Abstract
In this study, we explored the possible mechanisms underlying the neuroprotective and anti-oxidative effects of N-adamantyl-4-methylthiazol-2-amine (KHG26693) against in vivo glutamate-induced toxicity in the rat cerebral cortex. Our results showed that pretreatment with KHG26693 significantly attenuated glutamate-induced elevation of lipid peroxidation, tumor necrosis factor-α, interferon gamma, IFN-γ, interleukin-1β, nitric oxide, reactive oxygen species, NADPH oxidase, caspase-3, calpain activity, and Bax. Furthermore, KHG26693 pretreatment attenuated key antioxidant parameters such as levels of superoxide dismutase, catalase, glutathione, and glutathione reductase. KHG26693 also attenuated the protein levels of inducible nitric oxide synthase, neuronal nitric oxide synthase, nuclear factor erythroid 2-related factor 2, heme oxygenase-1, and glutamate cysteine ligase catalytic subunit caused by glutamate toxicity. Finally, KHG26693 mitigated glutamate-induced changes in mitochondrial ATP level and cytochrome oxidase c. Thus, KHG26693 functions as neuroprotective and anti-oxidative agent against glutamate-induced toxicity through its antioxidant and anti-inflammatory activities in rat brain at least in part.
Similar content being viewed by others
Abbreviations
- BAX:
-
Bcl-2 associated X protein
- CAT:
-
Catalase
- DCF-DA:
-
2′,7′-Dichlorofluorescin diacetate
- DMSO:
-
Dimethyl sulfoxide
- GCLC:
-
Glutamate cysteine ligase catalytic subunit
- GSH:
-
Reduced glutathione
- GR:
-
Glutathione reductase
- HO-1:
-
Heme oxygenase-1
- IFN-γ:
-
Interferon-γ
- IL-1β:
-
Interleukin-1β
- iNOS:
-
Inducible nitric oxide synthase
- MDA:
-
Malonyldialdehyde
- NO:
-
Nitric oxide
- nNOS:
-
Neuronal nitric oxide synthase
- NOX:
-
NADPH oxidase
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- PBS:
-
Phosphate-buffered saline
- ROS:
-
Reactive oxygen species
- SDS:
-
Sodium dodecyl sulfate
- SOD:
-
Superoxide dismutase
- TNF-α:
-
Tumor necrosis factor-α
References
Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126
Anzini M, Chelini A, Mancini A, Cappelli A, Frosini M, Ricci L, Valoti M, Magistretti J, Castelli L, Giordani A, Makovec F, Vomero S (2010) Synthesis and biological evaluation of amidine, guanidine, and thiourea derivatives of 2-amino(6-trifluoromethoxy) benzothiazole as neuroprotective agents potentially useful in brain diseases. J Med Chem 53:734–744
Babu GN, Kumar A, Singh RL (2011) Chronic pretreatment with acetyl-l-carnitine and ±DL-α-lipoic acid protects against acute glutamate-induced neurotoxicity in rat brain by altering mitochondrial function. Neurotox Res 19:319–329
Bano D, Young KW, Guerin CJ, Lefeuvre R, Rothwell NJ, Naldini L, Rizzuto R, Carafoli E, Nicotera P (2005) Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell 120:275–285
Bayir H, Kagan VE, Clark RS, Janesko-Feldman K, Rafikov R, Huang Z, Zhang X, Vagni V, Billiar TR, Kochanek PM (2007) Neuronal NOS-mediated nitration and inactivation of manganese superoxide dismutase in brain after experimental and human brain injury. J Neurochem 101:168–181
Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38:357–366
Belarbi K, Jopson T, Tweedie D, Arellano C, Luo W, Greig N, Rosi S (2012) TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflammation 9:23
Bhat NR, Zhang P, Lee JC, Hogan EL (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-α gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18:1633–1641
Castellani RJ, Lee HG, Zhu X, Perry G, Smith MA (2008) Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol 67:523–531
Chan KM, Delfert D, Junger KD (1989) A direct colorimetric assay for Ca+-stimulated ATPase activity. Anal Biochem 157:375–380
