Endocannabinoid System in Spinocerebellar Ataxia Type-3 and Other Autosomal-Dominant Cerebellar Ataxias: Potential Role in Pathogenesis and Expected Relevance as Neuroprotective Targets

Abstract

Spinocerebellar ataxias (SCAs) are a group of hereditary and progressive neurological disorders characterized by a loss of balance and motor coordination typically associated with cerebellar atrophy. The most prevalent SCA types are all polyQ disorders like Huntington’s disease, sharing the most relevant events in pathogenesis with this basal ganglia disorder, but with most of the damage concentrated in cerebellar neurons, and in their afferent and efferent connections (e.g., brainstem nuclei). SCAs have no cure and effective symptom-alleviating and disease-modifying therapies are not currently available. However, based on results obtained in studies conducted in murine models and information derived from analyses in post-mortem tissue samples from patients, which show notably higher levels of CB 1 receptors found in different cerebellar neuronal subpopulations, the blockade of these receptors has been proposed for acutely modulating motor incoordination in cerebellar ataxias, whereas their chronic activation has been proposed for preserving specific neuronal losses. Additional studies in post-mortem tissues from SCA patients have also demonstrated elevated levels of CB 2 receptors in Purkinje neurons as well as in glial elements in the granular layer and in the cerebellar white matter, with a similar profile found for endocannabinoid hydrolyzing enzymes, then suggesting that activating CB 2 receptors and/or inhibiting these enzymes may also serve to develop cannabinoid-based neuroprotective therapies. The present review will address both aspects. On one hand, the endocannabinoid system becomes dysregulated in the cerebellum and also in other CNS structures (e.g., brainstem, basal ganglia) in SCAs, which may contribute to the progression of pathogenic events in these diseases. On the other hand, these endocannabinoid alterations may be pharmacologically corrected or enhanced, and this may have therapeutic consequences, either alleviating specific symptoms or eliciting neuroprotective effects, an objective presently under investigation.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…On the other hand, some older studies indicate that enhancing CB1-dependent signaling may affect in ataxic symptoms [185,186]. CB2 activation is proposed for neuroprotection [187].…”

Endocannabinoids regulate cerebellar GABAergic transmission in a synapse type‐dependent manner

“…The upregulation of CBRs in the CNS has been detected in epilepsy and numerous neurodegenerative diseases, possibly leading to protect neurons from excitotoxicity (Pacher et al., 2006). A more recent pathological study on the cerebellum reported that post‐mortem tissues from patients with type 3 of spinocerebellar ataxia (SCA‐3) had elevated expression levels of CB 1 Rs and CB 2 Rs in PCs (Gómez‐Ruiz et al., 2019; Rodríguez‐Cueto et al., 2014). This upregulation is also although to contribute to the inhibition of neuronal excitation, thus protecting PCs from neurodegeneration in the SCA‐3 cerebellum (Gómez‐Ruiz et al., 2019; Rodríguez‐Cueto et al., 2014; Stephens, 2016).…”

“…A more recent pathological study on the cerebellum reported that post‐mortem tissues from patients with type 3 of spinocerebellar ataxia (SCA‐3) had elevated expression levels of CB 1 Rs and CB 2 Rs in PCs (Gómez‐Ruiz et al., 2019; Rodríguez‐Cueto et al., 2014). This upregulation is also although to contribute to the inhibition of neuronal excitation, thus protecting PCs from neurodegeneration in the SCA‐3 cerebellum (Gómez‐Ruiz et al., 2019; Rodríguez‐Cueto et al., 2014; Stephens, 2016). Alternatively, the upregulation may disturb PC output signals, and perturb accurate signal transmission at synapses between PCs and their target neurons.…”

“…(h) The time course of the mIPSC frequency (left). 2-AG reduced the frequency (left) but not the amplitude (right) of mIPSCs in PCs (n = 9) in the SCA-3 cerebellum (Gómez-Ruiz et al, 2019;Rodríguez-Cueto et al, 2014;Stephens, 2016). Alternatively, the upregulation may disturb PC output signals, and perturb accurate signal transmission at synapses between PCs and their target neurons.…”

Cannabis and Inflammation in HIV: A Review of Human and Animal Studies

“…Both natural and synthetic cannabinoids are neuroprotective after various types of CNS insults, such as stroke [ 103 ]. Preclinical models show activation of CBRs can trigger removal of activated immune cells [ 75 ], downregulate pro-inflammatory cytokine and chemokine production [ 104 ], and inhibit HIV-associated synapse loss and neural injury [ 105 ]. In vitro, THC treatment suppresses several pro-inflammatory factors, including TNF-α, IL-6, and IL-8, and decreases monocyte-derived interleukin IL-1ß production and astrocyte secretion of MCP-1 and IL-6 from a human coculture system [ 106 ].…”