role in therapeutic benefits [6,7]. As the global cannabis market has grown rapidly, trace detection of cannabinoids is crucial for various purposes [8][9][10], e.g., quality control, research & development, and forensic identification. ...
Many countries have legalized cannabis and its derived products for multiple purposes. Consequently, it has become necessary to develop a rapid, effective, and reliable tool for detecting delta-9-tetrahydrocannabinol (THC) and cannabinol (CBN), which are important biologically active compounds in cannabis. Herein, we have fabricated SERS chips by using glancing angle deposition and tuned dimensions of silver nanorods (AgNRs) for detecting THC and CBN at low concentrations. Experimental and computational results showed that the AgNR substrate with film thickness (or nanorod length) of 150 nm, corresponding to nanorod diameter of 79 nm and gap between nanorods of 23 nm, can effectively sense trace THC and CBN with good reproducibility and sensitivity. Due to limited spectral studies of the cannabinoids in previous reports, this work also explored towards identifying characteristic Raman lines of THC and CBN. This information is critical to further reliable data analysis and interpretation. Moreover, multianalyte detection of THC and CBN in a mixture was successfully demonstrated by applying an open-source independent component analysis (ICA) model. The overall method is fast, sensitive, and reliable for sensing trace THC and CBN. The SERS chip-based method and spectral results here are useful for a variety of cannabis testing applications, such as product screening and forensic investigation.
... This compound is a potent agonist of the transient receptor potential cation channel, subfamily A, member 1 (TRPA1), and an antagonist of the transient receptor potential cation channel, subfamily M, member 8 (TPRM8). Recently, it has been observed that cannabinol (CBN) influences disease progression but not survival in the mouse model of amyotrophic lateral sclerosis (ALS) [22]. Cannabigerol (CBG), a non-psychoactive phytocannabinoid, has a low affinity for the cannabinoid CB1 and CB2 receptors, but inhibits AEA uptake, affecting the ECS. ...
Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
... Owing to the presence of an additional aromatic ring as compared to THC, CBN is metabolically more stable and its bioavailability after oral or inhaled administration has been reported in the range of 10-40% [69]. Preclinical and limited clinical evaluations have also shown that CBN has good brain penetrance with excellent safety and pharmacokinetic profiles in animals and humans [70][71][72][73][74][75]. However, pharmacological and mechanistic studies on CBN as a treatment for age-associated neurodegenerative diseases have not been reported. ...
The oxytosis/ferroptosis regulated cell death pathway recapitulates many features of mitochondrial dysfunction associated with the aging brain and has emerged as a potential key mediator of neurodegeneration. It has thus been proposed that the oxytosis/ferroptosis pathway can be used to identify novel drug candidates for the treatment of age-associated neurodegenerative diseases that act by preserving mitochondrial function. Previously, we identified cannabinol (CBN) as a potent neuroprotector. Here, we demonstrate that not only does CBN protect nerve cells from oxytosis/ferroptosis in a manner that is dependent on mitochondria and it does so independently of cannabinoid receptors. Specifically, CBN directly targets mitochondria and preserves key mitochondrial functions including redox regulation, calcium uptake, membrane potential, bioenergetics, biogenesis, and modulation of fusion/fission dynamics that are disrupted following induction of oxytosis/ferroptosis. These protective effects of CBN are at least partly mediated by the promotion of endogenous antioxidant defenses and the activation of AMP-activated protein kinase (AMPK) signaling. Together, our data highlight the potential of mitochondrially-targeted compounds such as CBN as novel oxytotic/ferroptotic inhibitors to rescue mitochondrial dysfunction as well as opportunities for the discovery and development of future neurotherapeutics.
... Most of these studies were carried out in the classic mutant SOD-1 mouse model (23). These studies included the phytocannabinoids Δ 9 -tetrahydrocannabinol (Δ 9 -THC) (24) and cannabinol (25), in both cases with positive results, and, to a lesser extent, the Δ 9 -THC:cannabidiol mixture, Sativex® (26). Neuroprotection was also obtained with synthetic cannabinoids such as the non-selective cannabimimetic WIN55,212-2 (27), the selective CB 2 agonist AM1241 (28,29) and after the inactivation of the endocannabinoid-degradation enzyme fatty acid amide hydrolase (FAAH) (27). ...
The activation of the cannabinoid receptor type‐2 (CB2) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB2 receptor through investigating the consequences of its inactivation. TDP‐43(A315T) transgenic mice were crossed with CB2 receptor knock‐out mice to generate double mutants. Temporal and qualitative aspects of the pathological phenotype of the double mutants were compared to TDP‐43 transgenic mice expressing the CB2 receptor. The double mutants exhibited significantly accelerated neurological decline, such that deteriorated rotarod performance was visible at 7 weeks, whereas rotarod performance was normal up to 11 weeks in transgenic mice with intact expression of the CB2 receptor. A morphological analysis of spinal cords confirmed an earlier death (visible at 65 days) of motor neurons labelled with Nissl staining and ChAT immunofluorescence in double mutants compared to TDP‐43 transgenic mice expressing the CB2 receptor. Evidence of glial reactivity, measured using GFAP and Iba‐1 immunostaining, was seen in double mutants at 65 days, but not in TDP‐43 transgenic mice expressing the CB2 receptor. However, at 90 days, both genotypes exhibited similar changes for all these markers, although surviving motor neurons of transgenic mice presented some morphological abnormalities in absence of the CB2 receptor that were not as evident in the presence of this receptor. This faster deterioration seen in double mutants led to premature mortality compared with TDP‐43 transgenic mice expressing the CB2 receptor. We also investigated the consequences of a pharmacological inactivation of the CB2 receptor using the selective antagonist AM630 in TDP‐43 transgenic mice, but results showed only subtle trends towards a greater deterioration. In summary, our results confirmed the potential of the CB2 receptor agonists as a neuroprotective therapy in ALS and strongly support the need to progress towards an evaluation of this potential in patients.
... Interestingly, cannabinoid receptor loss has been indicated as a pathophysiology of Huntington's disease [352,353], which may suggest that the purported protective action of cannabinoids is independent of cannabinoid receptor binding. Subcutaneously delivered CBN delayed the onset of amyotrophic lateral sclerosis (ALS) symptoms in murine models but failed to affect survival, so was postulated to mask the early spasticity associations without affecting disease progression [354]. A synergistic effect of CBN with CBD at reducing mechanical sensitisation in rat masseter muscles was observed in one study, however high concentrations of CBD ameliorated the efficacy of CBN [355]. ...
Cannabis sativa (Cannabis) is one of the world’s most well-known, yet maligned plant species. However, significant recent research is starting to unveil the potential of Cannabis to produce secondary compounds that may offer a suite of medical benefits, elevating this unique plant species from its illicit narcotic status into a genuine biopharmaceutical. This review summarises the lengthy history of Cannabis and details the molecular pathways that underpin the production of key secondary metabolites that may confer medical efficacy. We also provide an up-to-date summary of the molecular targets and potential of the relatively unknown minor compounds offered by the Cannabis plant. Furthermore, we detail the recent advances in plant science, as well as synthetic biology, and the pharmacology surrounding Cannabis. Given the relative infancy of Cannabis research, we go on to highlight the parallels to previous research conducted in another medically relevant and versatile plant, Papaver somniferum (opium poppy), as an indicator of the possible future direction of Cannabis plant biology. Overall, this review highlights the future directions of cannabis research outside of the medical biology aspects of its well-characterised constituents and explores additional avenues for the potential improvement of the medical potential of the Cannabis plant.
... One common hypothesis for the underlying motor neuron vulnerability is susceptibility to excitotoxicity and oxidative damage (Robberecht, 2000). Treatment with Δ 9 -THC led to delayed ALS progression in SOD1 mice and increased survival (Weydt et al., 2005). Overexpression of SOD1 leads to a loss of motor neurons, progressive paralysis, reduced lifespan, axonal denervation, and protein aggregation in the mouse model and ALS patients (Philips and Rothstein, 2015). ...
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.
... SOD1 model of amyotrophic lateral sclerosis. CBN delayed motor abnormalities at Day 17 in the chronic treatment regimen, compared with vehicle control, but disease progression was not affected(Weydt et al., 2005). In a model of Huntington's disease,Aiken et al. (2004) found that CBN reduced LDH activity in PC12 cells (20 and 100 μM), but the authors did not investigate the mechanism(s) of this effect. ...
Embase and PubMed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, apart from cannabidiol and Δ⁹‐tetrahydrocannabinol, including Δ⁹‐tetrahydrocannabinolic acid, Δ⁹‐tetrahydrocannabivarin, cannabidiolic acid, cannabidivarin, cannabichromene, cannabichromenic acid, cannabichromevarin, cannabigerol, cannabigerolic acid, cannabigerivarin, cannabigerovarinic acid, cannabichromevarinic acid, cannabidivarinic acid, and cannabinol. Out of 2,341 studies, 31 articles met inclusion criteria. Cannabigerol (range 5 to 20 mg·kg⁻¹) and cannabidivarin (range 0.2 to 400 mg·kg⁻¹) displayed efficacy in models of Huntington's disease and epilepsy. Cannabichromene (10–75 mg·kg⁻¹), Δ⁹‐tetrahydrocannabinolic acid (20 mg·kg⁻¹), and tetrahydrocannabivarin (range 0.025–2.5 mg·kg⁻¹) showed promise in models of seizure and hypomobility, Huntington's and Parkinson's disease. Limited mechanistic data showed cannabigerol, its derivatives VCE.003 and VCE.003.2, and Δ⁹‐tetrahydrocannabinolic acid mediated some of their effects through PPAR‐γ, but no other receptors were probed. Further studies with these phytocannabinoids, and their combinations, are warranted across a range of neurodegenerative disorders.
... For instance, CBG is considered as antimicrobial [30,31] and as counteracting neuroinflammation by targeting glial cells [32]. Potential to combat amyotrophic lateral sclerosis is based in the actions of a synthetic derivative, VCE-003.2, in the SOD1G93A rodent model of the disease [33,34]. CBG seems to inhibit ALR2 aldose reductase, which is of relevance in diabetes [35], and to be of interest in eating disorders as it produces both hyperphagia in rats [36] and further food consumption in satiated rats [37]. ...
Background
Recent approved medicines whose active principles are Δ⁹Tetrahidrocannabinol (Δ⁹-THC) and/or cannabidiol (CBD) open novel perspectives for other phytocannabinoids also present in Cannabis sativa L. varieties. Furthermore, solid data on the potential benefits of acidic and varinic phytocannabinoids in a variety of diseases are already available. Mode of action of cannabigerol (CBG), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabidivarin (CBDV) and cannabigerivarin (CBGV) is, to the very least, partial.
Hypothesis/Purpose
Cannabinoid CB1 or CB2 receptors, which belong to the G-protein-coupled receptor (GPCR) family, are important mediators of the action of those cannabinoids. Pure CBG, CBDA, CBGA, CBDV and CBGV from Cannabis sativa L. are differentially acting on CB1 or CB2 cannabinoid receptors.
Study Design
Determination of the affinity of phytocannabinoids for cannabinoid receptors and functional assessment of effects promoted by these compounds when interacting with cannabinoid receptors.
Methods
A heterologous system expressing the human versions of CB1 and/or CB2 receptors was used. Binding to membranes was measured using radioligands and binding to living cells using a homogenous time resolved fluorescence resonance energy transfer (HTRF) assay. Four different functional outputs were assayed: determination of cAMP levels and of extracellular-signal-related-kinase phosphorylation, label-free dynamic mass redistribution (DMR) and ß-arrestin recruitment.
Results
Affinity of cannabinoids depend on the ligand of reference and may be different in membranes and in living cells. All tested phytocannabinoids have agonist-like behavior but behaved as inverse-agonists in the presence of selective receptor agonists. CBGV displayed enhanced potency in many of the functional outputs. However the most interesting result was a biased signaling that correlated with differential affinity, i.e. the overall results suggest that the binding mode of each ligand leads to specific receptor conformations underlying biased signaling outputs.
Conclusion
Results here reported and the recent elucidation of the three-dimensional structure of CB1 and CB2 receptors help understanding the mechanism of action that might be protective and the molecular drug-receptor interactions underlying biased signaling.
