Edaravone ameliorates memory, hippocampal morphology, and inflammation in a rat model of Alzheimer’s disease

Year 2023, Volume: 9 Issue: 3, 288 - 295, 30.09.2023

Şeyma Özsoy , Elif Azize Özşahin Delibaş , Gürkan Yiğittürk

Abstract

Oxidative stress and neural inflammation play a role in the pathogenesis of Alzheimer's disease (AD). Edaravone (EDA) has an antioxidant-free radical scavenger property. The purpose of this study to evaluate the effect of EDA on memory, hippocampal morphology, and inflammation in a streptozocin (STZ)-induced AD model. This study used 18 Wistar albino adult rats, weighing 200-220 g. Following general anesthesia, 3 mg/kg STZ was dissolved in 0.9% NaCl and administered intracerebroventricularly (ICV) in both lateral ventricles to 12 rats in a total of 5 µl. The animals were allowed to recover for two weeks and then divided into two groups. Six rats were given 0.9% NaCl i.p. for 15 days, and the other six were administered EDA 40 mg/kg i.p. for 15 days, once a day. The control group of six rats did not undergo any surgical procedures or medications. After treatment, a passive avoidance learning (PAL) test was used, followed by the removal of the brain tissue in all animals. Nissl staining was used to count neurons in the hippocampal CA1 and CA3 regions, and TNF-α and IL-6 levels in the brain were measured. In the STZ group, significantly shorter latency time, and decreased number of neurons in the CA1 and CA3 hippocampal regions compared to the control group were observed. EDA significantly prolonged the latency time and increased hippocampal CA1 and CA3 neuron counts compared to the STZ group. TNF-α and IL-6 levels were higher in the STZ+saline group than in the control group. Similarly, EDA treatment reduced TNF-α and IL-6 levels when compared to the STZ+saline and control groups. For the first time, we demonstrated the neuroprotective and anti-inflammatory potential of EDA in an experimental AD model. Our results may provide evidence for EDA therapy in addition to the standard regimen in patients with cognitive decline.

