title: 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.
authors.affiliation: Department of Physiology, Istanbul Medipol University , Istanbul , Turkey.
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
authors.affiliation: Department of Neurology, University Hospital , Essen , Germany.
authors.forename: Raluca
authors.initials: R
authors.lastname: Reitmeir
authors.affiliation: Department of Medical Biology, Istanbul Medipol University , Istanbul , Turkey.
authors.forename: Ülkan
authors.initials: Ü
authors.lastname: Kilic
authors.affiliation: Department of Physiology, Istanbul Medipol University , Istanbul , Turkey.
authors.forename: Ahmet Burak
authors.initials: AB
authors.lastname: Caglayan
authors.affiliation: Department of Physiology, Istanbul Medipol University , Istanbul , Turkey.
authors.forename: Mustafa Caglar
authors.initials: MC
authors.lastname: Beker
authors.affiliation: Department of Physiology, Istanbul Medipol University , Istanbul , Turkey.
authors.forename: Taha
authors.initials: T
authors.lastname: Kelestemur
authors.affiliation: Department of Physiology, Istanbul Medipol University , Istanbul , Turkey.
authors.forename: Muhsine Sinem
authors.initials: MS
authors.lastname: Ethemoglu
authors.affiliation: Department of Physiology, Istanbul Medipol University , Istanbul , Turkey.
authors.forename: Gurkan
authors.initials: G
authors.lastname: Ozturk
authors.affiliation: Department of Neurology, University Hospital , Essen , Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
keywords: middle cerebral artery occlusion; neurological recovery; neuronal plasticity; restorative therapy; statin; tract tracing