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.

Inhibition of CXCL12 Signaling Attenuates the Postischemic Immune Response and Improves Functional Recovery after Stroke

“…Only animals that were not able to cross the rotating pole were randomly assigned into treatment groups. 15 Subsequently, starting on day 2 after pMCAO, rats were housed in standard laboratory cages or EE cages for 3 days. Neurologic score was assessed by the rotating pole test at postoperative day 5 as described previously 14 and brain tissue from the same set of animals has been used for analyses in the present study.…”

“…Neurologic function was assessed by the rotating pole test that measures coordination and integration of movement and has been described previously. 15 Infarct volumes were determined as decribed previously. 14 …”

“…12 Likewise, enriched housing initiated days after experimental stroke enhances long-term functional recovery, which occurs without decreasing infarct size. Here, the beneficial processes stimulate glia cells to encapsulate the infarct [13][14][15] or enhance neuronal plasticity. 16 Importantly, enriched housing has a profound effect on the inflammatory reponse after brain injury 14 and modulates cell genesis.…”

Genesis of ER stress in Huntington’s Disease

“…Sigma-1R activation was reported to induce neuronal re-growth and functional recovery following experimental stroke in a rat model [189] and a phase II trial was conducted with the Sigma-1R agonist cutamesine (SA4503) in patients with ischemic stroke [190]. A recent study showed that another Sigma-1R agonist, PRE084, improved behavioral symptoms in a Parkinson's disease mouse model [191].…”

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

“…A model has been proposed in which the sigma-1 receptors are "silent" under normal physiological conditions, whereas in disease, the receptor behaves as a chaperone that binds 'client' proteins, modulates cellular activity and promotes survival (Su et al 2010). This hypothesis has received some support from studies demonstrating that sigma-1 silencing would suppress recovery after experimental stroke (Ruscher et al 2011) and promote retinal degeneration after acute damage to the optic nerve (Mavlyutov et al 2012).…”