Chaparro-Huerta V, Rivera-Cervantes MC, Flores-Soto ME, Go’mez-Pinedo U, Beas-Za’rate C (2005) J Neuroimmunol 165:53–62
Chaparro-Huerta V, Flores-Soto ME, Gudiño-Cabrera G, Rivera-Cervantes MC, Bitzer-Quintero OK, Beas-Zárate C (2008) Role of p38 MAPK and proinflammatory cytokines expression in glutamate-induced neuronal death of neonatal rats. Int J Dev Neurosci 26:487–495
Cho CH, Kim J, Ahn JY, Hahn HG, Cho SW (2015) N-adamantyl-4-methylthiazol-2-amine suppresses lipopolysaccharide-induced brain inflammation by regulating NF-κB signaling in mice. J Neuroimmunol 289:98–104
Cho CH, Kim EA, Kim J, Choi SY, Yang SJ, Cho SW (2016) N-Adamantyl-4-methylthiazol-2-amine suppresses amyloid β-induced neuronal oxidative damage in cortical neurons. Free Rad Biol 50:678–690
Choi SH, Park BK, Lee KW, Chang J, Lee Y, Kwon HJ (2015) Effect of respiratory syncytial virus on the growth of hepatocellular carcinoma cell-lines. BMB Rep 48:565–570
Clark JB, Nicklas WJ (1970) The metabolism of rat brain mitochondria. Preparation and characterization J Biol Chem 245:4724–4731
Conrad M, Sato H (2012) The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-):cystine supplier and beyond. Amino Acids 42:231–246
Dawson VL, Dawson TM, Bartley DA, Uhl GR, Snyder SH (1993) Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. J Neurosci 13:2651–2661
El-Achkar GA, Jouni M, Mrad MF, Hirz T, El Hachem N, Khalaf A, Hammoud S, Fayyad-Kazan H, Eid AA, Badran B, Merhi RA, Hachem A, Hamade E, Habib A (2015) Thiazole derivatives as inhibitors of cyclooxygenases in vitro and in vivo. Eur J Pharmacol 750:66–73
Eom SA, Kim DW, Shin MJ, Ahn EH, Chung SY, Sohn EJ, Jo HS, Jeon SJ, Kim DS, Kwon HY, Cho SW, Han KH, Park J, Eum WS, Choi SY (2015) Protective effects of PEP-1-catalase on stress-induced cellular toxicity and MPTP-induced Parkinson’s disease. BMB Rep 48:395–400
Fumagalli E, Funicello M, Rauen T, Gobbi M, Mennini T (2008) Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol 578:171–176
Gallardo-Godoy A, Gever J, Fife KL, Silber BM, Prusiner SB, Renslo AR (2011) 2-Aminothiazoles as therapeutic leads for prion diseases. J Med Chem 54:1010–1021
García O, Massieu L (2003) Glutamate uptake inhibitor L-trans-pyrrolidine 2,4-dicarboxylate becomes neurotoxic in the presence of subthreshold concentrations of mitochondrial toxin 3-nitropropionate: involvement of mitochondrial reducing activity and ATP production. J Neurosci Res 74:956–966
Geronikaki AA, Pitta EP, Liaras KS (2013) Thiazoles and thiazolidinones as antioxidants. Curr Med Chem 20:4460–4480
Gribkoff VK, Bozik ME (2008) KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis. CNS Neurosci Ther 14:215–226
Guemez-Gamboa A, Estrada-Sánchez AM, Montiel T, Páramo B, Massieu L, Morán J (2011) Activation of NOX2 by the stimulation of ionotropic and metabotropic glutamate receptors contributes to glutamate neurotoxicity in vivo through the production of reactive oxygen species and calpain activation. J Neuropathol Exp Neurol 70:1020–1035
Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658
Havsteen BH (2002) The biochemistry and medical significance of the flavonoids. Pharmacol Ther 96:67–202
Hirata Y, Yamamoto H, Atta MS, Mahmoud S, Oh-hashi K, Kiuchi K (2001) Chloroquine inhibits glutamate-induced death of a neuronal cell line by reducing reactive oxygen species through sigma-1 receptor. J Neurochem 119:839–847
Hosseini A, Sadeghnia HR, Rajabian A (2016) Protective effects of peel and seed extracts of Citrus aurantium on glutamate-induced cytotoxicity in PC12 cell line. Folia Neuropathol 54:262–272
Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275:16023–16029