Keywords

Alzheimer, Edaravone, streptozotocin, memory, inflammation

References

• [1] Chan, S. W. C. (2011). Family caregiving in dementia: the asian perspective of a global problem. Dementia and Geriatric Cognitive Disorders. 30(6):469-478. DOI: 10.1159/000322086
• [2] Khan, S., Barve, K. H., & Kumar, M. S. (2020). Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease. Curr Neuropharmacol. 18(11):1106-1125. DOI: 10.2174/1570159X18666200528142429.
• [3] Lashley, T., Schott, J.M., Weston, P., Murray, C.E., Wellington, H., Keshavan, A., Foti, S. C., Foiani, M., Toombs, J., Rohrer, J.D., Heslegrave, A., & Zetterberg, H. (2018). Molecular biomarkers of Alzheimer's disease: progress and prospects. Dis Model Mech. 2018; 11(5):dmm031781. DOI: 10.1242/dmm.031781.
• [4] Martins, R. N., Villemagne, V., Sohrabi, H. R., Chatterjee, P., Shah, T.M., Verdile, et al. (2018). Alzheimer’s disease: a journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies-gains from AIBL and DIAN cohort studies. J. Alzheimers Dis. 62:965-992. DOI: 10.3233/JAD-171145.
• [5] Yamazaki, D., Horiuchi, J., Ueno, K., Ueno, T., Saeki, S., Matsuno, M., Naganos, S., et al. (2014). Glial dysfunction causes age-related memory impairment in Drosophila. Neuron. 84(4):753-763. DOI:10.1016/j.neuron.2014.09.039.
• [6] Han, B. H., Zhou, M. L., Johnson, A. W., Singh, I., Liao, F., Vellimana, A. K., et al. (2015). Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proc Natl Acad Sci USA. 112(8):E881-90. DOI: 10.1073/pnas.1414930112.
• [7] Cameron, B., & Landreth, G. E. (2010). Inflammation, microglia and Alzheimer's disease. Neurobiol Dis. 37(3):503-509. DOI: 10.1016/j.nbd.2009.10.006.
• [8] Wang, W. Y., Tan, M. S., Yu, J. T., & Tan, L. (2015). Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 3(10):136. DOI: 10.3978/j.issn.2305-5839.2015.03.49.
• [9] Watanabe, K., Tanaka, M., Yuki, S., Hirai, M., & Yamamoto, Y. (2018). How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J Clin Biochem Nutr. 62(1):20-38. DOI: 10.3164/jcbn.17-62.
• [10] Higashi, Y., Jitsuiki, D., Chayama, K., & Yoshizumi, M. (2006). Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger for treatment of cardiovascular diseases. Recent Pat Cardiovasc Drug Discov. 1(1):85-93. DOI: 10.2174/157489006775244191.
• [11] Dang, R., Wang, M., Li, X., Wang, H., Liu, L., Wu, Q., Zhao, J., Ji, P., Zhong, L., Licinio, J., & Xie, P. (2022). Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. J Neuroinflammation. 19(1):41. DOI: 10.1186/s12974-022-02400-6.
• [12] Liu, J., Jiang, Y., Zhang, G., Lin, Z., & Du, S. (2019). Protective effect of edaravone on blood-brain barrier by affecting NRF-2/HO-1 signaling pathway. Exp Ther Med. 18(4):2437-2442. DOI: 10.3892/etm.2019.7859.
• [13] Okuyama, S., Morita, M., Sawamoto, A., Terugo, T., Nakajima, M., & Furukawa, Y. (2015). Edaravone enhances brain-derived neurotrophic factor production in the ischemic mouse brain. Pharmaceuticals (Basel, Switzerland). 8:176-185. DOI: 10.3390/ph8020176.
• [14] Kraus, R. L., Pasieczny, R., Lariosa-Willingham, K., Turner, M. S., Jiang, A., & Trauger, J. W. (2005). Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem. 94:819-27. DOI: 10.1111/j.1471-4159.2005.03219.x.
• [15] Miyamoto, N., Maki, T., Pham, L. D., Hayakawa, K., Seo, J. H., Mandeville, E. T., Mandeville, J. B., Kim, K. W., Lo, E. H., & Arai, K. (2013). Oxidative stress interferes with white matter renewal after prolonged cerebral hypoperfusion in mice. Stroke. 44:3516-321. DOI: 10.1161/STROKEAHA.113.002813.
• [16] Yuan, Y., Zha, H., Rangarajan, P., Ling, E. A., & Wu, C. (2014). Anti-inflammatory effects of Edaravone and Scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia. BMC Neurosci. 15:125. DOI: 10.1186/s12868-014-0125-3.
