Deneysel Travmatik Beyin Hasarında Nebivololün Hipokampus Üzerine Etkisinin Değerlendirilmesi

Yıl 2026, Cilt: 12 Sayı: 1, 56 - 61, 20.01.2026

Fırat Aşır , Zeynep Türe , Gül Ebru Aydeniz Acar , Hayat Ayaz , Ayşenur Sevinç Akdeniz , Mehmet Ölmez , Esma Yıldırım , Mehmet Zülfi Demir

https://doi.org/10.30934/kusbed.1793969

Öz

Amaç: Travmatik beyin hasarı (TBI), dünya genelinde yüksek mortalite ve uzun dönem morbiditeye yol açan başlıca nörolojik sorunlardan biridir. Sekonder hasar mekanizmaları arasında yer alan oksidatif stres, nöroinflamasyon ve astrogliyal aktivasyon, özellikle hipokampal bölgede belirgin nöronal dejenerasyona neden olmaktadır. Nitrik oksit aracılı vazodilatör ve antioksidan özelliklere sahip üçüncü kuşak bir β1-adrenerjik reseptör blokörü olan nebivolol, son yıllarda olası nöroprotektif etkileri ile dikkat çekmektedir. Bu çalışma, deneysel TBI modeli oluşturulan sıçanlarda nebivololün hipokampal hasar üzerine histopatolojik ve immünohistokimyasal etkilerini incelemeyi; özel olarak astrositik aktivasyonun belirteci olan S100 protein ekspresyonundaki değişiklikleri değerlendirmeyi amaçlamaktadır.

Yöntem: Çalışmada 24 adet erkek Sprague–Dawley sıçan rastgele üç gruba ayrılmıştır (n = 8): Kontrol, TBI ve TBI + Nebivolol. Travmatik beyin hasarı, ağırlık düşürme yöntemi (50 g/1 m) ile oluşturulmuştur. Nebivolol 10 mg/kg/gün dozunda oral yolla 14 gün süreyle uygulanmıştır. On dördüncü gün elde edilen hipokampal dokular hematoksilen–eozin ile histopatolojik olarak, S100 proteini için ise immünohistokimyasal yöntemle incelenmiştir. İstatistiksel analizler tek yönlü ANOVA veya Kruskal–Wallis testleri ile gerçekleştirilmiş; p < 0,05 anlamlı kabul edilmiştir.
Bulgular: TBI grubunda belirgin nöronal dejenerasyon, nükleer piknoz, vasküler dilatasyon ve sinaptik organizasyon kaybı izlenmiştir. Pyramidal nöronlarda, glial hücrelerde ve vasküler endotelde güçlü S100 immünreaktivitesi saptanmış; bu bulgu astrositik aktivasyonun göstergesi olarak değerlendirilmiştir. TBI + Nebivolol grubunda ise nöronal morfolojinin korunduğu, vasküler dilatasyonun azaldığı ve aksonal düzenin belirgin ölçüde iyileştiği gözlenmiştir. Ayrıca, bu grupta S100 ekspresyonu anlamlı şekilde azalmış, özellikle pyramidal nöronlar ve glial hücrelerde immünreaktivite belirgin ölçüde gerilemiştir.
Sonuç: Nebivolol tedavisi, deneysel TBI modeli oluşturulan sıçanlarda hipokampal hasarı azaltmış; histopatolojik iyileşmenin yanı sıra S100 protein ekspresyonunun baskılanması ile astrositik aktivasyonun sınırlandığı gösterilmiştir. Bu sonuçlar, nebivololün TBI’da sekonder nöronal hasarı ve astrogliyal yanıtı azaltarak potansiyel bir nöroprotektif ajan olabileceğini ortaya koymaktadır. Bununla birlikte, nebivololün terapötik etkinliğinin doğrulanabilmesi için daha geniş örneklemlerle, ek moleküler düzeyde analizler ve davranışsal değerlendirmelerle desteklenmiş ileri çalışmalara gereksinim vardır.

Anahtar Kelimeler

travmatik beyin hasarı , hipokampus , nebivolol , s100 proteini , immünohistokimya , nöroproteksiyon

Etik Beyan

Etik onay, Dicle Üniversitesi Deney Hayvanları Yerel Etik Kurulu’ndan alınmıştır (tarih: 07/04/2021 ve sayı: 2021/18)

Destekleyen Kurum

Bu çalışma, Dicle Üniversitesi Bilimsel Araştırma Projeleri Koordinatörlüğü (DÜBAP) tarafından TIP.22.018 numaralı proje ile desteklenmiştir.