Jo HS, Yeo HJ, Cha HJ, Kim SJ, Cho SB, Park JH, Lee CH, Yeo EJ, Choi YJ, Eum WS, Choi SY (2016) Transduced Tat-DJ-1 protein inhibits cytokines-induced pancreatic RINm5F cell death. BMB Rep 49:297–302
Ju SM, Youn GS, Cho YS, Choi SY, Park J (2015) Celastrol ameliorates cytokine toxicity and pro-inflammatory immune responses by suppressing NF-κB activation in RINm5F beta cells. BMB Rep 48:172–177
Jourdi H, Yanagihara T, Martinez U, Bi X, Lynch G, Baudry M (2005) Effects of positive AMPA receptor modulators on calpain-mediated spectrin degradation in cultured hippocampal slices. Neurochem Int 46:31–40
Kalia LV, Kalia SK, Salter MW (2008) NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol 7:742–755
Kaplan JH (2002) Biochemistry of Na+, K+-ATPase. Annu Rev Biochem 71:511–535
Kaspar JW, Niture SK, Jaiswal AK (2009) Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med 47:1304–1309
Kim EA, Hahn HG, Kim KS, Kim TU, Choi SY, Cho SW (2010) Suppression of glutamate-induced excitotoxicity by 2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride in rat glial cultures. Cell Mol Neurobiol 30:807–815
Kim EA, Han AR, Choi J, Ahn JY, Choi SY, Cho SW (2014) Anti-inflammatory mechanisms of N-adamantyl-4-methylthiazol-2-amine in lipopolysaccharide-stimulated BV-2 microglial cells. Int Immunopharmacol 22:73–83
Kim H, Youn GS, An SY, Kwon HY, Choi SY, Park J (2016) 2,3-Dimethoxy-2′-hydroxychalcone ameliorates TNF-α-induced ICAM-1 expression and subsequent monocyte adhesiveness via NF-kappaB inhibition and HO-1 induction in HaCaT cells. BMB Rep 49:57–62
Kim S, Kim HY, Kim JH, Choi JH, Ham WK, Jeon YJ, Kang H, Kim TY (2015) Enhancement of potency and stability of human extracellular superoxide dismutase. BMB Rep 48:91–96
Kirkland RA, Saavedra GM, Cummings BS, Franklin JL (2010) Bax regulates production of superoxide in both apoptotic and nonapoptotic neurons: role of caspases. J Neurosci 30:16114–16127
Korhonen R, Lahti A, Kankaanranta H, Moilanen E (2005) Nitric oxide production and signalling in inflammation. Curr Drug Targets Inflamm Allergy 4:471–479
Kumar A, Singh RL, Babu GN (2010) Cell death mechanisms in the early stages of acute glutamate neurotoxicity. Neurosci Res 66:271–278
Kunwar A, Sandur SK, Krishna M, Priyadarsini KI (2009) Curcumin mediates time and concentration dependent regulation of redox homeostasis leading to cytotoxicity in macrophage cells. Eur J Pharmacol 611:8–16
Lebrun-Julien F, Duplan L, Pernet V, Osswald I, Sapieha P, Bourgeois P, Dickson K, Bowie D, Barker PA, Di Polo A (2009) Excitotoxic death of retinal neurons in vivo occurs via a non-cell-autonomous mechanism. J Neurosci 29:5536–5545
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489
Li Z, Silber BM, Rao S, Gever JR, Bryant C, Gallardo-Godoy A, Dolghih E, Widjaja K, Elepano M, Jacobson MP, Prusiner SB, Renslo AR (2013) 2-Aminothiazoles with improved pharmacotherapeutic properties for treatment of prion disease. Chem Med Chem 8:847–857
Lombardi G, Varsaldi F, Miglio G, Papini MG, Battaglia A, Canonico PL (2002) Cabergoline prevents necrotic neuronal death in an in vitro model of oxidative stress. Eur J Pharmacol 457:95–99
Ma S, Liu H, Jiao H, Wang L, Chen L, Liang J, Zhao M, Zhang X (2012) Neuroprotective effect of ginkgolide K on glutamate-induced cytotoxicity in PC 12 cells via inhibition of ROS generation and Ca2+ influx. Neurotoxicol 33:59–69
Manucha W (2007) Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity. Clin Investig Arterioscler 75:275–282
Margaill I, Plotkine M, Lerouet D (2005) Antioxidant strategies in the treatment of stroke. Free Radic Biol Med 39:429–443
Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147