• [17] Lu, Y., Dong, Y., Tucker, D., Wang, R., Ahmed, M. E., Brann, D., & Zhang, Q. (2017). Treadmill Exercise Exerts Neuroprotection and Regulates Microglial Polarization and Oxidative Stress in a Streptozotocin-Induced Rat Model of Sporadic Alzheimer’s Disease. J Alzheimers Dis. 56(4):1469-1484. DOI: 10.3233/JAD-160869.
• [18] Salkovic-Petrisic, M., & Hoyer, S. (2007). Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: An experimental approach. J Neural Transm Suppl. 72:217-233. DOI: 10.1007/978-3-211-73574-9_28.
• [19] Paxinos, G., & Watson, C. (1998). The rat brain in stereotaxic coordinates. Spiral Bound, 4th ed. New York: Academic Press.
• [20] Elibol, B., Terzioglu-Usak, S., Beker, M., & Sahbaz, C. (2019). Thymoquinone (TQ) demonstrates its neuroprotective effect via an anti-inflammatory action on the Aβ(1–42)-infused rat model of Alzheimer's disease. Psychiatry and Clinical Psychopharmacology. 29:379-386. DOI: 10.1080/24750573.2019.1673945.
• [21] Moreira, P. I., Duarte, A. I., Santos, M. S., Rego, A. C., & Oliveira, C. R. (2009). An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer's disease. J Alzheimers Dis. 16(4):741-61. DOI: 10.3233/JAD-2009-0972.
• [22] Gómez-Ramos, A., Díaz-Nido, J., Smith, M. A., Perry, G., & Avila, J. (2003). Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells. J Neurosci Res. 71:863-870. DOI: 10.1002/jnr.10525.
• [23] Sonnen, J. A., Breitner, J. C., Lovell, M. A., Markesbery, W. R., Quinn, J. F., & Montine, T. J. (2008). Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models. Free Radic Biol Med. 45(3):219-230. DOI: 10.1016/j.freeradbiomed.2008.04.022.
• [24] Lee, Y. J., Han, S. B., Nam, S. Y., Oh, K. W., & Hong, J. T. (2010). Inflammation and Alzheimer's disease. Arch Pharm Res. 33:1539-1556. DOI: 10.1007/s12272-010-1006-7.
• [25] Chen, Z., & Zhong, C. (2014). Oxidative stress in Alzheimer's disease. Neurosci Bull. 30(2):271-81. DOI: 10.1007/s12264-013-1423-y.
• [26] Greenough, M. A., Camakaris, J., & Bush, A. I. (2013). Metal dyshomeostasis and oxidative stress in Alzheimer's disease. Neurochem Int. 62(5):540-555. DOI: 10.1016/j.neuint.2012.08.014.
• [27] Dias-Santagata, D., Fulga, T. A., Duttaroy, A., & Feany, M. B. (2007). Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest. 117:236-245. DOI: 10.1172/JCI28769.
• [28] Yan, M. H., Wang, X., & Zhu, X. (2013). Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med. 62:90-101. DOI: 10.1016/j.freeradbiomed.2012.11.014.
• [29] Butterfield, D. A., & Lauderback, C. M. (2002). Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic. Biol. Med. 32(11):1050-106. DOI: 10.1016/s0891-5849(02)00794-3.
• [30] Reed, T. T., Pierce, W. M., Markesbery, W. R., & Butterfield, D. A. (2009). Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD. Brain Res. 1274:66-76. DOI: 10.1016/j.brainres.2009.04.009.
• [31] Selkoe, D. J. (2002). Alzheimer's disease is a synaptic failure. Science. 298(5594):789-791. DOI: 10.1126/science.1074069.
• [32] Cheng, X., Yang, L., He, P., Li, R., & Shen, Y. (2010). Differential Activation of Tumor Necrosis Factor Receptors Distinguishes between Brains from Alzheimer’s Disease and Non-Demented Patients. J Alzheimers Dis. 19(2):621-630. DOI: 10.3233/JAD-2010-1253.
• [33] Cevik, B., Solmaz, V., Yigitturk, G., Cavusoğlu, T., Peker, G., & Erbas, O. (2017). Neuroprotective effects of erythropoietin on Alzheimer's dementia model in rats. Adv Clin Exp Med. 26(1):23-29. DOI: 10.17219/acem/61044.
• [34] Montgomery, S. L., & Bowers, W. J. (2012). Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol. 7:42-49. DOI: 10.1007/s11481-011-9287-2.
