LİPOPOLİSAKKARİT İLE İNDÜKLENMİŞ HİPOKAMPAL TOKSİSİTEDE RAMELTEON'UN ETKİSİ

Öz

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

Öz

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.

Anahtar Kelimeler

• Lipopolysaccharide
• Hippocampus
• Ramelteon
• Neuroinflammation

Kaynakça

1. 1. Tsai MC, Chen WJ, Tsai MS, Ching CH, Chuang JI. Melatonin attenuates brain contusion‐induced oxidative insult, inactivation of signal transducers and activators of transcription 1, and upregulation of suppressor of cytokine signaling‐3 in rats. Journal of pineal research. 2011; 51(2): 233-245.
2. 2. Solov’eva T, Davydova V, Krasikova I, Yermak I. Marine compounds with therapeutic potential in gram-negative sepsis. Marine Drugs. 2013; 11(6): 2216-2229.
3. 3. Jain KK. Role of neuroinflammation in the pathogenesis of neurologic disorders and principles of management.
4. 4. Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG. Does neuroinflammation fan the flame in neurodegenerative diseases? Molecular neurodegeneration. 2009; 4(1): 1-13.
5. 5. Savran M, Ozmen O, Erzurumlu Y, Savas HB, Asci S, Kaynak M. The impact of prophylactic lacosamide on LPS-induced neuroinflammation in aged rats. Inflammation. 2019; 42(5): 1913-1924.
6. 6. Bradl M, Hohlfeld R. Molecular pathogenesis of neuroinflammation. Journal of Neurology, Neurosurgery & Psychiatry. 2003; 74(10): 1364-1370.
7. 7. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC. CNS immune privilege: hiding in plain sight. Immunological reviews. 2006; 213(1): 48-65.
8. 8. Fu HQ, Yang T, Xiao W, Fan L, Wu Y, Terrando N, Wang TL. Prolonged neuroinflammation after lipopolysaccharide exposure in aged rats. PloS one. 2014; 9(8): e106331.

