Enhanced neuroprotective effects for co-administration of g-csf with simvastatin on intracerebral hemorrhage in rats

Abstract

ABSTRACTaIM: Based on the neuroprotective effect of either G-CSF or statins in various neurological disease models, the purpose of this study was to evaluate the superiority of combined therapy G-CSF with simvastatin in experimental intracerebral hemorrhage (ICH). MaterIaL and MetHOds:Primary ICH was induced in male Sprague Dawley rats. G-CSF (50μg/kg), simvastatin (2 mg/kg), combined G-CSF and simvastatin, or phosphate buffered saline was given at 24 hours post-ICH. Neurobehavioral outcomes were assessed in all rats. The pathological changes of neuronal ultrastructure were examined with transmission electron microscopy at the given time. Simultaneously, immunohistochemical labeling and TUNEL assay were performed.resuLts: Co-administration of G-CSF with simvastatin significantly promoted functional recovery and expedited the recovery time. Transmission electron microscopy revealed that combination treatment significantly improved ultrastructural outcomes. Histological examination showed that the expressions of Brdu co-labeled with NSE and GFAP, Factor VIII were higher in combined treatment than in control group. Additionally, the number of cell apoptosis was higher in control group than in experimental groups and lowest in combination group. cOncLusIOn: Our results indicated that combination treatment of stroke with G-CSF and simvastatin augments the neuroprotective effect in rats after ICH.keywOrds: Hematoma, Granulocyte-colony stimulating factor, Simvastatin, Rat ÖZ aMaÇ: Çeşitli nörolojik hastalık modellerinde G-CSF veya statinlerin nöroprotektif etkisi temelinde bu çalışmanın amacı deneysel intraserebral kanamada (ICH) kombine G-CSF ve simvastatin tedavisinin üstünlüğünü değerlendirmekti. yÖnteM ve gereÇLer: Erkek Sprague Dawley Sıçanlarında primer intraserebral kanama (ICH) indüklendi. ICH'den 24 saat sonra G-CSF (50μg/kg), simvastatin (2 mg/kg), kombine G-CSF ve simvastatin veya fosfat tamponlu salin verildi. Nörodavranışsal sonuçlar tüm sıçanlarda değerlendirildi. Nöronal alt yapıdaki patolojik değişiklikler belirtilen sürede transmisyon elektron mikroskopisiyle incelendi. Aynı zamanda immünohistokimyasal etiketleme ve TUNEL testi yapıldı.BuLguLar: G-CSF'nin simvastatinle birlikte uygulanması işlevsel iyileşmeyi önemli ölçüde arttırdı ve iyileşme süresini kısalttı. Transmisyon elektron mikroskopisi kombinasyon tedavisinin ultrayapısal sonuçlarda önemli bir düzelme oluşturduğunu gösterdi. Histolojik incelemeler NSE ve GFAP, Faktör VIII ile etiketlenmiş Brdu ekspresyonlarının kombine tedavi grubunda kontrol grubundan daha yüksek olduğunu gösterdi. Ayrıca hücre apopitozu sayısı kontrol grubunda deneysel gruplardan yüksekti ve kombinasyon grubunda en düşüktü.sOnuÇ: Sonuçlarımız inmenin G-CSF ve simvastatin ile kombinasyon tedavisinin sıçanlarda ICH sonrasında nöroprotektif etkiyi güçlendirdiğine işaret etmektedir.anaHtar sÖZcÜkLer: Hematom, Granülosit koloni stimülasyon faktörü, Simvastatin, Sıçan

Ultrastructural Characteristics of Neuronal Death and White Matter Injury in Mouse Brain Tissues After Intracerebral Hemorrhage: Coexistence of Ferroptosis, Autophagy, and Necrosis

“…However, the ultrastructural pathology of the inflammation has not been clearly characterized in animal models ( 22 ). Besides neuronal death and the inflammatory response in the acute phase of ICH, axonal damage, including demyelination ( 16 , 23 , 24 ), and synapse changes ( 25 ) also contribute to ICH pathology and may play vital roles in long-term outcomes such as mood and cognition changes ( 26 – 28 ).…”

“…Subarachnoid hemorrhage also has been associated with structural changes in endothelial cell vacuoles, erythrocytes, leukocytes, and mast cells, and with cellular necrosis ( 30 , 31 ). In animal models of ICH, neuronal damage, nucleolus condensation, mitochondrial swelling, and synapse destruction have been reported ( 5 , 12 , 13 , 18 , 25 ). However, no study has systematically examined the ultrastructural features of collagenase-induced ICH in mice over time.…”

Intracerebral Hemorrhage: Perihemorrhagic Edema and Secondary Hematoma Expansion: From Bench Work to Ongoing Controversies

“…Statins also reduce BBB dysfunction, edema, tissue loss, and improve CBF in the perihemorrhagic zone (92, 93). Combination of granulocyte-colony stimulating factor (G-CSF) and statins further enhance their neuroprotective capacity with less cell apoptosis than with either agents alone (94). Combination of statins and deferoxamine showed a greater effect on PHE and hematoma volume than either agent alone (95).…”

Neuroprotection in Stroke: Past, Present, and Future

“…The combination of the anti-inflammatory properties of atorvastatin and the antioxidant properties of probucol also produces increased neuroprotection in pMCAO rats [102]. Simvastatin combined with granulocyte colony-stimulating factor (G-CSF) reduced recovery time in a rat model of intracerebral hemorrhage and improved outcome [103]. Another strategy for combination therapy is the use of one drug to block the negative effects of another, such as tPA.…”