The beneficial effects of riluzole on GFAP and iNOS expression in intrahippocampal Aβ rat model of Alzheimer’s disease

Document Type : Research Paper



2 TUMS, Tehran, Iran

3 Shahed Univ.


Background and Objective: Alzheimer’s disease (AD) is a neurodegenerative disorder specified by deposition of b-amyloid (Ab) and neuronal loss that leads to learning and memory disturbances. One of the most important causes of AD is glutamate-dependent excitotoxicity in brain regions that is vulnerable to AD. According to previous reported results, it was revealed that riluzole, as a glutamate release inhibitor, could improve learning and memory in an experimental model of AD. The aim of this study was to determine the effects of riluzole on Hippocampal astrogliosis and amyloidosis in a rat model of AD.
Materials and Methods: In the present study, the effects of riluzole administration at a dose of 10 mg/kg/day p.o. on hippocampal glial fibrillary acid protein (GFAP) as an astrogliosis marker and inducible nitric oxide synthase (iNOS) level in Ab (25-35)-injected rats was evaluated.
Results: The results showed that in Ab (25–35)-injected rats, the intrahippocampal GFAP (p Conclusion: This study indicates that in rat model of AD, riluzole is able to attenuate NO synthesis with reducing hippocampal iNOS level, probably through inhibition of glutamatergic signaling pathway.


