Endocannabinoid-Hydrolysing Enzymes in the Post-Mortem Cerebellum of Humans Affected by Hereditary Autosomal Dominant Ataxias

Rodríguez‐Cueto, Carmen; Benito, Cristina; Romero, Julián; Hernández, Medardo; Gómez‐Ruiz, Maria; Fernández‐Ruiz, Javier

doi:10.1159/000358127

Cited by 12 publications

(14 citation statements)

References 48 publications

(37 reference statements)

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“…fatty acid amide hydrolase (FAAH), monoacyl-glycerol lipase (MAGL). We were able to detect immunoreactivity for the FAAH and MAGL enzymes in the granular layer, Purkinje cells, neurons of the dentate nucleus and areas of white matter in the cerebellum of patients at levels notably higher than control subjects, and, using double-labeling procedures, we found co-localization of FAAH and MAGL with calbindin, supporting the presence of these enzymes in Purkinje neurons (Rodrı´guez-Cueto et al, 2014b). The interest of these two enzymes is that they are also susceptible to be pharmacologically manipulated, so that their inhibitors may become in potential disease-modifying therapies in these disorders.…”

Section: Introductionsupporting

confidence: 66%

“…Nrf-2, NFjB) or to bind the peroxisome-proliferator activating receptors (PPARs), all of them already demonstrated in numerous chronic neurodegenerative disorders (Ferna´ndez-Ruiz et al, 2010. In a further study (Rodrı´guez-Cueto et al, 2014b), we analyzed endocannabinoid-inactivating enzymes, e.g. fatty acid amide hydrolase (FAAH), monoacyl-glycerol lipase (MAGL).…”

Section: Introductionmentioning

confidence: 99%

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Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3

et al. 2016

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Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem cerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option. Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease - cerebellum and brainstem. These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivo brain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters. Concerning the endocannabinoid signaling, our data indicated no changes in CB receptors. By contrast, CB receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus. We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleoylethanolamide in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered. Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3.

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Section: Introductionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3

et al. 2016

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“…We recently found that endocannabinoid signaling appears to be dysregulated in the cerebellum SCA patients (including SCA-3), with important alterations to CB 1 and CB 2 receptors [15], and to FAAH and MAGL enzymes in post-mortem tissue [16]. Such alterations were also found recently in a transgenic mouse model of SCA-3 [17], which reproduces many of the neurological and neuropathological signs of the disease [28].…”

Section: Introductionmentioning

confidence: 88%

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

et al. 2017

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Spinocerebellar ataxia type-3 (SCA-3) is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of SCA-3 is not restricted to these two brain regions but rather, it is also evident in other structures (e.g., the basal ganglia), we studied the possible changes to endocannabinoid signaling in the striatum of these transgenic mice. SCA-3 mutant mice suffer defects in motor coordination, balance and they have an abnormal gait, reflecting a cerebellar/brainstem neuropathology. However, they also show dystonia-like behavior (limb clasping) that may be related to the malfunction/deterioration of specific neurons in the striatum. Indeed, we found a loss of striatal projecting neurons in SCA-3 mutant mice, accompanied by a reduction in glial glutamate transporters that could potentially aggravate excitotoxic damage. In terms of endocannabinoid signaling, no changes in CB2 receptors were evident, yet an important reduction in CB1 receptors was detected by qPCR and immunostaining. The reduction in CB1 receptors was presumed to occur in striatal afferent and efferent neurons, also potentially aggravating excitotoxicity. We also measured the endocannabinoid lipids in the striatum and despite a marked increase in the FAAH enzyme in this area, no overall changes in these lipids were found. Collectively, these studies confirm that the striatal endocannabinoid system is altered in SCA-3 mutant mice, adding to the equivalent changes found in other strongly affected CNS structures in this type of ataxia (i.e.: the cerebellum and brainstem). These data open the way to search for drugs that might correct these changes.

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“…This may be particularly relevant in certain pathological conditions (e.g. autosomal dominant inherited ataxias: Rodríguez‐Cueto et al ., , ) where dysregulation in these inactivating mechanisms has been seen to affect CNS structures [e.g. elevated fatty acid amide hydrolase (FAAH) activity], leading to excess degradation of endocannabinoids.…”

Section: Cannabinoids As Neuroprotectantsmentioning

confidence: 99%

The biomedical challenge of neurodegenerative disorders: an opportunity for cannabinoid‐based therapies to improve on the poor current therapeutic outcomes

Fernández‐Ruiz

2018

British J Pharmacology

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At the beginning of the 21st century, the therapeutic management of neurodegenerative disorders remains a major biomedical challenge, particularly given the worldwide ageing of the population over the past 50 years that is expected to continue in the forthcoming years. This review will focus on the promise of cannabinoid-based therapies to address this challenge. This promise is based on the broad neuroprotective profile of cannabinoids, which may cooperate to combat excitotoxicity, oxidative stress, glia-driven inflammation and protein aggregation. Such effects may be produced by the activity of cannabinoids through their canonical targets (e.g. cannabinoid receptors and endocannabinoid enzymes) and also via non-canonical elements and activities in distinct cell types critical for cell survival or neuronal replacement (e.g. neurons, glia and neural precursor cells). Ultimately, the therapeutic events driven by endocannabinoid signalling reflect the activity of an endogenous system that regulates the preservation, rescue, repair and replacement of neurons and glia.

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Endocannabinoid-Hydrolysing Enzymes in the Post-Mortem Cerebellum of Humans Affected by Hereditary Autosomal Dominant Ataxias

Cited by 12 publications

References 48 publications

Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3

Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

The biomedical challenge of neurodegenerative disorders: an opportunity for cannabinoid‐based therapies to improve on the poor current therapeutic outcomes

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