... The efficacy of CBN, CBG, and of a synthetic derivative of CBG (i.e., VCE-003.2) in a transgenic mice model (SOD1-G93A) suggests a potential role for these cannabinoids in combatting amyotrophic lateral sclerosis [29,30]. VCE-003.2 and CBG were shown to decrease the production of proinflammatory chemokines in astrocytes via the activation of PPAR-γ [30]. ...
While natural Δ⁹-tetrahidrocannabinol (Δ⁹THC), cannabidiol (CBD), and their therapeutic potential have been extensively researched, some cannabinoids have not been widely investigated. The present article compiles data from the literature that highlights research on and the therapeutic possibilities of lesser known phytocannabinoids, which we have divided into varinic, acidic, and “minor” (i.e., cannabinoids that are not present in high quantities in common varieties of Cannabis sativa L). A growing interest in these compounds, which are enriched in some cannabis varieties, has already resulted in enough preclinical information to show that they are promising therapeutic agents for a variety of diseases. Each phytocannabinoid has a “preferential” mechanism of action, and often target the cannabinoid receptors CB1 and/or CB2. The recent resolution of the structure of cannabinoid receptors demonstrates the atypical nature of cannabinoid binding, and that different binding modes depend on the agonist or partial agonist/inverse agonist, which allows for differential signaling, even acting on the same cannabinoid receptor. In addition, other players and multiple signaling pathways may be targeted/engaged by phytocannabinoids, thereby expanding the mechanistic possibilities for therapeutic use.
... Further, commercially available Sativex® (2.7 mg of Δ9 -THC and 2.5 mg of CBD) treatment delayed ALS progression in the early stages of disease in ALS hSOD(G93A) transgenic mice [203]. However, the molecular mechanisms remain undefined [204]. ...
Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of “personalized medicine” as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.
... Amyotrophic lateral sclerosis: In humans, there is evidence of reduced expression of CB1R in the spinal cord of ALS patients (Butovsky et al., 2014). Studies have shown that activation of CB1R delays disease onset but does not affect overall survival (Bilsland et al., 2006;Weydt et al., 2005). Nevertheless, further studies are necessary to address the involvement of CB1R in ALS. ...
... Pisanti et al. (2017) reviewed the therapeutic effect of CBD against Alzheimer's disease, cancers, epilepsy, inflammatory diseases, and Parkinson's disease. Treatment with CBN delayed the onset of amyotrophic lateral sclerosis in mice (Weydt et al., 2005). Turner and Elsohly (1981) showed the superior antibacterial and anti-inflammatory activity of cannabichromene compared to phenylbutazone. ...
Hemp (Cannabis sativa L.) seeds have been consumed in Asian communities since prehistoric times. Recently, Australia, Canada, and the United States have legalized the cultivation and consumption of hempseed at low (<0.3%) tetrahydrocannabinol levels, and there's a growing interest in hempseed due to its nutritional value and pharmaceutical potential. This review aims to summarize the chemical composition, nutritional value, and potential health benefits of hempseed, as researched via in vitro and in vivo trials. The application of hempseed in the food industry is limited due to its poor performance on some functional properties, so the latest processing methods developed to improve these properties were compared. Additionally, manufacturing technologies incorporating hemp seeds into existing food products are also elaborated. This review would promote further in‐depth research on this recently approved food resources and maximize its utilization in new food product development.
... Most pharmacological studies on the use of cannabinoids in experimental ALS were conducted in the classic transgenic mouse that overexpresses a mutated form (G93A) of SOD-1 despite mutations in this enzyme representing only a small percentage of ALS cases. The model was developed in the 1990s and was used to investigate the neuroprotective effects of Δ 9 -THC [257], cannabinol (CBN) [258], WIN 55,, and the selective CB 2 agonist AM1241 [250,259], in all cases with beneficial effects. Similar findings were obtained from double mutants generated by crossing mutant SOD-1 mice with mice deficient in endocannabinoid genes FAAH or CB 1 knockout mice [247]. ...
The endocannabinoid system (ECS) exerts a modulatory effect of important functions such as neurotransmission, glial activation, oxidative stress, or protein homeostasis. Dysregulation of these cellular processes is a common neuropathological hallmark in aging and in neurodegenerative diseases of the central nervous system (CNS). The broad spectrum of actions of cannabinoids allows targeting different aspects of these multifactorial diseases. In this review, we examine the therapeutic potential of the ECS for the treatment of chronic neurodegenerative diseases of the CNS focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. First, we describe the localization of the molecular components of the ECS and how they are altered under neurodegenerative conditions, either contributing to or protecting cells from degeneration. Second, we address recent advances in the modulation of the ECS using experimental models through different strategies including the direct targeting of cannabinoid receptors with agonists or antagonists, increasing the endocannabinoid tone by the inhibition of endocannabinoid hydrolysis, and activation of cannabinoid receptor-independent effects. Preclinical evidence indicates that cannabinoid pharmacology is complex but supports the therapeutic potential of targeting the ECS. Third, we review the clinical evidence and discuss the future perspectives on how to bridge human and animal studies to develop cannabinoid-based therapies for each neurodegenerative disorder. Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to each disease and the multiple unexplored pathways in cannabinoid pharmacology that could be useful for the treatment of neurodegenerative diseases.
... 49,173 It is the most sedative 621-625 of the cannabinoids, suggesting a potential role in insomnia and sleep disorders. Other benefits include anti-inflammatory, 105,217,417,626 analgesic, 203 anticonvulsant, 363,463,623,624 burn relief by TRPV2 agonism and mediation of CGRP release, 203,414 ALS, 506 antibacterial effects against MRSA strains, 367 promotion of bone formation, 595,627-629 appetite stimulant, 592 glaucoma, 388,630 and psoriasis. 380,381 CBG is found in larger quantities in low THC cannabis strains, and especially in hemp strains. ...
Background.—Comprehensive literature reviews of
historical perspectives and evidence supporting cannabis/
cannabinoids in the treatment of pain, including migraine
and headache, with associated neurobiological mechanisms
of pain modulation have been well described. Most of the
existing literature reports on the cannabinoids Δ9
-tetrahydrocannabinol (THC) and cannabidiol (CBD), or
cannabis in general. There are many cannabis strains that
vary widely in the composition of cannabinoids, terpenes,
flavonoids, and other compounds. These components work
synergistically to produce wide variations in benefits, side
effects, and strain characteristics. Knowledge of the individual
medicinal properties of the cannabinoids, terpenes, and
flavonoids is necessary to cross-breed strains to obtain
optimal standardized synergistic compositions. This will
enable targeting individual symptoms and/or diseases,
including migraine, headache, and pain.
