Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism

Abstract

The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt). No treatment-induced behavioural-histological restoration occurred in sigma-1 receptor knockout mice subjected to 6-hydroxydopamine lesions and treated with PRE-084. Immunoreactivity for the sigma-1 receptor protein was evident in both astrocytes and neurons in the substantia nigra and the striatum, and its intracellular distribution was modulated by PRE-084 (the treatment resulted in a wider intracellular distribution of the protein). Our results suggest that sigma-1 receptor regulates endogenous defence and plasticity mechanisms in experimental parkinsonism. Boosting the activity of this protein may have disease-modifying effects in Parkinson's disease.

The effects of sigma (σ1) receptor‐selective ligands on muscarinic receptor antagonist‐induced cognitive deficits in mice

“…The chaperone activity of σ1 receptor has also been proposed to promote the secretion of mature BDNF from its precursor pro-BDNF (Hashimoto, 2013). Although the mechanism of action of LS-1-137 in currently undefined, the observed dosedependent effect of LS-1-137 on BDNF release is consistent with a number of recent studies suggesting that σ1 receptor agonism potentiates BDNF release Hashimoto, 2013;Ring and Regan, 2013;Francardo et al, 2014;Peviani et al, 2014).…”

“…The chaperone activity of σ1 receptor has also been proposed to promote the secretion of mature BDNF from its precursor pro-BDNF (Hashimoto, 2013). Although the mechanism of action of LS-1-137 in currently undefined, the observed dosedependent effect of LS-1-137 on BDNF release is consistent with a number of recent studies suggesting that σ1 receptor agonism potentiates BDNF release Hashimoto, 2013;Ring and Regan, 2013;Francardo et al, 2014;Peviani et al, 2014).While the neuroprotective properties of LS-1-137 may play a role in the attenuation of the behavioural effects of scopolamine, it seems more likely that the ability of σ1 receptor agonists to modulate cholinergic transmission may be more germane to the in vivo effects of LS-1-137 reported in this communication. Several studies have shown σ1 receptor activation increases cholinergic neurotransmission in (i) rat hippocampal slices and (ii) the rat hippocampus and cortex.…”

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

“…Although the mechanisms of action underlying the neuroprotective effects of S1R activation are not fully understood, some studies have suggested that such effects may include modulation of kinase activity (45,52,53). As dysregulation of AKT and JNK kinases has been implicated in the pathology of HD (45,54,55), it would be interesting to further investigate whether modulation of kinase activity contributes to the neuroprotective effects of pridopidine in HD mice.…”

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

“…Those results support the notion that Sig-1Rs, by interacting with endogenous myristic acid, play a pivotal role in the p35 myristoylation and degradation. Discussion Sig-1Rs have been reported to play a role in the pathogenesis of neurodegenerative disorders including AD (30,45,46), Parkinson's disease (47,48), and motor neuron disorders (49)(50)(51). The underlying molecular mechanisms of Sig-1R action remain to be totally clarified.…”