• [35] Tarkowski, E., Liljeroth, A. M., Minthon, L., Tarkowski, A., Wallin, A., & Blennow, K. (2003). Cerebral pattern of pro-and anti-inflammatory cytokines in dementias. Brain Res Bull. 61(3):255-260. DOI: 10.1016/s0361-9230(03)00088-1.
• [36] Erta, M., Quintana, A., & Hidalgo, J. (2012). Interleukin-6, a Major Cytokine in the Central Nervous System. Int J Biol. Sci. 8:1254-1266. DOI: 10.7150/ijbs.4679.
• [37] Vallières, L., Campbell, I. L., Gage, F. H., & Sawchenko, P. E. (2002). Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J. Neurosci. 22:486-492. DOI: 10.1523/JNEUROSCI.22-02-00486.2002.
• [38] Lyra, E., Silva, N. M., Goncalves, R. A., Pascoal, T. A., Lima-Filho, R. A. S., Resende, et al. (2021). Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer’s disease. Translational Psychiatry. 11:251. DOI: 10.1038/s41398-021-01349-z.
• [39] Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. et al. (2000). Inflammation and Alzheimer's disease. Neurobiol Aging. 21(3):383-421. DOI: 10.1016/s0197-4580(00)00124-x.
• [40] Brosseron, F., Krauthausen, M., Kummer, M., & Heneka, M. T. (2014). Body fluid cytokine levels in mild cognitive impairment and Alzheimer's disease: a comparative overview. Mol Neurobiol. 50(2):534-44. DOI: 10.1007/s12035-014-8657-1.
• [41] Cruz, M. P. (2018). Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis. P T. 43(1):25-28.
• [42] Wang, G., Zeng, X., Gong, S., Wang, S., Ge, A., Liu, W., Ge, J., & He, Q. (2022). Exploring the Mechanism of Edaravone for Oxidative Stress in Rats with Cerebral Infarction Based on Quantitative Proteomics Technology. Evid Based Complement Alternat Med. 2022:8653697. DOI: 10.1155/2022/8653697.
• [43] Ito, H., Wate, R., Zhang, J., Ohnishi, S., Kaneko, S., Ito, H., Nakano, S., & Kusaka, H. (2008). Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol. 213(2):448-55. DOI: 10.1016/j.expneurol.2008.07.017.
• [44] Saberi, S., Stauffer, J. E., Schulte, D. J., & Ravits, J. (2015). Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants. Neurol Clin. 33:855-876. DOI: 10.1016/j.ncl.2015.07.012.
• [45] Ahmadinejad, F., Geir Møller, S., Hashemzadeh-Chaleshtori, M., Bidkhori, G., & Jami, M. S. (2017). Molecular Mechanisms behind Free Radical Scavengers Function against Oxidative Stress. Antioxidants. 6(3):51. DOI: 10.3390/antiox6030051.
• [46] Wu, S., Sena, E., Egan, K., Macleod, M., & Mead, G. (2014). Edaravone improves functional and structural outcomes in animal models of focal cerebral ischemia: a systematic review. Int J Stroke. 9(1):101-6. DOI: 10.1111/ijs.12163.
• [47] Yang, J., Cui, X., Li, J., Zhang, C., Zhang, J., & Liu, M. (2015). Edaravone for acute stroke: Meta-analyses of data from randomized controlled trials. Dev Neurorehabil. 18(5):330-335. DOI: 10.3109/17518423.2013.830153.
• [48] Xiong, N., Xiong, J., Khare, G., Chen, C., Huang, J., Zhao, Y., Zhang, Z., Qiao, X., Feng, Y., Reesaul, H., Zhang, Y., Sun, S., Lin, Z., & Wang, T. (2011). Edaravone guards dopamine neurons in a rotenone model for Parkinson's disease. PLoS One. 6(6):e20677. DOI: 10.1371/journal.pone.0020677.
• [49] Wu, C. Y., Zha, H., Xia, Q. Q., Yuan, Y., Liang, X. Y., Li, J. H., Guo, Z. Y., & Li, J. J. (2013). Expression of angiotensin II and its receptors in activated microglia in experimentally induced cerebral ischemia in the adult rats. Mol Cell Biochem. 382(1-2):47-58. DOI: 10.1007/s11010-013-1717-4.
• [50] Fujiwara, N., Som, A. T., Pham, L. D., Lee, B. J., Mandeville, E. T., Lo, E. H., & Arai, K. (2016). A free radical scavenger edaravone suppresses systemic inflammatory responses in a rat transient focal ischemia model. Neurosci Lett. 633:7-13. DOI: 10.1016/j.neulet.2016.08.048.