Objective.—Review the medical literature for the use of
cannabis/cannabinoids in the treatment of migraine,
headache, facial pain, and other chronic pain syndromes, and
for supporting evidence of a potential role in combatting the
opioid epidemic. Review the medical literature involving
major and minor cannabinoids, primary and secondary
terpenes, and flavonoids that underlie the synergistic
entourage effects of cannabis. Summarize the individual
medicinal benefits of these substances, including analgesic
and anti-inflammatory properties.
Conclusion.—There is accumulating evidence for various
therapeutic benefits of cannabis/cannabinoids, especially in
the treatment of pain, which may also apply to the treatment
of migraine and headache. There is also supporting evidence
that cannabis may assist in opioid detoxification and weaning,
thus making it a potential weapon in battling the opioid
epidemic. Cannabis science is a rapidly evolving medical
sector and industry with increasingly regulated production
standards. Further research is anticipated to optimize
breeding of strain-specific synergistic ratios of cannabinoids,
terpenes, and other phytochemicals for predictable user
effects, characteristics, and improved symptom and diseasetargeted
therapies.
... Interestingly, CB 2 agonist treatment delivered after symptom onset has been reported to prolong survival (Shoemaker et al, 2007), in agreement with the differential targeting of two distinct stages of the disease by small molecules acting on CB 2 . Likewise, our results suggest that the biphasic effect of cannabinoid administration (delaying onset but not affecting overall survival; Weydt et al, 2005) in ALS can be interpreted in terms of interference with the beneficial and detrimental phases of microglial activation. ...
Astrocytes are involved in non-cell-autonomous pathogenic cascades in amyotrophic lateral sclerosis (ALS); however, their role is still debated. We show that astrocytic NF-κB activation drives microglial proliferation and leukocyte infiltration in the SOD1 (G93A) ALS model. This response prolongs the presymptomatic phase, delaying muscle denervation and decreasing disease burden, but turns detrimental in the symptomatic phase, accelerating disease progression. The transition corresponds to a shift in the microglial phenotype showing two effects that can be dissociated by temporally controlling NF-κB activation. While NF-κB activation in astrocytes induced a Wnt-dependent microglial proliferation in the presymptomatic phase with neuroprotective effects on motoneurons, in later stage, astrocyte NF-κB-dependent microglial activation caused an accelerated disease progression. Notably, suppression of the early microglial response by CB2R agonists had acute detrimental effects. These data identify astrocytes as important regulators of microglia expansion and immune response. Therefore, stage-dependent microglia modulation may be an effective therapeutic strategy in ALS.
... Furthermore, delta(9)-THC protected against excitotoxicity and reduced oxidative damage on spinal cord neuronal primary cultures from hSODG93A mice (Raman et al., 2004), suggesting that delta(9)-THC could be helpful to reduce glutamate levels in ALS. Another example is cannabidiol (CBD), which is able to induce a delay in disease onset in hSODG93A mice (Weydt et al., 2005). Yet more studies are required to understand the molecular mechanisms of the effects of cannabinoids in ALS. ...
... In a preclinical model of multiple sclerosis, CBD was shown to improve clinical recovery and rotarod scores in animals, correlating with and indicative of a neuroprotective effect. 30 In addition, CBD and Δ 9 -tetrahydrocannabinol have both been implicated in slowing the progression and promoting the survival of neurones in a preclinical model of 15,42 These studies, in addition to the results presented here, highlight the potential utility of CBD as an analgesic and neuroprotective agent in OA. ...
Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a noneuphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine whether CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. Osteoarthritis was induced in male Wistar rats (150-175 g) by intra-articular injection of sodium monoiodoacetate (MIA; 3 mg). On day 14 (end-stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology, whereas pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 after MIA. Joint nerve myelination was calculated by G-ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100-300 μg) were assessed. In end-stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (P < 0.0001; n = 8). Acute, transient joint inflammation was reduced by local CBD treatment (P < 0.0001; n = 6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (P < 0.0001; n = 8), and was also found to be neuroprotective (P < 0.05; n = 6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.
... Chronic treatment with the phytocannabinoid 9 -tetrahydrocannabinol ( 9 -THC) delayed motor impairment and improved survival in the SOD-1 G93A transgenic mouse (Raman et al., 2004). Other cannabinoid compounds, including the less psychotropic plant-derived cannabinoid cannabinol (Weydt et al., 2005), the non-selective synthetic agonist WIN55,212-2 (Bilsland et al., 2006), and the selective cannabinoid receptor type-2 (CB2) agonist AM1241 (Kim et al., 2006;Shoemaker et al., 2007), produced similar effects. Genetic or pharmacological inhibition of fatty acid amide hydrolase (FAAH), one of the key enzymes in endocannabinoid degradation, was also beneficial in SOD-1 G93A transgenic mice (Bilsland et al., 2006). ...
Targeting the CB2 receptor afforded neuroprotection in SOD1(G93A) mutant mice, a model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB2 receptors were facilitated by their up-regulation in the spinal cord in SOD1(G93A) mutant mice. Herein, we have investigated whether a similar CB2 receptor up-regulation, as well as parallel changes in other endocannabinoid elements, are evident in the spinal cord of dogs with degenerative myelopathy (DM), caused from mutations in the superoxide dismutase 1 gene (SOD1). We used well-characterized post-mortem spinal cords from unaffected and DM-affected dogs. Tissues were used first to confirm the loss of motor neurons using Nissl staining, which was accompanied by glial reactivity (elevated GFAP and Iba-1 immunoreactivity). Next, we investigated possible differences in the expression of endocannabinoid genes measured by qPCR between DM-affected and control dogs. We found no changes in the CB1 receptor (also found with CB1 receptor immunostaining) as well as in NAPE-PLD, DAGL, FAAH and MAGL enzymes. In contrast, CB2 receptor levels were significantly elevated in DM-affected dogs determined by qPCR and Western-blotting, results reconfirmed in the grey matter using CB2 receptor immunostaining. Using double-labelling immunofluorescence, CB2 receptor immunolabelling co-localized with GFAP but not Iba-1, indicating up-regulation of CB2 receptors on astrocytes in DM-affected dogs. In summary, our results demonstrated a marked up-regulation of CB2 receptors occurring in the spinal cord in canine DM, which was concentrated in activated astrocytes. Such receptors may be used as a potential target to enhance the neuroprotective effects exerted by these glial cells.