9. 9. Owens T, Babcock AA, Millward JM, & Toft-Hansen H. Cytokine and chemokine inter-regulation in the inflamed or injured CNS. Brain Research Reviews. 2005; 48(2): 178-184.
10. 10. Dantzer R, Kelley KW. Twenty years of research on cytokine- induced sickness behavior. Brain, behavior, and immunity. 2007; 21(2): 153-160.
11. 11. Flierl MA, Stahel PF, Rittirsch D, Huber-Lang M, Niederbichler AD, Hoesel LM, Ipaktchi K. Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis. Critical Care. 2009; 13(1): 1-9.
12. 12. Badshah H, Ali T, Rehman SU, Amin FU, Ullah F, Kim TH, Kim MO. Protective effect of lupeol against lipopolysaccharide-induced neuroinflammation via the p38/c-Jun N-terminal kinase pathway in the adult mouse brain. Journal of Neuroimmune Pharmacology. 2016; 11(1): 48-60.
13. 13. Tripathi A, Paliwal P, Krishnamurthy S. Piracetam attenuates LPS-induced neuroinflammation and cognitive impairment in rats. Cellular and Molecular Neurobiology. 2017; 37(8): 1373- 1386.
14. 14. Shaw KN, Commins S, O'Mara SM. Lipopolysaccharide causes deficits in spatial learning in the watermaze but not in BDNF expression in the rat dentate gyrus. Behavioural brain research. 2001; 124(1): 47-54.15.
15. 15. Qin L, Wu X, Block ML, et. al systemic LPS causes chronic neuroinflammation and progressive neurodegeneration, Glia. 2007; 55(5): 453-62.
16. 16. Skelly DT, Hennessy E, Dansereau MA, Cunningham C. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1β, TNF-α and IL-6 challenges in C57BL/6 mice. PloS one. 2013; 8(7): e69123.
17. 17. Jiao D, Jiang Q, Liu Y, Ji L. Nephroprotective effect of wogonin against cadmium-induced nephrotoxicity via inhibition of oxidative stress–induced MAPK and NF-kB pathway in Sprague Dawley rats. Human & Experimental Toxicology. 2019; 38(9): 1082-1091.
18. 18. Kireev RA, Vara E, Viña J, Tresguerres JA. Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats. Age. 2014; 36(5): 1-15.
19. 19. Parada E, Buendia I, León R, Negredo P, Romero A, Cuadrado A, Egea J. Neuroprotective effect of melatonin against ischemia is partially mediated by alpha‐7 nicotinic receptor modulation and HO‐1 overexpression. Journal of pineal research. 2014; 56(2): 204-212.
20. 20. O’Neal-Moffitt G, Delic V, Bradshaw PC, Olcese J. Prophylactic melatonin significantly reduces Alzheimer’s neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPPswe/PS1 mice. Molecular neurodegeneration. 2015; 10(1): 1-21.
21. 21. Pintado C, Gavilán MP, Gavilán E, García-Cuervo L, Gutiérrez A, Vitorica J, Ruano D. Lipopolysaccharide-induced neuroinflammation leads to the accumulation of ubiquitinated proteins and increases susceptibility to neurodegeneration induced by proteasome inhibition in rat hippocampus. Journal of neuroinflammation. 2012; 9(1): 1-10.
22. 22. Knierim JJ. The hippocampus. Current Biology. 25(23): R1116-R1121.
23. 23. Witter MP, Kleven H, Flatmoen AK. Comparative contemplations on the hippocampus. Brain, Behavior and Evolution. 2017; 90(1): 15-24.
24. 24. Ardestani PM, Evans AK, Yi B, Nguyen T, Coutellier L, Shamloo M. Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist. Neuropharmacology. 2017; 116: 371-386.
25. 25. Prema A, Justin Thenmozhi A, Manivasagam T, Mohamed Essa M, Guillemin GJ. Fenugreek seed powder attenuated aluminum chloride-induced tau pathology, oxidative stress, and inflammation in a rat model of Alzheimer’s disease. Journal of Alzheimer's Disease. 2017; 60(s1): S209-S220.
26. 26. Pandi-Perumal SR, Spence DW, Verster JC, Srinivasan V, Brown GM, Cardinali DP, Hardeland R. Pharmacotherapy of insomnia with ramelteon: safety, efficacy and clinical applications. Journal of Central Nervous System Disease. 2011; 3: JCNSD-S1611.