Mizuno T, Zhang G, Takeuchi H, Kawanokuchi J, Wang J, Sonobe Y, ** S, Takada N, Komatsu Y, Suzumura A (2008) Interferon gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPAGluR1 receptor. FASEB J 22:1797–1806
Murotomi K, Takagi N, Takeo S, Tanonaka K (2011) NADPH oxidase-mediated oxidative damage to proteins in the postsynaptic density after transient cerebral ischemia and reperfusion. Mol Cell Neurosci 46:681–688
Nasr P, Gursahani HI, Pang Z, Bondada V, Lee J, Hadley RW, Geddes JW (2003) Influence of cytosolic and mitochondrial Ca2+, ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid. Neurochem Int 43:89–99
Niture SK, Kaspar JW, Shen J, Jaiswal AK (2010) Nrf2 signaling and cell survival. Toxicol Appl Pharmacol 244:37–42
Olney JW (2003) Excitotoxicity, apoptosis and neuropsychiatric disorders. Curr Opin Pharmacol 3:101–109
Pang Z, Geddes JW (1997) Mechanisms of cell death induced by the mitochondrial toxin 3-nitropropionic acid: acute excitotoxic necrosis and delayed apoptosis. J Neurosci 17:3064–3073
Patel M, Day BJ, Crapo JD, Fridovich I, McNamara JO (1996) Requirement for superoxide in excitotoxic cell death. Neuron 16:345–355
Pestana RR, Kinjo ER, Hernandes MS, Britto LR (2010) Reactive oxygen species generated by NADPH oxidase are involved in neurodegeneration in the pilocarpine model of temporal lobe epilepsy. Neurosci Lett 484:187–191
Petros AM, Olejniczak ET, Fesik SW (2004) Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta 1644:83–94
Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci U S A 94:10925–10930
Qureshi GA, Baig S, Sarwar M, Parvez SH (2004) Neurotoxicity, oxidative stress and cerebrovascular disorders. Neurotoxicology 25:121–138
Racker E (1955) Glutathione reductase from bakers’ yeast and beef liver. J Biol Chem 217:855–865
Raghupathi R, Strauss KI, Zhang C, Krajewski S, Reed JC, McIntosh TK (2003) Temporal alterations in cellular Bax:Bcl-2 ratio following traumatic brain injury in the rat. J Neurotrauma 20:421–435
Reznick AZ, Kagan VE, Ramsey R, Tsuchiya M, Khwaja S, Serbinova EA, Packer L (1992) Antioxidant effects I Lpropionyl carnitine protection of the heart against ischemia–reperfusion injury: the possible role of iron chelation. Arch Biochem Biophys 296:394–401
Río PD, Massieu L (2008) Mild mitochondrial inhibition in vivo enhances glutamate-induced neuronal damage through calpain but not caspase activation: role of ionotropic glutamate receptors. Exp Neurol 212:179–188
Satoh A, Nagatomi Y, Hirata Y, Ito S, Suzuki G, Kimura T, Maehara S, Hikichi H, Satow A, Hata M, Ohta H, Kawamoto H (2009) Discovery and in vitro and in vivo profiles of 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide as novel class of an orally active metabotropic glutamate receptor 1 (mGluR1) antagonist. Bioorg Med Chem Lett 19:5464–5468
Schreibelt G, van Horssen J, van Rossum S, Dijkstra CD, Drukarch B, de Vries HE (2007) Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology. Brain Res Rev 56:322–330
Shahani N, Sawa A (2011) Nitric oxide signaling and nitrosative stress in neurons: role for S-nitrosylation. Antioxid Redox Signal 14:1493–1504
Smith T, Groom A, Zhu B, Turski L (2000) Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 6:62–66
Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM (2004) Decline in transcriptional activity of Nrf2 causes agerelated loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A 101:3381–3386
Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA, Swanson RA (2008) Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol 64:654–663
Takano J, Tomioka M, Tsubuki S, Higuchi M, Iwata N, Itohara S, Maki M, Saido TC (2005) Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains. J Biol Chem 280:16175–16184