... However, the molecular mechanisms remain undefined. On the contrary, survival was not affected (Weydt et al., 2005). ...
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.
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, as currently available medications such as riluzole and edaravone aim to slow disease progression and manage symptoms, they are often expensive, have adverse side effects, and offer limited therapeutic outcomes. Therefore, it is crucial to explore complementary and alternative medicines in ALS treatment along with their possible mechanism(s). This paper investigates the potential benefits of herbal remedies in ALS management, focusing on their ability to alleviate symptoms, improve quality of life, and potentially delay disease progression.
Method: The review includes articles published from 1999 to 2024 and was searched using various databases including Web of Science, Scopus, Google Scholar, and Clinical Trial. The search was performed using different keywords such as ‘amyotrophic lateral sclerosis’, ‘pathogenesis’, ‘prevalence’, ‘herbal products’, ‘natural medicines’, ‘safety’, ‘efficacy’, ‘clinical trials’, ‘herbal-drug interaction’, ‘in vitro’, ‘in vivo’, phytochemicals, ‘alternative medicine’. Further studies were screened by assessing abstracts, cross-references, and previously published reviews and research articles.
Results: A number of herbal products are reported in preclinical and clinical studies indicating their efficacy against ALS. These prominent phytoconstituents exhibiting anti-amyotrophic lateral sclerosis effect are mainly present in different parts of the plant and include curcumin, epigallocatechin gallate, quercetin, resveratrol, tetrahydrocannabidiol, diallyl trisulfide, withanolides, genistein, and madecassoside. The plant extract containing these phytoconstituents exerts its therapeutic effect via modulating inflammatory mediators, trapping free radicals, targeting various enzymes, and/or by harnessing autophagy.
Conclusion: Although, various preclinical studies have shown the beneficial effects of herbs in treating this debilitating disease. Further investigation is necessary to confirm the safety and efficacy of these botanical therapies in clinics.
Natural bioactives possess a wide range of chemical structures that can exert a plethora of pharmacological and toxicological actions, resulting in neuroprotection or neurotoxicity. These pharmacodynamic properties can positively or negatively impact human and animal global healthcare. Remarkably, Ayurvedic botanical Cannabis has been used worldwide by different ethnicities and religions for spiritual, commercial, recreational, nutraceutical, cosmeceutical, and medicinal purposes for centuries. Cannabis-based congeners have been approved by the United States of America's (USA) Food & Drug Administration (FDA) and other global law agencies for various therapeutic purposes. Surprisingly, the strict laws associated with possessing cannabis products have been mitigated in multiple states in the USA and across the globe for recreational use. This has consequently led to a radical escalation of exposure to cannabis-related substances of abuse. However, there is a lacuna in the literature on the acute and chronic effects of Cannabis and its congeners on various neuropathologies. Moreover, in the post-COVID era, there has been a drastic increase in the incidence and prevalence of numerous neuropathologies, leading to increased morbidity and mortality. There is an impending necessity for a safe, economically viable, multipotent, natural bioactive to prevent and treat various neuropathologies. The ayurvedic herb, Cannabis is one of the oldest botanicals known to humans and has been widely used. However, the comprehensive effect of Cannabis on various neuropathologies is not well established. Hence, this review presents effects of Cannabis on various neuropathologies.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a selective loss of motor neurons from the spinal cord, brainstem and motor cortex. With a prevalence of about 5.5–9.9 per 100,000 persons, ALS is the most common form of motor neuron disease (MND). Although the mechanisms underlying the pathophysiology of this condition are not yet fully understood, it is believed that excitotoxicity, inflammation and oxidative stress play an important role in selective motor neuron death. Despite intensive research, up to this point no cure for ALS has been identified. There is increasing evidence that cannabinoids, due to their anti-glutamatergic and anti-inflammatory actions, may show neuroprotective effects in ALS patients and slow the progression of the disease. Furthermore, cannabis-based medicine may be useful in managing symptoms like pain, spasticity or weight loss. The aim of this chapter is to summarize the current state of research regarding the efficacy and safety of medical cannabis in the treatment of ALS.
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates, known as Lewy bodies. It is known that mitochondria dysfunctions, including impaired localization, transport and mitophagy, represent features of PD. Cannabinoids are arising as new therapeutic strategies against neurodegenerative diseases. In this study, we aimed to evaluate the potential protective effects of cannabinol (CBN) pre-treatment in an in vitro PD model, namely retinoic acid-differentiated SH-SY5Y neuroblastoma cells treated with 1-methyl-4-phenylpyridinium (MPP+). With this aim, we performed a transcriptomic analysis through next-generation sequencing. We found that CBN counteracted the loss of cell viability caused by MPP+ treatment. Then, we focused on biological processes relative to mitochondria functions and found that CBN pre-treatment was able to attenuate the MPP+-induced changes in the expression of genes involved in mitochondria transport, localization and protein targeting. Notably, MPP+ treatment increased the expression of the genes involved in PINK1/Parkin mitophagy, while CBN pre-treatment reduced their expression. The results suggested that CBN can exert a protection against MPP+ induced mitochondria impairment.
Amyotrophic lateral sclerosis (ALS), a neurodegenerative condition that leads to muscle wasting, weakness, and stiffness, is characterized by progressive loss of upper and lower extremity muscle cells. The development of therapies that do more than just slow disease progression is essential. Cannabinoids with a broad-spectrum neuroprotection profile appear to significantly the potential for management of ALS. Cannabinoids can reduce excitotoxicity and neuroinflammation via activating CB1 and CB2 receptors. To increase treatment efficacy and reduce side effects, cannabinoids, particularly THC and CBD, can effectively alleviate ALS-related symptoms, including spasticity and neuropathic pruritus. This chapter aims to provide a comprehensive summary of the effectiveness and the molecular pathways that cannabis activates to exert its potential pharmacotherapeutic effects for alleviating ALS-related symptoms.
