Mine KAYNAK, Mehtap SAVRAN, Halil AŞÇI, Kanat GÜLLE, İlter İLHAN

LİPOPOLİSAKKARİT İLE İNDÜKLENMİŞ HİPOKAMPAL TOKSİSİTEDE RAMELTEON'UN ETKİSİ

Amaç Tıptaki gelişmelere rağmen sepsis dünya çapında hala önemli bir sağlık sorunu olmaya devam etmektedir ve beyin dokusu sepsisin erken döneminde hasar gören yapılardan biridir. Nöroinflamasyon (NI), septik beyin hasarında ana mekanizma olarak kabul edilir. Ramelteon (RML), seçici olmayan (MT1/MT2) bir melatonin reseptör agonistidir ve 2005 yılında uykusuzluk endikasyonu için FDA tarafından onaylanmıştır. RML, diğer melatonerjik agonist ilaçlar arasında her iki reseptör alt tipi için nispeten daha yüksek afinite gösterir. Gereç ve Yöntem RML'nin lipopolisakarit (LPS) ile indüklenen NI üzerindeki koruyucu etkisini araştırmak için yirmi sekiz erkek Wistar Albino sıçan kullanıldı. Kontrol, LPS (5 mg/kg, intraperitoneal), RML (8 mg/kg, oral) ve LPS + RML (LPS'den 45 dakika önce) grupları oluşturuldu. Son ilaç uygulamasından 6 saat sonra sıçanlar sakrifiye edildi. Hemogram analizi için kan, histopatolojik değerlendirme için kortikal ve hipokampal dokular toplandı. Bulgular LPS, lökosit ve nötrofil/lenfosit oranını (NLR) artırırken, lenfosit ve trombosit sayısını azalttı. Buna karşın RML ile, NLR’de anlamlı bir azalma ve trombosit sayısında anlamlı bir artış izlendi. Histokimyasal değerlendirmede LPS grubuna ait hipokampal ve kortikal alanlarda belirgin inflamatuar hücre infiltrasyonu ve apoptoz gözlendi. RML, bu alanlarda inflamatuar yanıtı ve apoptotik cisimleri azalttı. Sonuç RML, hipokampusta gözlenen LPS'ye bağlı NI'de antiinflamatuar ve antiapoptotik mekanizmalar aracılığıyla koruyucu olabilir.

Anahtar Kelimeler:

Lipopolisakkarit, Hipokampus, Ramelteon, Nöroinflamasyon

EFFECT OF RAMELTEON ON LIPOPOLYSACCHARIDE INDUCED HIPPOCAMPAL TOXICITY

Objective Despite the advances in medicine, sepsis still remains a major health problem worldwide and brain tissue is one of the structures damaged in the early period of sepsis. Neuroinflammation (NI) is considered as the main mechanism in septic brain injury. Ramelteon (RML) is a non-selective (MT1 / MT2) melatonin receptor agonist and was approved by the FDA in 2005 with the indication of insomnia. RML shows relatively higher affinity for both receptor subtypes among other melatonergic agonist drugs. Material and Method Twenty-eight male Wistar Albino rats were used to investigate the protective effect of RML on lipopolysaccharide (LPS) induced NI. Control, LPS (5 mg/kg, intraperitoneally), RML (8 mg/kg, orally) and LPS + RML (45 minutes before LPS) groups were created. Six hours following the last drug administration, rats were sacrificed. Blood for hemogram analysis and cortical and hippocampal tissues for histopathological evaluation were collected. Results LPS increased white blood cell and neutrophil/ lymphocyte ratio (NLR) while it decreased lymphocyte and platelet counts. RML decreased NLR and increased platelet counts significantly. In histochemical evaluation, marked inflammatory cell infiltration and apoptosis were observed in both hippocampal and cortical areas of LPS group. RML decreased the inflammatory response and apoptotic bodies in these areas. Conclusion RML may be protective on LPS-induced NI observed in hippocampus via anti-inflammatory and anti-apoptotic mechanisms.

Keywords:

Lipopolysaccharide, Hippocampus, Ramelteon, Neuroinflammation,

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