Proje Numarası

This study was funded by Dicle University Project Research Platform (DUBAP) with project number: TIP.22.018

Evaluation of the Effect of Nebivolol on Hippocampus in Experimental Traumatic Brain Injury

Öz

Abstract
Objective: Traumatic brain injury (TBI) is a major cause of mortality and long-term disability worldwide. Secondary injury mechanisms such as oxidative stress, neuroinflammation, and astroglial activation contribute significantly to neuronal degeneration, particularly in the hippocampus. Nebivolol, a third-generation β1-adrenergic blocker with nitric oxide–mediated vasodilatory and antioxidant properties, has been proposed as a potential neuroprotective agent. This study aimed to investigate the histopathological and immunohistochemical effects of nebivolol on hippocampal damage after experimental TBI in rats, with a specific focus on S100 protein expression as a marker of astroglial activation.
Materials and Methods: Twenty-four male Sprague–Dawley rats were randomly divided into three groups (n = 8 each): Control, TBI, and TBI + Nebivolol. TBI was induced using the weight-drop method (50 g/1 m). Nebivolol was administered orally at a dose of 10 mg/kg/day for 14 days. Hippocampal tissues were collected on day 14 and examined histologically with hematoxylin–eosin (H&E) and immunohistochemically for S100 expression. Statistical analyses were performed using one-way ANOVA or Kruskal–Wallis tests, with p < 0.05 considered significant.
Results: In the TBI group, marked neuronal degeneration, nuclear pyknosis, vascular dilatation, and synaptic disorganization were observed in the hippocampus. Strong S100 expression was detected in pyramidal neurons, glial cells, and vascular endothelium, indicating astroglial activation. In contrast, the TBI + Nebivolol group exhibited preserved neuronal morphology, reduced vascular dilatation, and improved axonal organization. Immunohistochemically, S100 expression was significantly decreased in pyramidal neurons and glial cells compared to the TBI group, suggesting attenuation of astrocytic activation.
Conclusion: Nebivolol treatment ameliorated hippocampal injury in rats with experimental TBI by reducing oxidative stress–related histopathological changes and suppressing S100 expression. These findings support the potential role of nebivolol as a neuroprotective agent in TBI by limiting astroglial activation and secondary neuronal damage. Further studies with larger cohorts, additional molecular analyses, and behavioral assessments are needed to confirm its therapeutic potential.

Anahtar Kelimeler

traumatic brain injury , hippocampus , nebivolol , s100 protein , immunohistochemistry , neuroprotection

Etik Beyan

Ethical approval was taken from Dicle University, Animal Experiments Local Ethical Committee (date:07/04/2021 and number:2021/18).

Destekleyen Kurum

This study was funded by Dicle University Project Research Platform (DUBAP) with project number: TIP.22.018

Proje Numarası

This study was funded by Dicle University Project Research Platform (DUBAP) with project number: TIP.22.018

