title: The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke.
abstract: Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. Enriched housing of stroke-injured rats provides multi-modal sensorimotor stimulation, which improves recovery, although the specific mechanisms involved have not been identified. In rats housed in an enriched environment for two weeks after permanent middle cerebral artery occlusion, we found increased sigma-1 receptor expression in peri-infarct areas. Treatment of rats subjected to permanent or transient middle cerebral artery occlusion with 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride, an agonist of the sigma-1 receptor, starting two days after injury, enhanced the recovery of lost sensorimotor function without decreasing infarct size. The sigma-1 receptor was found in the galactocerebroside enriched membrane microdomains of reactive astrocytes and in neurons. Sigma-1 receptor activation increased the levels of the synaptic protein neurabin and neurexin in membrane rafts in the peri-infarct area, while sigma-1 receptor silencing prevented sigma-1 receptor-mediated neurite outgrowth in primary cortical neuronal cultures. In astrocytic cultures, oxygen and glucose deprivation induced sigma-1 receptor expression and actin dependent membrane raft formation, the latter blocked by sigma-1 receptor small interfering RNA silencing and pharmacological inhibition. We conclude that sigma-1 receptor activation stimulates recovery after stroke by enhancing cellular transport of biomolecules required for brain repair, thereby stimulating brain plasticity. Pharmacological targeting of the sigma-1 receptor provides new opportunities for stroke treatment beyond the therapeutic window of neuroprotection.
authors.affiliation: Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University, BMCA13, 22184 Lund, Sweden.
authors.forename: Karsten
authors.initials: K
authors.lastname: Ruscher
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
authors.forename: Mattias
authors.initials: M
authors.lastname: Rickhag
authors.forename: Istvan
authors.initials: I
authors.lastname: Ladunga
authors.forename: Liza
authors.initials: L
authors.lastname: Soriano
authors.forename: Lennart
authors.initials: L
authors.lastname: Gisselsson
authors.forename: Håkan
authors.initials: H
authors.lastname: Toresson
authors.forename: Lily
authors.initials: L
authors.lastname: Ruslim-Litrus
authors.forename: Donna
authors.initials: D
authors.lastname: Oksenberg
authors.forename: Roman
authors.initials: R
authors.lastname: Urfer
authors.forename: Barbro B
authors.initials: BB
authors.lastname: Johansson
authors.forename: Karoly
authors.initials: K
authors.lastname: Nikolich
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wieloch
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004777:Environment; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D009068:Movement / Q000187:drug effects; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D021381:Protein Transport / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D018709:Statistics, Nonparametric; D014162:Transfection / Q000379:methods; D000097605:Sigma-1 Receptor
chemical_list: D051242:Caveolin 1; D005947:Glucose; D018697:Nootropic Agents; D010879:Piperazines; D034741:RNA, Small Interfering; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; C101789:SA 4503