27. 27. Laudon M, Frydman-Marom A. Therapeutic effects of melatonin receptor agonists on sleep and comorbid disorders. International journal of molecular sciences. 2014; 15(9): 15924-15950.
28. 28. Owen RT. Ramelteon: profile of a new sleep-promoting medication. Drugs of Today. 2006; 42(4): 255-264.
29. 29. Shimizu N, Nozawa M, Sugimoto K, Yamamoto Y, Minami T, Hayashi T, Uemura H. Therapeutic efficacy and anti-inflammatory effect of ramelteon in patients with insomnia associated with lower urinary tract symptoms. Research and Reports in Urology. 2013; 5: 113.
30. 30. Babaee A, Eftekhar-Vaghefi SH, Asadi-Shekaari M, Shahrokhi N, Soltani SD, Malekpour-Afshar R, Basiri M. Melatonin treatment reduces astrogliosis and apoptosis in rats with traumatic brain injury. Iranian journal of basic medical sciences. 2015; 18(9): 867.
31. 31. Motaghinejad M, Motaghinejad O, Hosseini P. Attenuation of morphine physical dependence and blood levels of cortisol by central and systemic administration of ramelteon in rat. Iranian Journal of Medical Sciences. 2015; 40(3): 240.
32. 32. Uchinaka A, Kawashima Y, Sano Y, Ito S, Sano Y, Nagasawa K, Nagata K. Effects of ramelteon on cardiac injury and adipose tissue pathology in rats with metabolic syndrome. Annals of the New York Academy of Sciences. 2018; 1421(1): 73-87.
33. 33. Cao C, Gao T, Cheng M, Xi F, Zhao C, Yu W. Mild hypothermia ameliorates muscle wasting in septic rats associated with hypothalamic AMPK-induced autophagy and neuropeptides. Biochemical and Biophysical Research Communications. 2017; 490(3): 882-888.
34. 34. Savran M, Aslankoç R, Ozmen O, Erzurumlu Y, Savas H B, Temel EN, Boztepe, S. Agomelatine could prevent brain and cerebellum injury against LPS-induced neuroinflammation in rats. Cytokine. 2020; 127: 154957.
35. 35. Stroethoff M, Christoph I, Behmenburg F, Raupach A, Bunte S, Senpolat S, Huhn R. Melatonin receptor agonist ramelteon reduces ischemia-reperfusion injury through activation of mitochondrial potassium channels. Journal of Cardiovascular Pharmacology. 2018; 72(2): 106-111.
36. 36. Vesna J, Danica J, Kamil K, Viktorija DS, Silva D, Sanja T, Aleksandar D. Effects of fullerenol nanoparticles and amifostine on radiation-induced tissue damages: Histopathological analysis. Journal of Applied Biomedicine. 2016; 14(4): 285-297.
37. 37. Chong DL, Sriskandan S. ro-inflammatory mechanisms in sepsis. Sepsis-Pro-Inflammatory and Anti-Inflammatory Responses. 2011; 17: 86-107.
38. 38. Nardocci G, Martin A, Abarzúa S, Rodríguez J, Simon F, Reyes EP, Fernández R. Sepsis progression to multiple organ dysfunction in carotid chemo/baro-denervated rats treated with lipopolysaccharide. Journal of Neuroimmunology. 2015; 278: 44-52.
39. 39. Li Y, Zhu H, Pan L, Zhang B, Che H. microRNA-103a-3p confers protection against lipopolysaccharide-induced sepsis and consequent multiple organ dysfunction syndrome by targeting HMGB1. Infection, Genetics and Evolution. 2021; 89: 104681.
40. 40. Liu YL, Hsu CC, Huang HJ, Chang CJ, Sun SH, Lin AMY. Gallic acid attenuated LPS-induced neuroinflammation: protein aggregation and necroptosis. Molecular neurobiology. 2020; 57(1): 96-104.
41. 41. Pérez-Nievas BG, Madrigal JL, García-Bueno B, Zoppi S, Leza JC. Corticosterone basal levels and vulnerability to LPS-induced neuroinflammation in the rat brain. Brain research. 2010; 1315: 159-168.
42. 42. Alam Q, Krishnamurthy S. Dihydroquercetin ameliorates LPS-induced neuroinflammation and memory deficit. Current Research in Pharmacology and Drug Discovery. 2022; 3: 100091.
43. 43. Olajide OA, Kumar A, Velagapudi R, Okorji UP, Fiebich BL. Punicalagin inhibits neuroinflammation in LPS‐activated rat primary microglia. Molecular nutrition & food research. 2014; 58(9): 1843-1851.
