Targeting glial cannabinoid <scp>CB<sub>2</sub></scp> receptors to delay the progression of the pathological phenotype in <scp>TDP‐43</scp> (<scp>A315T</scp>) transgenic mice, a model of amyotrophic lateral sclerosis

Espejo-Porras, Francisco; García-Toscano, Laura; Rodríguez‐Cueto, Carmen; Santos‐García, Irene; Lago, Eva de; Fernández‐Ruiz, Javier

doi:10.1111/bph.14216

Cited by 50 publications

(86 citation statements)

References 53 publications

(85 reference statements)

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“…Then, once genotyped, wild-type and transgenic mice were identified by numbered earmarks and, prior to the start of the different experiments, they were randomly allocated to the different treatment groups. For data collection, in all behavioral and histological analyses, researchers were blinded to the animal treatment, whereas for the biochemical analyses, due to the form in which the data are collected, blinding was not considered necessary, as previously described 28 .…”

Section: Methodsmentioning

confidence: 99%

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Martínez-González

Rodríguez‐Cueto

Cabezudo

et al. 2020

Sci Rep

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Pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS.

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Section: Methodsmentioning

confidence: 99%

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Martínez-González

Rodríguez‐Cueto

Cabezudo

et al. 2020

Sci Rep

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“…), HU‐308 (Espejo‐Porras et al . ), Sativex (Moreno‐Martet et al . ), WIN55, 212‐2 (Bilsland et al .…”

Section: Resultsmentioning

confidence: 99%

“…) while others used rod endurance time (Espejo‐Porras et al . ; Raman et al . ), total distance each mouse travelled (Bilsland et al .…”

Section: Resultsmentioning

confidence: 99%

“…The search process and criteria for excluding articles using PRISMA flow diagram.agonists: AM1241(Kim et al 2006;Shoemaker et al 2007;Seely 2009), Cannabinol (CBN) (Weydt et al 2005), HU-308 (Espejo-Porras et al 2018), Sativex (Moreno-Martet et al 2014), WIN55, 212-2 (Bilsland et al 2006; Espejo-Porras et al 2018; Shoemaker et al 2007), Tetrahydrocannabinol (THC) (Raman et al 2004) and VCE-003.2 (Rodriguez-Cueto et al 2018). One study did not use a cannabinoid agonist agent but instead a Monoacylglycerol lipase (MAGL) inhibitor (KML29) which increases the concentration of endogenous cannabinoids(Pasquarelli et al 2017).Nine studiesEspejo-Porras et al 2018;Kim et al 2006;Moreno-Martet et al 2014;Pasquarelli et al 2017;Raman et al 2004; Rodriguez-Cueto et al 2018;Seely 2009;Shoemaker et al 2007) administered interventions at early symptomatic phase. One study started cannabinoid treatment at day 150…”

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Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: a systematic review and meta‐analysis

Urbi

Owusu

Hughes

et al. 2019

Journal of Neurochemistry

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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. Open science badges This article has received a badge for *Preregistration* because the study was pre‐registered at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=89274. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. https://doi.org/10.1111/jnc.14651.

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“…The second looks at cannabidiol, a non-euphoric plant cannabinoid and its effects on cognition and withdrawal to Δ 9 -tetrahydrocannabinol (THC), the classical euphoric plant cannabinoid (Myers, Siegele, Foss, Tuma, & Ward, 2019). The two remaining papers look at different aspects of muscular and neurodegeneration: One focusses on non-euphoric plant cannabinoids in an mdx mouse dystrophic model (Iannotti et al, 2019), while the second looks at astroglial CB 2 receptor regulation of a mouse model of ALS (Espejo-Porras et al, 2019).…”

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confidence: 99%

Cannabinoids and their actions: An update

Alexander

Molina-Holgado

2019

British J Pharmacology

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Targeting glial cannabinoid CB₂ receptors to delay the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis

Cited by 50 publications

References 53 publications

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: a systematic review and meta‐analysis

Cannabinoids and their actions: An update

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Targeting glial cannabinoid CB2 receptors to delay the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis

Cited by 50 publications

References 53 publications

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: a systematic review and meta‐analysis

Cannabinoids and their actions: An update

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Targeting glial cannabinoid CB₂ receptors to delay the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis