TY - JOUR

T1 - The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke

AU - Ruscher, Karsten

AU - Shamloo, Mehrdad

AU - Rickhag, Karl Mattias

AU - Ladunga, Istvan

AU - Soriano, Liza

AU - Gisselsson, Lennart

AU - Toresson, Håkan

AU - Ruslim-Litrus, Lily

AU - Oksenberg, Donna

AU - Urfer, Roman

AU - Johansson, Barbro B

AU - Nikolich, Karoly

AU - Wieloch, Tadeusz

PY - 2011/3

Y1 - 2011/3

N2 - 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.

AB - 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.

KW - Animals

KW - Astrocytes

KW - Brain

KW - Caveolin 1

KW - Cell Hypoxia

KW - Cells, Cultured

KW - Disease Models, Animal

KW - Dose-Response Relationship, Drug

KW - Environment

KW - Gene Expression Regulation

KW - Glucose

KW - Infarction, Middle Cerebral Artery

KW - Male

KW - Movement

KW - Neurites

KW - Neuronal Plasticity

KW - Neurons

KW - Nootropic Agents

KW - Piperazines

KW - Protein Transport

KW - Psychomotor Performance

KW - RNA, Small Interfering

KW - Rats

KW - Rats, Inbred SHR

KW - Receptors, sigma

KW - Recovery of Function

KW - Statistics, Nonparametric

KW - Transfection

U2 - 10.1093/brain/awq367

DO - 10.1093/brain/awq367

M3 - Journal article

C2 - 21278085

VL - 134

SP - 732

EP - 746

JO - Brain

JF - Brain

SN - 0006-8950

IS - Pt 3

ER -