44. 44. Zhang F, Zhang JG, Yang W, Xu P, Xiao YL, Zhang HT. 6-Gingerol attenuates LPS-induced neuroinflammation and cognitive impairment partially via suppressing astrocyte overactivation. Biomedicine & Pharmacotherapy. 2018; 107: 1523-1529.
45. 45. De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Cipriani A. Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. The Lancet. 2022; 400(10347): 170-184.
46. 46. Peres MF, Masruha MR, Zukerman E, Moreira-Filho CA, Cavalheiro EA. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert opinion on investigational drugs. 2006; 15(4): 367-375.
47. 47. Stroethoff M, Goetze L, Torregroza C, Bunte S, Raupach A, Heinen A, Huhn R. The melatonin receptor agonist ramelteon induces cardioprotection that requires MT2 receptor activation and release of reactive oxygen species. Cardiovascular Drugs and Therapy. 2020; 34(3); 303-310.
48. 48. Zhang Y, Li X, Grailer JJ, Wang N, Wang M, Yao J, Li X. Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome. Journal of pineal research. 2016; 60(4): 405-414.
49. 49. Zhang XY, Xu ZP, Wang W, Cao JB, Fu Q, Zhao WX, Mi, WD. Vitamin C alleviates LPS-induced cognitive impairment in mice by suppressing neuroinflammation and oxidative stress. International immunopharmacology. 2018; 65: 438-447.
50. 50. Tyrtyshnaia AA, Lysenko LV, Madamba F, Manzhulo IV, Khotimchenko MY, Kleschevnikov AM. Acute neuroinflammation provokes intracellular acidification in mouse hippocampus. Journal of neuroinflammation. 2016; 13(1): 1-11.
51. 51. Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nature neuroscience. 2016; 19(1): 20-27.
52. 52. Zhang J, Shi X, Hao N, Chen Z, Wei L, Tan L, Zhu G. Simvastatin reduces neutrophils infiltration into brain parenchyma after intracerebral hemorrhage via regulating peripheral neutrophils apoptosis. Frontiers in neuroscience. 2018; 12: 977.
53. 53. Zhong Y, Zhang X, Hu X, Li Y. Effects of repeated lipopolysaccharide treatment on growth performance, immune organ index, and blood parameters of Sprague-Dawley rats. Journal of veterinary research. 2018; 62(3): 341-346.
54. 54. Zaki OS, Safar MM, Ain-Shoka AA, Rashed LA. Bone marrow mesenchymal stem cells combat lipopolysaccharide-induced sepsis in rats via amendment of P38-MAPK signaling cascade. Inflammation. 2018; 41(2): 541-554.
55. 55. Hwang SY, Shin TG, Jo IJ, Jeon K, Suh GY, Lee TR, Sim MS. Neutrophil-to-lymphocyte ratio as a prognostic marker in critically- ill septic patients. The American journal of emergency medicine. 2017; 35(2): 234-239.
56. 56. Brooks HF, Osabutey CK, Moss RF, Andrews PLR, Davies DC. Caecal ligation and puncture in the rat mimics the pathophysiological changes in human sepsis and causes multi-organ dysfunction. Metabolic brain disease. 2007; 22(3): 353-373.
57. 57. Huang HC, Tsai HJ. Wang CC, Tsao CM, Ka SM, Liaw WJ, Wu CC. Levosimendan mitigates coagulopathy and organ dysfunction in rats with endotoxemia. Journal of the Chinese Medical Association. 2017; 80(7): 432-441.
58. 58. Martins PS, Kallas EG, Neto MC, Dalboni MA, Blecher, S, Salomão R. Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. Shock. 2003; 20(3): 208-212.
59. 59. Power C, Fanning N, Redmond HP. Cellular apoptosis and organ injury in sepsis: a review. Shock. 2002; 18(3): 197-211.
60. 60. Kandezi N, Majdi F, Davoudizadeh R, Motaghinejad M, Safari S. Preventive Properties of Ramelteon against Cocaine-Induced Autophagia and Apoptosis: A Hypothetic Role of TNF-α Receptor Involvement and JNK/Bcl-2-Beclin1 or Bcl-2/Bax Signaling Pathway. International journal of preventive medicine. 2020; 11(3): 11-36.
61. 61. McKenna JT, Christie MA, Jeffrey BA, McCoy JG, Lee E, Connolly NP, Strecker RE. Chronic ramelteon treatment in a mouse model of Alzheimer’s disease. Archives italiennes de biologie., 2012; 150(1): 5.