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

Journal article
Authors V. Francardo
F. Bez
T. Wieloch
Hans Nissbrandt
K. Ruscher
M. A. Cenci
Published in Brain
Volume 137
Pages 1998-2014
ISSN 0006-8950
Publication year 2014
Published at Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 1998-2014
Language en
Links dx.doi.org/10.1093/brain/awu107
Keywords mouse, neuroprotection, 6-hydroxydopamine, Parkinson's disease, MAPK signalling, CENTRAL-NERVOUS-SYSTEM, NITRIC-OXIDE SYNTHASE, BINDING-SITES, RAT MODEL, NEUROTROPHIC FACTOR, SIGNALING PATHWAYS, SUBSTANTIA-NIGRA, DOPAMINERGIC, NEURODEGENERATION, NEURONAL PLASTICITY, EXPERIMENTAL STROKE, Clinical Neurology, Neurosciences
Subject categories Neurology, Neurosciences

Abstract

Sigma-1 receptor ligands may have neuroprotective and neurorestorative properties. In a mouse model of parkinsonism, Francardo et al. show that chronic treatment with the sigma-1 receptor agonist PRE-084 increases the density of striatal dopaminergic fibres and improves forelimb use. Boosting sigma-1 receptor activity may have disease-modifying effects in ParkinsonA ' s disease.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.

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