1. Stuchbury G, Münch G. Alzheimer's associated inflammation, potential drug targets and future therapies. Journal of Neural Transmission 2005; 112(3):429-53.
2. Jellinger KA, Attems J. Prevalence of dementia disorders in the oldestold: An autopsy study. Acta Neuropathologica 2010; 119(4): 421–433.
3. Shah RS, Lee HG, Xiongwei Z, Perry G, Smith MA, Castellani RJ. Current approaches in the treatment of Alzheimer's disease. Biomedicine and Pharmacotherapy 2008; 62(4):199-207.
4. Munch G, Schinzel R, Loske C, Wong A, Durany N, Li JJ, et al. (1998). Alzheimer’s disease-synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. Journal of Neural Transmission 1998; 105: 439-461.
5. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Medicine 2008; 14(8):837-42.
6. De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, et al. Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proceedings of the National Academy of Sciences of the United States of America 2009; 106(6):1971-6.
7. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. Journal of Neuroscience 2007; 27: 796-807.
8. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416: 535-539.
9. Bennett MR. The concept of long term potentiation of transmission at synapses. Progress in Neurobiology 2000; 60: 109-137.
10. Klegeris A, McGeer EG, McGeer PL. Therapeutic approaches to inflammation in neurodegenerative disease. Current Opinion in Neurology 2007; 20: 351-357.
11. Heneka MT, Feinstein DL. Expression and function of inducible nitric oxide synthase in neurons. Journal of Neuroimmunology 2001; 114: 8-18.
12. Bal-Price A, Brown GC. Inflammatory neurodegeneration mediated by nitric oxide from activated glia, inhibiting neuronal respiration, causing glutamate release and excitoxicity. Journal of Neuroscience 2001; 21: 6480-6491.
13. Jekabsone A, Neher J, Borutaite V, Brown GC. Nitric oxide from neuronal nitric oxide synthase sensitises neurons to hypoxiainduced death via competitive inhibition of cytochrome oxidase. Journal of Neurochemistry 2007; 103: 346-356.
14. Cao YJ, Dreixler JC, Couey JJ, Houamed KM. Modulation of recombinant and native neuronal SK channels by the neuroprotective drug riluzole. European Journal of Pharmacology 2002; 449:47-54.
15. Azbill RD, Mu X, Springer JE. Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Research 2000; 871:175–80.
16. Sohanaki H, Baluchnejadmojarad T, Nikbakht F, Roghani M. Pelargonidin improves memory deficit in amyloid beta25-35 rat model of Alzheimer's disease by inhibition of glial activation, cholinesterase, and oxidative stress. Biomedicine & pharmacotherapy 2016; 83: 85–91.
17. Verhave PS, Jongsma MJ, Van Den Berg RM, Vanwersch RA, Smit AB, Philippens IH. Neuroprotective effects of riluzole in early phase Parkinson's disease on clinically relevant parameters in the marmoset MPTP model, Neuropharmacology 2012; 62 (4): 1700–1707.
18. Lonart G, Wang J, Johnson KM. Nitric oxide induces neurotransmitter release from hippocampal slices. European Journal of Pharmacology 1992; 220: 271–272.
19. Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nature reviews. Neuroscience 2007; 8: 766–775.
20. Stepanichev MY, Onufriev MV, Yakovlev AA, Khrenov AI, Peregud DI, Vorontsova ON, et al. Amyloid-beta (25–35) increases activity of neuronal NO-synthase in rat brain. Neurochemistry International 2008; 52, 1114–1124.
21. Valles SL, Dolz-Gaiton P, Gambini J, Borras C, Lloret A, Pallardo FV, et al. Estradiol or genistein prevent Alzheimer's disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes. Brain Research 2010; 1312: 138–144.
22. Scuderi C, Esposito G, Blasio A, Valenza M, Arietti P, Steardo L Jr, et al. Palmitoylethanolamide counteracts reactive astrogliosis induced by beta-amyloid peptide, Journal of Cellular and Molecular Medicine 2011; 15 (12): 2664–2674.
23. Chhor V, Le Charpentier T, Lebon S, Oré MV, Celador IL, Josserand J, et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behavior and Immunity 2013; 32: 70–85.
24. Chao CC, Hu S, Ehrlich, L, Peterson PK. Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behavior and Immunity 1995; 9: 355–365.
25. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathology 2010; 119: 7–35.
26. Wyss-Coray, T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nature Medicine 2003; 9: 453–457.
27. Perez JL, Carrero I, Gonzalo P, Arevalo-Serrano J, Sanz-Anquela JM, Ortega J, et al. Soluble oligomeric forms of beta-amyloid (Abeta) peptide stimulate Abeta production via astrogliosis in the rat brain. Experimental Neurology 2010; 223: 410–421.
28. Dewachter I, Van Dorpe J, Spittaels K, Tesseur I, Van Den Haute C, Moechars D, et al. Modeling Alzheimer’s disease in transgenic mice: effect of age and of presenilin1 on amyloid biochemistry and pathology in APP/London mice, Experimental Gerontology 2000; 35: 831–841.
29. Olney JW, Price MT, Samson L, Labruyere J. The role of specific ions in glutamate neurotoxicity. Neuroscience letters 1986; 65: 65-71.
30. W. Danysz, C.G. Parsons, I. Bresink, G. Quack, Glutamate in CNS T. Nishikawa, H. Niigawa, T. Nishimura, Temporal and regional disorders, Drugs News and Perspectives 1995; 8: 261–277.
31. Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, Quack G. Neuroprotection by memantine against neurodegeneration induced by β-amyloid(1–40). Brain Research 2002; 958: 210–221.
32. Danbolt NC. Glutamate uptake. Progress in Neurobiology 2001; 65(1):1-105.
33. Pereira AC, Gray JD, Kogan JF, Davidson RL, Rubin TG, Okamoto M, et al. Age and Alzheimer's disease gene expression profiles reversed by the glutamate modulator riluzole. Molecular Psychiatry 2017; 22(2):296-305.
34. Hunsberger HC, Hickman JE, Reed MN. Riluzole rescues alterations in rapid glutamate transients in the hippocampus of rTg4510 mice. Metabolic Brain Disease 2016; 31(3):711-5.
35. Wu Y, Satkunendrarajah K, Teng Y, Chow DS, Buttigieg J, Fehlings MG. Delayed post-injury administration of riluzole is neuroprotective in a preclinicalrodent model of cervical spinal cord injury. Journal of Neurotrauma 2013; 30(6): 441–452.
36. Mokhtari Z, Baluchnejadmojarad T, Nikbakht F, Mansouri M, Roghani M. Riluzole ameliorates learning and memory deficits in Ab25-35- induced rat model of Alzheimer’s disease and is independent of cholinoceptor activation. Biomedicine and Pharmacotherapy 2017; 87: 135–144.