Tejada-Simon MV, Serrano F, Villasana LE, Kanterewicz BI, Wu GY, Quinn MT, Klann E (2005) Synaptic localization of a functional NADPH oxidase in the mouse hippocampus. Mol Cell Neurosci 29:97–106
Tenneti L, Lipton SA (2000) Involvement of activated caspase-3-like proteases in N-methyl-D-aspartate-induced apoptosis in cerebrocortical neurons. J Neurochem 74:134–142
Tomioka M, Shirotani K, Iwata N, Lee HJ, Yang F, Cole GM, Seyama Y, Saido TC (2002) In vivo role of caspases in excitotoxic neuronal death: generation and analysis of transgenic mice expressing baculoviral caspase inhibitor, p35, in postnatal neurons. Mol Brain Res 108:18–32
Uddin GM, Kim CY, Chung D, Kim KA, Jung SH (2015) One-step isolation of sappanol and brazilin from Caesalpinia sappan and their effects on oxidative stress-induced retinal death. BMB Rep 48:289–294
Vámos E, Párdutz A, Varga H, Bohár Z, Tajti J, Fülöp F, Toldi J, Vécsei L (2009) l-kynurenine combined with probenecid and the novel synthetic kynurenic acid derivative attenuate nitroglycerin-induced nNOS in the rat caudal trigeminal nucleus. Neuropharmacology 57:425–429
Venters HD, Dantzer R, Kelley KW (2000) A new concept in neurodegeneration: TNFalpha is a silencer of survival signals. Trends Neurosci 23:175–180
Wang XQ, **ao AY, Sheline C, Hyrc K, Yang A, Goldberg MP, Choi DW, Yu SP (2003) Apoptotic insults impair Na+, K+-ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress. J Cell Sci 116:2099–2110
Wang XY, Yang HW (2016) Upregulation of CBS/H2S system contributes to asymmetric dimethylarginine-triggered protection against the neurotoxicity of glutamate to PC12 cells by inhibiting NOS/NO pathway. Exp Cell Res 346:111–118
Xu W, Wong TP, Chery N, Gaertner T, Wang YT, Baudry M (2007) Calpain-mediated mGluR1alpha truncation: a key step in excitotoxicity. Neuron 53:399–412
Yang SJ, Lee WJ, Kim EA, Nam KD, Hahn HG, Choi SY, Cho SW (2014) Effects of N-adamantyl-4-methylthiazol-2-amine on hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats. Eur J Pharmacol 736:26–34
Zhang Q, Ding M, Cao Z, Zhang J, Ding F, Ke K (2013) Pyrroloquinoline quinine protects rat brain cortex against acute glutamate-induced neurotoxicity. Neurochem Res 38:1661–1671
Zhang YM, Bhavnani BR (2005) Glutamate-induced apoptosis in primary cortical neurons is inhibited by equine estrogens via down-regulation of caspase-3 and prevention of mitochondrial cytochrome c release. BMC Neurosci 6:13
Zimmermann AK, Loucks FA, Schroeder EK, Bouchard RJ, Tyler KL, Linseman DA (2007) Glutathione binding to the Bcl-2 homology-3 domain groove: a molecular basis for antioxidant function at mitochondria. J Biol Chem 282:29296–29304
Acknowledgements
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A09056947 and 2015R1D1A3A01015793) and by a Student Research Grant from the University of Ulsan College of Medicine, Seoul, Korea.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All the experimental procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Asan Institute for Life Sciences, Asan Medical Center, which abides by the Institute of Laboratory Animal Resources guidelines.
Conflict of Interest
The authors declare that they have no competing interests.
Additional information
Seung-Ju Yang and Eun-A Kim contributed equally to this article.
Rights and permissions
About this article
Cite this article
Yang, SJ., Kim, EA., Chang, MJ. et al. N-Adamantyl-4-Methylthiazol-2-Amine Attenuates Glutamate-Induced Oxidative Stress and Inflammation in the Brain. Neurotox Res 32, 107–120 (2017). https://doi.org/10.1007/s12640-017-9717-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-017-9717-x