Kaynakça

• Maas AIR, Menon DK, Manley GT, et al. Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol. 2022;21(11):1004-1060. doi:10.1016/s1474-4422(22)00309-x
• Aşır F, Aslanoğlu B, Tutal Gürsoy G, Tuncer MC. Resveratrol showed anti-inflammatory effects on hippocampus via suppressing NFκB. Folia Morphologica. 2024;83(3):571-577. doi:10.5603/fm.97799
• Capizzi A, Woo J, Verduzco-Gutierrez M. Traumatic Brain Injury: An Overview of Epidemiology, Pathophysiology, and Medical Management. Med Clin North Am. 2020;104(2):213-238. doi:10.1016/j.mcna.2019.11.001
• Rapp A, Kobeissi H, Fahim DK. Updated Review of the Management of and Guidelines for Traumatic Brain Injury. J Clin Med. 2025;14(19):6796
• Zheng RZ, Lee KY, Qi ZX, et al. Neuroinflammation Following Traumatic Brain Injury: Take It Seriously or Not. Front Immunol. 2022;13:855701. doi:10.3389/fimmu.2022.855701
• Zhao Q, Li H, Li H, Xie F, Zhang J. Research progress of neuroinflammation-related cells in traumatic brain injury: A review. Medicine (Baltimore). 23 2023;102(25):e34009. doi:10.1097/md.0000000000034009
• Ng SY, Lee AYW. Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets. Front Cell Neurosci. 2019;13:528. doi:10.3389/fncel.2019.00528
• Ulger BV, Erbis H, Turkcu G, et al. Nebivolol ameliorates hepatic ischemia/reperfusion injury on liver but not on distant organs. J Invest Surg. 2015;28(5):245-252. doi:10.3109/08941939.2015.1031923
• Alali AS, Mukherjee K, McCredie VA, et al. Beta-blockers and Traumatic Brain Injury: A Systematic Review, Meta-analysis, and Eastern Association for the Surgery of Trauma Guideline. Ann Surg. 2017;266(6):952-961. doi:10.1097/sla.0000000000002286
• Fongemie J, Felix-Getzik E. A Review of Nebivolol Pharmacology and Clinical Evidence. Drugs. 2015;75(12):1349-71. doi:10.1007/s40265-015-0435-5
• Mansour MS, Seidy NSE, Fathey YI. Evaluation of beta-blocker effects on patients with traumatic brain injury: interventional double-blinded randomized controlled trial. Ain-Shams Journal of Anesthesiology. 2023;15(1):65. doi:10.1186/s42077-023-00364-0
• Uzar E, Acar A, Evliyaoğlu O, et al. The anti-oxidant and anti-apoptotic effects of nebivolol and zofenopril in a model of cerebral ischemia/reperfusion in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2012;36(1):22-28. doi:10.1016/j.pnpbp.2011.08.011
• Singh P, Ali SA. Multifunctional role of S100 protein family in the immune system: an update. Cells. 2022;11(15). doi:10.3390/cells11152274
• Gonzalez LL, Garrie K, Turner MD. Role of S100 proteins in health and disease. Biochim Biophys Acta Mol Cell Res. 2020;1867(6):118677. doi:10.1016/j.bbamcr.2020.118677
• Blais Lécuyer J, Mercier É, Tardif PA, et al. S100B protein level for the detection of clinically significant intracranial haemorrhage in patients with mild traumatic brain injury: a subanalysis of a prospective cohort study. Emerg Med J. 2021;38(4):285-289. doi:10.1136/emermed-2020-209583
• Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006;147 Suppl 1(Suppl 1):S232-40. doi:10.1038/sj.bjp.0706400
• Oguzoglu A, Şenol N, Doguc D, Taşan Ş, Erzurumlu Y, Aşcı H. The effect of nebivolol on acute brain damage in a rat model of LPS-induced inflammation. SDÜ Tıp Fak Derg. 2025;32:27-35. doi:10.17343/sdutfd.1518104
• Aydeniz Acar GE, Akdeniz AS, Türe Z, et al. HOXA1 expression in placentas of woman with fetal growth restriction. Perinatal Journal. 2024;32(2):166-72. doi: 10.59215/prn.24.0322012
• Kaur P, Sharma S. Recent Advances in Pathophysiology of Traumatic Brain Injury. Curr Neuropharmacol. 2018;16(8):1224-1238. doi:10.2174/1570159x15666170613083606
• Gnyliukh N, Wei J, Neuhaus W, Boukherroub R, Szunerits S. The role of S100B protein as a diagnostic biomarker for brain injury. Sens Bio-Sens Res. 2025;50:100888. doi:10.1016/j.sbsr.2025.100888
• Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochir (Wien). 2017;159(2):209-225. doi:10.1007/s00701-016-3046-3 García-Domínguez M. Relationship of S100 proteins with neuroinflammation. Biomolecules. 2025;15(8). doi:10.3390/biom15081125 Michetti F, Clementi ME, Di Liddo R, et al. The S100B protein: a multifaceted pathogenic factor more than a biomarker. Int J Mol Sci. 2023;24(11). doi:10.3390/ijms24119605
• Naeem AG, El-Naga RN, Michel HE. Nebivolol elicits a neuroprotective effect in the cuprizone model of multiple sclerosis in mice: emphasis on M1/M2 polarization and inhibition of NLRP3 inflammasome activation. Inflammopharmacology. 2022;30(6):2197-2209. doi:10.1007/s10787-022-01045-4
• Akçay A, Acar G, Kurutaş E, et al. Beneficial effects of nebivolol treatment on oxidative stress parameters in patients with slow coronary flow. Turk Kardiyol Dern Ars. 2010;38(4):244-49.
• Gupta S, Wright H. Nebivolol: a highly selective β1-adrenergic receptor blocker that causes vasodilation by increasing nitric oxide. Cardiovasc Ther. 2008;26:189-202. doi:10.1111/j.1755-5922.2008.00054.x