Axonal Outgrowth and Dendritic Plasticity in the Cortical Peri-Infarct Area After Experimental Stroke

Abstract

Background and Purpose Axonal remodeling is critical to brain repair after stroke. The present study investigated axonal outgrowth after stroke and the signaling pathways mediating axonal outgrowth in cortical neurons. Methods Using a rodent model of middle cerebral artery occlusion, we examined high molecular weight neurofilament (NFH) immunoreactive axons and myelin basic protein (MBP) positive oligodendrocytes in the peri-infarct area. In vitro, using cultured cortical neurons in a microfluidic chamber challenged by oxygen-glucose deprivation (OGD), we investigated mechanisms selectively regulating axonal outgrowth after OGD. Results NFH+ axons and MBP+ oligodendrocytes substantially increased in the peri-infarct area during stroke recovery, concomitantly with an increase in dendrites and spines identified by Golgi-Cox staining. In vitro, cortical neurons subjected to OGD exhibited significant increases in axonal outgrowth and in phosphorylated NFH protein levels, concurrently with downregulation of phosphatase tensin homolog deleted on chromosome 10 (PTEN), activation of Akt, and inactivation of glycogen synthase kinase-3β(GSK-3β) in regenerated axons. Blockage of phosphoinositide 3-kinase (PI3K) with pharmacological inhibitors suppressed Akt activation and attenuated phosphorylation of GSK-3β, which resulted in suppression of pNFH and axonal outgrowth after OGD, whereas GSK-3 inhibitors augmented axonal regeneration and elevated pNFH levels after OGD. Conclusions Stroke induces axonal outgrowth and myelination in rodent ischemic brain during stroke recovery, and the PI3K/Akt/GSK-3β signaling pathway mediates axonal regeneration of cortical neurons after OGD.

Sonic Hedgehog Signaling Pathway Mediates Cerebrolysin-Improved Neurological Function After Stroke

“…19 During stroke recovery, axonal outgrowth is closely associated with myelinating oligodendrocytes in the periinfarct regions, and axonal remodeling is correlated to neurological function. 3,20 Thus, it is likely that the enhancement of axonal remodeling and oligodendrogenesis by cerebrolysin could lead to the improved functional recovery after stroke.…”

Exosomes in stroke pathogenesis and therapy

“…Mature oligodendrocytes are terminally differentiated and are vulnerable to cerebral ischemia. During brain repair processes, new oligodendrocytes generated by OPCs form myelin sheaths around the regenerated axons in periinfarct gray and white matter (48)(49)(50)(51). Recent studies indicate that cerebral endothelial cells actively and mutually interact with oligodendrocytes to facilitate angiogenesis and oligodendrogenesis during repair after stroke (52).…”

Ischemic Postconditioning Relieves Cerebral Ischemia and Reperfusion Injury Through Activating T-LAK Cell–Originated Protein Kinase/Protein Kinase B Pathway in Rats

“…Frozen brain sections were stained with 100 μmol/L dihydroethidium in phosphate buffered saline (PBS) for 90 minutes at room temperature. To determine the fluorescence intensity of oxidized dihydroethidium, 6 microscopic fields in the peri-infarct cortex 16 were captured randomly by a fluorescence microscope (Carl Zeiss, Jena, Germany), with a setting of 20× magnification. The total number of cells in all images was counted and the percentage of nuclear dihydroethidium-positive cells was calculated.…”