Cannabinoids, including those found in cannabis, have shown promise as potential therapeutics for numerous health issues, including pathological pain and diseases that produce an impact on neurological processing and function. Thus, cannabis use for medicinal purposes has become accepted by a growing majority. However, clinical trials yielding satisfactory endpoints and unequivocal proof that medicinal cannabis should be considered a frontline therapeutic for most examined central nervous system indications remains largely elusive. Although cannabis contains over 100 + compounds, most preclinical and clinical research with well-controlled dosing and delivery methods utilize the various formulations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most abundant compounds in cannabis. These controlled dosing and delivery methods are in stark contrast to most clinical studies using whole plant cannabis products, as few clinical studies using whole plant cannabis profile the exact composition, including percentages of all compounds present within the studied product. This review will examine both preclinical and clinical evidence that supports or refutes the therapeutic utility of medicinal cannabis for the treatment of pathological pain, neurodegeneration, substance use disorders, as well as anxiety-related disorders. We will predominately focus on purified THC and CBD, as well as other compounds isolated from cannabis for the aforementioned reasons but will also include discussion over those studies where whole plant cannabis has been used. In this review we also consider the current challenges associated with the advancement of medicinal cannabis and its derived potential therapeutics into clinical applications.
The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆⁹-tetrahydrocannabinol (∆⁹-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆⁹-THC is known to bring about the ‘high’ associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆⁹-THC, ∆⁹-tetrahydrocannabinolic acid (∆⁹-THCa), ∆⁹-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.
With the advent of medical cannabis usage globally, there has been a renewed interest in exploring the chemical diversity of this unique plant. Cannabis produces hundreds of unique phytocannabinoids, which not only have diverse chemical structures but also a range of cellular and molecular actions, interesting pharmacological properties, and biological actions. In addition, it produces other flavonoids, stilbenoids, and terpenes that have been variably described as conferring additional or so-called entourage effects to whole-plant extracts when used in therapeutic settings. This review explores this phytochemical diversity in relation to specific bioactivity ascribed to phytocannabinoids as neuroprotective agents. It outlines emergent evidence for the potential for selected phytocannabinoids and other cannabis phytochemicals to mitigate factors such as inflammation and oxidative stress as drivers of neurotoxicity, in addition to focusing on specific interactions with pathological misfolding proteins, such as amyloid β, associated with major forms of neurodegenerative diseases such as Alzheimer’s disease.
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3–5 years post diagnosis. The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS. Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS. There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain. However, a clinical trial in pALS with these objectives has not been conducted.
Methods and analysis
The Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease trial is a randomised, double-blind, placebo-controlled cannabis trial in pALS conducted at the Gold Coast University Hospital, Australia. The investigational product will be a cannabis-based medicine extract (CBME) supplied by CannTrust Inc., Canada, with a high-cannabidiol-low-tetrahydrocannabinol concentration. A total of 30 pALS with probable or definite ALS diagnosis based on the El Escorial criteria, with a symptom duration of <2 years, age between 25 and 75
years and with at least 70% forced vital capacity (FVC) will be treated for 6 months. The primary objective of the study is to evaluate the efficacy of CBME compared with placebo in slowing the disease progression measured by differences in mean ALS Functional Rating Scale-Revised and FVC score between the groups at the end of treatment. The secondary objectives are to evaluate the safety and tolerability of CBME by summarising adverse events, the effects of CBME on spasticity, pain, weight loss and quality of life assessed by the differences in mean Numeric Rating Scale for spasticity and Numeric Rating Scale for pain, percentage of total weight loss and ALS specific quality of life-Revised questionnaire.
Ethics and dissemination
The study has been approved by the local Institutional Review Board. The results of this study will be published in a peer-reviewed journal.
Trial registration number
NCT03690791
Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease causing progressive degeneration of motor neurons, ultimately resulting in death. Till now, no medicinal strategy has been proved to be completely successful in ameliorating the disease’s symptoms, except riluzole that only has a moderate effect. A limited therapeutic intervention of ALS encourages patients to opt for alternative medicine and therapies. Traditional Chinese herbal medicines (TCM) have been shown to overcome neuroinflammation, excitatory amino acid toxicity, oxidative stress, apoptosis and autophagy. In this regard, Chinese herbal medicines (CHMs) have been explored as a therapeutic option to manage clinical manifestations of ALS and other neurological diseases. In this review, we summarize the therapeutic benefits of CHMs on various neurodegenerative disorders, particularly ALS. The mechanistic details of various Chinese herbs along with their active molecules that delay the disease onset have also been discussed.
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that results from motor neuron damage. Cannabinoids have been proposed as treatments for ALS because of their anti‐excitotoxicity, anti‐oxidant and anti‐inflammatory effects. Preclinical studies in mice models of ALS have been published using a range of cannabinoid formulations and doses. To date, there has been no rigorous evaluation of these trials to assess a potential cannabinoid treatment effect. This review and meta‐analysis was undertaken to provide evidence for or against a treatment effect of cannabinoids in murine ALS models. Evidence of a treatment effect in mice may provide motivation for trials in human ALS. We identified a total of 10 studies; nine studies using cannabinoid treatment in transgenic SOD1‐G93A ALS‐model mice and one study in TDP‐43 transgenic mice. Eight of the nine studies that used SOD1‐G93A mice expressed similarly high copy numbers of the transgene while one study used a low‐copy number line. Outcomes evaluated were survival time and disease progression. The latter was measured by motor function and bodyweight decline. Meta‐analysis of the mean difference in survival time across the seven studies showed an increase in survival of 3.84 days (95% CI: 0.35–7.32 days; p = 0.031) for cannabinoid treated compared to control SOD1‐G93A mice. It was not possible to conduct meta‐analyses for motor function decline or weight loss. However, eight of nine studies reported significant improvements in measures of motor function decline and one reported non‐significant improvements. Weight loss was significantly attenuated in four of five studies reporting this measure while the other study reported a non‐significant attenuation. This review provides some evidence for the efficacy of cannabinoids in prolonging survival time in an ALS mouse model. A delay in disease progression is also suggested following cannabinoid treatment though it was not possible to consolidate the results from reviewed studies. However, studies have moderate to high risk of bias and are highly heterogeneous. Although this review provides some evidence to support the conduct of a cannabinoid trial in human ALS, more standardized studies on specific cannabinoids are necessary before supporting therapeutic potential of cannabinoids in treating patients with ALS.
