The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke

Karsten Ruscher, Mehrdad Shamloo, Mattias Rickhag, Istvan Ladunga, Liza Soriano, Lennart Gisselsson, Hkan Toresson, Lily Ruslim-Litrus, Donna Oksenberg, Roman Urfer, Barbro B. Johansson, Karoly Nikolich, Tadeusz Wieloch

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)732-746
Number of pages15
JournalBrain
Volume134
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • astrocyte
  • membrane raft
  • neurite outgrowth
  • sigma-1 receptor
  • stroke recovery

ASJC Scopus subject areas

  • Clinical Neurology

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