The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke
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The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke. / Ruscher, Karsten; Shamloo, Mehrdad; Rickhag, Karl Mattias; Ladunga, Istvan; Soriano, Liza; Gisselsson, Lennart; Toresson, Håkan; Ruslim-Litrus, Lily; Oksenberg, Donna; Urfer, Roman; Johansson, Barbro B; Nikolich, Karoly; Wieloch, Tadeusz.
I: Brain, Bind 134, Nr. Pt 3, 03.2011, s. 732-46.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 132931091