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Read the Editorial Highlight for this article on page 168.
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Background and Purpose
Cannabinoid CB2 receptors are up‐regulated in reactive microglia in the spinal cord of TDP‐43 (A315T) transgenic mice, an experimental model of amyotrophic lateral sclerosis. To determine whether this up‐regulation can be exploited pharmacologically, we investigated the effects of different treatments that affect CB2 receptor function.
Experimental Approach
We treated TDP‐43 (A315T) transgenic mice with the non‐selective agonist WIN55,212‐2, alone or combined with selective CB1 or CB2 antagonists, as well as with the selective CB2 agonist HU‐308, and evaluated their effects on the pathological phenotype.
Key Results
WIN55,212‐2 had modest beneficial effects in the rotarod test, Nissl staining of motor neurons, and GFAP and Iba‐1 immunostainings in the spinal cord, which were mediated in part by CB2 receptor activation. HU‐308 significantly improved the rotarod performance of the transgenic mice, with complete preservation of Nissl‐stained motor neurons in the ventral horn. Reactive astrogliosis labelled with GFAP was also attenuated by HU‐308 in the dorsal and ventral horns, in which CB2 receptors colocalize with this astroglial marker. Furthermore, HU‐308 reduced the elevated Iba‐1 immunostaining in the ventral horn of TDP‐43 transgenic mice, but did not affect this immunoreactivity in white matter, in which CB2 receptors also colocalize with this microglial marker.
Conclusions and Implications
Our study shows an important role for glial CB2 receptors in limiting the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice. Such benefits appear to derive from the activation of CB2 receptors concentrated in astrocytes and reactive microglia located in spinal dorsal and ventral horns.
Linked Articles
This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc
Cannabis Sativa has been used for medicinal and other purposes for millennia. In the 1990s the CB1 and CB2 receptors and the endogenous ligands of the endo-cannabinoid system proper were discovered: Anandamide N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG). External mediation of the bodily endo-cannabinoid system with exogenous phytochemical cannabinoids and other active compounds within Cannabis representative of the full interactive proliferation of naturally occurring constituents appears from manifest interdigitated cross-mediational systemic complexity and phylogenetic receptor analysis to imply the likelihood of potential synergistic therapeutic efficacy via evolutionary adaptations beginning from as far back as the Cambrian period or more. This approach utilizing the full proliferation of interactive compounds or some selected intra-active multi-constituent portion thereof, has been demonstrably curtailed by legal, political and systemic interference. This document will spell out the demonstrated functional potential and implied therapeutic utility of cannabinoids and cannabis extracts, support the aforementioned evolutionary hypothesis and demonstrated multifunctional medical utility with both phylogenetic and historical analysis, and then detail what appears to be the suppressed approach that may lead to the speedy and inexpensive treatment or cure of many dread diseases using Cannabis extracts, including but not limited to cancer. It is also clearly implied and well supported from historical and current medical perspectives that the raw drug itself is safe and effective in treating many conditions and should be available to dispense via prescription by all qualified medical professionals.
Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by progressive loss of voluntary motor neurons leading to muscle atrophy, weakness, weight loss, and respiratory failure. Evidence suggests that various molecular mechanisms including oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity, proteasomal dysfunction, and inflammation are responsible for ALS pathogenesis. In this chapter we summarize the various therapies tested on animal models targeting the above molecular mechanisms and compare their effects on body weight loss, muscle damage, disease onset, duration, and survival. We also review drugs that prevent body weight loss in animal models of ALS and analyze their structure-activity relationship.
A growing body of evidence indicates that diet can modulate health in aging to the extent of delaying the manifestation of age-related diseases. Nuts are among the antioxidant-rich foods that have been demonstrated to provide a degree of protection against age-related disorders We examined herein whether or not dietary supplementation with pecans could affect the course of pathology in a mouse model of the age-related human motor neuron disorder amyotropic lateral sclerosis (ALS). Transgenic mice expressing the G93A mutation of human superoxide dismutase-1 SOD-1 have been widely utilized to study the onset and progression of familial ALS. Mice provided a diet supplemented with 0.05% pecans displayed a significant delay in decline in motor neuron function, which was accompanied by increased survival of motor neurons and a decrease in reactive gliosis, as compared to non-supplemented mice. These findings support inclusion of pecans and/or other nuts as part of a comprehensive nutritional therapeutic approach that may augment pharmacological approaches.
Cannabinoids alter the functional activities of immune cells and have potential to serve as agents for treatment of neuroinflammatory disorders. They readily access the brain, have low toxicity, and can target selective receptors on specific cell types. To date, two cognate receptors have been identified, the CB1R and the CB2R. The CB1R is expressed primarily in the CNS and testis, while the CB2R is found on immune cells, including microglia and other immunocytes that may be recruited into the CNS. Activation of the CB2R may prove therapeutically manageable in ablating neuropathogenic disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, HIV encephalitis, and closed head injury. © 2014 Springer Science+Business Media New York. All rights reserved.
Mutations of human Cu,Zn superoxide dismutase (SOD) are found in about 20 percent of patients with familial amyotrophic lateral
sclerosis (ALS). Expression of high levels of human SOD containing a substitution of glycine to alanine at position 93--a
change that has little effect on enzyme activity--caused motor neuron disease in transgenic mice. The mice became paralyzed
in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age. The results show
that dominant, gain-of-function mutations in SOD contribute to the pathogenesis of familial ALS.
Marijuana has been proposed as treatment for a widening spectrum of medical conditions. Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. In areas where it is legal to do so, marijuana should be considered in the pharmacological management of ALS. Further investigation into the usefulness of marijuana in this setting is warranted.
Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Two of the primary hypotheses underlying motor neuron vulnerability are susceptibility to excitotoxicity and oxidative damage. There is rapidly emerging evidence that the cannabinoid receptor system has the potential to reduce both excitotoxic and oxidative cell damage. Here we report that treatment with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was effective if administered either before or after onset of signs in the ALS mouse model (hSOD(G93A) transgenic mice). Administration at the onset of tremors delayed motor impairment and prolonged survival in Delta(9)-THC treated mice when compared to vehicle controls. In addition, we present an improved method for the analysis of disease progression in the ALS mouse model. This logistic model provides an estimate of the age at which muscle endurance has declined by 50% with much greater accuracy than could be attained for any other measure of decline. In vitro, Delta(9)-THC was extremely effective at reducing oxidative damage in spinal cord cultures. Additionally, Delta(9)-THC is anti-excitotoxic in vitro. These cellular mechanisms may underlie the presumed neuroprotective effect in ALS. As Delta(9)-THC is well tolerated, it and other cannabinoids may prove to be novel therapeutic targets for the treatment of ALS.
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).
Marijuana is a complex substance containing over 60 different forms of cannabinoids, the active ingredients. Cannabinoids are now known to have the capacity for neuromodulation, via direct, receptor-based mechanisms at numerous levels within the nervous system. These have therapeutic properties that may be applicable to the treatment of neurological disorders; including anti-oxidative, neuroprotective, analgesic and anti-inflammatory actions; immunomodulation, modulation of glial cells and tumor growth regulation. This article reviews the emerging research on the physiological mechanisms of endogenous and exogenous cannabinoids in the context of neurological disease.
This international, open-label, multicentre extension of riluzole pivotal studies was designed to assess the long-term safety of riluzole in the treatment of amyotrophic lateral sclerosis (ALS).
The studies were carried out at 31 different centres, 23 in Europe and eight in North America. 516 patients with diagnosed probable or definite ALS and who had participated previously in one of two international multicentre randomized double-blind placebo-controlled, parallel-group trials, were enrolled in the extensions. 58 of these patients had taken part in a randomized phase II trial (placebo or riluzole 100 mg/day) and 458 in a randomized, dose-ranging phase III trial (placebo or riluzole, 50, 100 or 200 mg/day). All participants in the open-label continuation received 100 mg/day of riluzole (50 mg b.i.d.)
At the end of the open-label study, the average exposure time of the patients to riluzole was 28.7 +/- 14.4 months, with a maximum exposure time of 81 months. Most of the adverse events recorded reflected the progression of ALS, in particular the deterioration of the respiratory status of the patients. No particular adverse event, or frequency of adverse event, appeared to be related to the dose level of the previous double-blind riluzole treatment. Nor were any adverse events associated with the switch-over from double-blind placebo to open-label riluzole.
This open-label extension study reinforces and extends the results of the preceding double-blind trials regarding the safety of riluzole and shows that the drug is well tolerated for long periods of up to almost 7 years.
In the 60 years since Lou Gehrig died from amyotrophic lateral sclerosis (ALS) there have been numerous advances in our understanding of this disease. However, scant progress has been made regarding disease-altering treatments. Today most physicians still recommend vitamin E, which is the treatment Gehrig himself received. In this paper we will review what is currently known about the pathophysiology of ALS as well as the history of clinical trials in ALS. We indicate current and future directions in research and clinical trials, and also argue that a logical next step for clinical trials in ALS should be combination drug treatment.
SOD1 transgenic mice are the most widely used animal model of amyotrophic lateral sclerosis (ALS). In addition to providing valuable insights into the pathogenesis of ALS, these animals are used intensively in many laboratories as an in vivo model for investigating novel therapeutic interventions towards this devastating motorneuron disease. Such pre-clinical studies require objective and reliable quantification of the clinical phenotype of individual mice, most importantly of the neuromuscular abnormalities. Here we compare four parameters of the clinical phenotype: motor signs, body weight, rotarod performance and paw grip endurance for their usefulness in monitoring the SOD1 mouse model. We found that paw grip endurance is a sensitive and inexpensive alternative to the widely used rotarod test.
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).
Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are caused by mutations in the super oxide dismutase 1 (SOD1) gene and transgenic mice for these mutations recapitulate many features of this devastating neurodegenerative disease. Here we show that the amount of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), two endocannabinoids that have neuroprotective properties, increase in spinal cord of SOD1(G93A) transgenic mice. This increase occurs in the lumbar section of spinal cords, the first section to undergo neurodegeneration, and is significant before overt motor impairment. Our results show that chronic neurodegeneration induced by a genetic mutation increases endocannabinoid production possibly as part of an endogenous defense mechanism.
Although Charcot described amyotrophic lateral sclerosis (ALS) more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in this common adult motor neuron disease has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics has now identified mutations in one gene [Cu/Zn superoxide dismutase (SOD1)] as a primary cause and implicated others [encoding neurofilaments, cytoplasmic dynein and its processivity factor dynactin, and vascular endothelial growth factor (VEGF)] as contributors to, or causes of, motor neuron diseases. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response this provokes, these model systems highlight the involvement of nonneuronal cells in disease progression and provide new therapeutic strategies.
We have developed a medium-throughput cell-based assay to screen drugs for Huntington's disease (HD). The assay measures the ability of drugs to protect cultured neuronal (PC12) cells from death caused by an expanded polyglutamine (poly Q) form of huntingtin exon 1. Using this assay, we have blindly screened a library of 1040 compounds compiled by the NINDS: the NIH Custom Collection (NCC). Each compound was tested at five concentrations for its ability to protect cells against huntingtin-induced cell death as well as for its toxicity. Of the compounds tested, 18 prevented cell death completely, and 51 partially. Some of these also exhibited toxicity at higher doses. The majority of drugs (81%) were ineffective. Caspase inhibitors and cannabinoids showed reproducible protection in our assay. We believe these compounds, and others in our hit list, are appealing candidates for further investigation. Additionally, this assay is amenable to scaling up to screen additional compounds for treating Huntington's disease.
A pilot study of safety and tolerability of Delta 9-THC (Marinol) treatment for ALS
- D Gelinas
- R G Miller
- M E Abood
Gelinas D, Miller RG, Abood ME. A pilot study of safety and
tolerability of Delta 9-THC (Marinol) treatment for ALS.
Amyotroph Lateral Scler Other Motor Neuron Disord.
2002;3(Suppl. 1):23.