HMG-CoA Reductase Inhibition Promotes Neurological Recovery, Peri-Lesional Tissue Remodeling, and Contralesional Pyramidal Tract Plasticity after Focal Cerebral Ischemia

Abstract

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are widely used for secondary stroke prevention. Besides their lipid-lowering activity, pleiotropic effects on neuronal survival, angiogenesis, and neurogenesis have been described. In view of these observations, we were interested whether HMG-CoA reductase inhibition in the post-acute stroke phase promotes neurological recovery, peri-lesional, and contralesional neuronal plasticity. We examined effects of the HMG-CoA reductase inhibitor rosuvastatin (0.2 or 2.0 mg/kg/day i.c.v.), administered starting 3 days after 30 min of middle cerebral artery occlusion for 30 days. Here, we show that rosuvastatin treatment significantly increased the grip strength and motor coordination of animals, promoted exploration behavior, and reduced anxiety. It was associated with structural remodeling of peri-lesional brain tissue, reflected by increased neuronal survival, enhanced capillary density, and reduced striatal and corpus callosum atrophy. Increased sprouting of contralesional pyramidal tract fibers crossing the midline in order to innervate the ipsilesional red nucleus was noticed in rosuvastatin compared with vehicle-treated mice, as shown by anterograde tract tracing experiments. Western blot analysis revealed that the abundance of HMG-CoA reductase was increased in the contralesional hemisphere at 14 and 28 days post-ischemia. Our data support the idea that HMG-CoA reductase inhibition promotes brain remodeling and plasticity far beyond the acute stroke phase, resulting in neurological recovery.

Correlates of Post-Stroke Brain Plasticity, Relationship to Pathophysiological Settings and Implications for Human Proof-of-Concept Studies

“…RhoA has an inhibitory effect on neuronal growth, whereas Rac-1 and Cdc42 have growth-promoting activity (Tashiro and Yuste, 2004 ; Ponimaskin et al, 2007 ; Leemhuis et al, 2010 ; Sun et al, 2012 ). Notably, both erythropoietin and statins, which promote contralesional pyramidal tract plasticity post-stroke and enhance functional neurological recovery in rodents (Reitmeir et al, 2011 ; Kilic et al, 2014 ), modulate Rho-GTPase activity. Erythropoietin inhibits Rho-A, ROCK-1 and ROCK-2 after optical nerve crush, promoting axonal growth (Tan et al, 2012 ), while it promoted axonal and dendritic growth on hippocampal cells through activation of the phosphatidyl-inositol-3-kinase/Akt pathway (Ransome and Turnley, 2008 ) that promotes microtubule polymerization (Yoshimura et al, 2006 ).…”

Post-acute delivery of memantine promotes post-ischemic neurological recovery, peri-infarct tissue remodeling, and contralesional brain plasticity

“…In this respect, memantine differed from studies with growth factor (erythropoietin, VEGF), 17,18,22 neural precursor cell, 18 and hydroxymethylglutaryl-CoA reductase inhibitor 23 delivery, where we previously observed slowly evolving motor-coordination improvements that became detectable only after several weeks …”

Early treatment with atorvastatin exerts parenchymal and vascular protective effects in experimental cerebral ischaemia

“…Beginning the treatment simultaneously or in the hours following reperfusion induced a reduction in the neurological deficit 24 h later (Céspedes‐Rubio et al ., ; Cui et al ., ). The effect of a statin treatment started later, that is 24 to 72 h after experimental stroke, is better documented and has been shown to improve sensory‐motor recovery for up to 28 days without reducing the lesion itself (Shehadah et al ., ; Kilic et al ., ). When treatment was initiated even later, 7 days after MCAO, it also helped to reduce cognitive impairment 3 months later (Shimamura et al ., ).…”