title: 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.
authors.affiliation: 1 Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, BMC F11, Lund University, Lund, Sweden Veronica.Francardo@med.lu.se Angela.Cenci_Nilsson@med.lu.se.
authors.forename: Veronica
authors.initials: V
authors.lastname: Francardo
authors.affiliation: 1 Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, BMC F11, Lund University, Lund, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bez
authors.affiliation: 2 Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Wallenberg Neuroscience Centre, Lund University, Lund, Sweden.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wieloch
authors.affiliation: 3 Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Nissbrandt
authors.affiliation: 2 Laboratory for Experimental Brain Research, Division of Neurosurgery, Department of Clinical Sciences, Wallenberg Neuroscience Centre, Lund University, Lund, Sweden.
authors.forename: Karsten
authors.initials: K
authors.lastname: Ruscher
authors.affiliation: 1 Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, BMC F11, Lund University, Lund, Sweden Veronica.Francardo@med.lu.se Angela.Cenci_Nilsson@med.lu.se.
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011597:Psychomotor Performance / Q000187:drug effects; D017480:Receptors, sigma / Q000172:deficiency / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D004298:Dopamine; D009025:Morpholines; D016627:Oxidopamine; D017480:Receptors, sigma; D012701:Serotonin; D000097605:Sigma-1 Receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
keywords: 6-hydroxydopamine; MAPK signalling; Parkinson’s disease; mouse; neuroprotection