Abstract
The objective of the present study was to investigate the α7nAChR-mediated Nrf2-dependant protective activity against streptozotocin (STZ)-induced brain mitochondrial toxicity in Alzheimer’s disease (AD)-like rats. STZ (3 mg/kg) was injected through an intracerebroventricular route to induce AD-like dementia. Repeated Quercetin (50 mg/kg, i.p.) administration attenuated cognitive impairments in the STZ-challenged animals during Morris water-maze and Y-maze tests. Quercetin significantly mitigated the STZ-induced increase in cholinergic dysfunction, such as the increase in acetylcholinesterase activity, decrease in acetylcholine level, and activity of choline acetyltransferase, and increase in amyloid-beta aggregation and mitochondrial toxicity in respect of mitochondrial bioenergetics, integrity, and oxidative stress in memory-challenged rat hippocampus, prefrontal cortex and, amygdala. Further, Quercetin significantly attenuated STZ-induced reduction in the α7nAChRs and HO-1 expression levels in the selected rat brain regions. On the contrary, trigonelline (10 mg/kg, i.p.) and methyllycaconitine (2 mg/kg; i.p.) abolished the neuroprotective effects of Quercetin against STZ-induced behavioral, molecular, and biochemical alterations in the AD-like animals. Hence, Quercetin exhibits α7nAChR/Nrf2/HO-1-mediated neuroprotection against STZ-challenged AD-like animals. Thus, Quercetin could be considered as a potential therapeutic option in the management of AD.
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Abbreviations
- STZ:
-
Streptozotocin
- ICV:
-
Intracerebroventricular
- AcCoA:
-
Acetyl coenzyme A
- ChAT:
-
Choline acetyltransferase
- AChE:
-
Acetylcholinesterase
- α7nAChR:
-
Alpha7 nicotinic acetylcholine receptor
- APP:
-
Amyloid-beta precursor protein
- Aβ:
-
Amyloid beta
- MLA:
-
Methyllycaconitine
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- ROS:
-
Reactive oxygen species
References
Agrawal R, Mishra B, Tyagi E, Nath C, Shukla R (2010) Effect of curcumin on brain insulin receptors and memory functions in STZ (ICV) induced dementia model of rat. Pharmacol Res 61:247–252. https://doi.org/10.1016/j.phrs.2009.12.008
Ali T, Kim T, Rehman S, Khan MS, Amin F, Khan M, Ikram M, Kim MO (2018) Natural dietary supplementation of anthocyanins via PI3K/Akt/Nrf2/HO-1 pathways mitigate oxidative stress, neurodegeneration, and memory impairment in a mouse model of Alzheimer’s disease. Mol Neurobiol 55:6076–6093. https://doi.org/10.1007/s12035-017-0798-6
Alzheimer’s association (2015) Alzheimer’s disease facts and figures. Alzheimers Dement 11:332–384. https://doi.org/10.1016/j.jalz.2015.02.003
Anand P, Singh B (2013) A review on cholinesterase inhibitors for Alzheimer’s disease. Arch Pharm Res 36:375–399. https://doi.org/10.1007/s12272-013-0036-3
Ashrafpour M, Parsaei S, Sepehri H (2015) Quercetin improved spatial memory dysfunctions in rat model of intracerebroventricular streptozotocin-induced sporadic Alzheimer’s disease. Natl J Physiol Pharm Pharmacol 5:411–415. https://doi.org/10.5455/njppp.2015.5.2308201563
Beers RF Jr, Sizer IW (1952) A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem 195:133–140
Bertrand D, Lee CH, Flood D, Marger F, Donnelly-Roberts D (2015) Therapeutic potential of α7 nicotinic acetylcholine receptors. Pharmacol Rev 67:1025–1073. https://doi.org/10.1124/pr.113.008581
Bhutada P, Mundhada Y, Bansod K, Bhutada C, Tawari S, Dixit P, Mundhada D (2010) Ameliorative effect of quercetin on memory dysfunction in streptozotocin-induced diabetic rats. Neurobiol Learn Mem 94:293–302. https://doi.org/10.1016/j.nlm.2010.06.008
Boots AW, Haenen GR, Bast A (2008) Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol 585:325. https://doi.org/10.1016/j.ejphar.2008.03.008
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254. https://doi.org/10.1006/abio.1976.9999
Butterfield DA (2002) Amyloid beta-peptide (1–42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A Review Free Radic Res 36:1307–1313. https://doi.org/10.1080/1071576021000049890
Cai Q, Tammineni P (2017) Mitochondrial aspects of synaptic dysfunction in Alzheimer’s disease. J Alzheimer’s Dis 57:1087–1103. https://doi.org/10.3233/JAD-160726
Calkins MJ, Jakel RJ, Johnson DA, Chan K, Kan YW, Johnson JA (2004) Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci USA 102:244–249. https://doi.org/10.1073/pnas.0408487101
Chance B, Williams GR (1956) Respiratory enzymes in oxidative phosphorylation. VI. The effects of adenosine diphosphate on azide-treated mitochondria. J Biol Chem 221:477–489
Chen Y, Liang Z, Blanchard J, Dai C, Sun S, Lee MH, Grundke-Iqbal I, Iqbal K, Liu F, Gong C (2013) A non-transgenic mouse model (ICV-STZ mouse) of Alzheimer’s disease: similarities to and differences from the transgenic model (3xTg-AD mouse). Mol Neurobiol 47:711–725. https://doi.org/10.1007/s12035-012-8375-5
Conejero-Goldberg C, Davies P, Ulloa L (2008) Alpha7 nicotinic acetylcholine receptor: a link between inflammation and neurodegeneration. Neurosci Biobehav Rev 32:693–706. https://doi.org/10.1016/j.neubiorev.2007.10.007
Correa F, Mallard C, Nilsson M, Sandberg M (2012) Dual TNFα-induced effects on NRF2 mediated antioxidant defence in astrocyte-rich cultures: role of protein kinase activation. Neurochem Res 37:2842–2855. https://doi.org/10.1007/s11064-012-0878-y
Ding Y, Chen M, Wang M, Li Y, Wen A (2015) Posttreatment with 11-Keto-β-boswellic acid ameliorates cerebral ischemia–reperfusion injury: Nrf2/HO-1 pathway as a potential mechanism. Mol Neurobiol 52:1430–1439. https://doi.org/10.1007/s12035-014-8929-9
Dobryakova YV, Gurskaya OY, Markevich VA (2015) Administration of nicotinic receptor antagonists during the period of memory consolidation affects passive avoidance learning and modulates synaptic efficiency in the CA1 region in vivo. Neuroscience 284:865–871. https://doi.org/10.1016/j.neuroscience.2014.10.038
Dong F, Wang S, Wang Y, Yang X, Jiang J, Wu D, Qu X, Fan H, Yao R (2017) Quercetin ameliorates learning and memory via the Nrf2-ARE signaling pathway in d-galactose-induced neurotoxicity in mice. Biochem Biophys Res Commun 491:636–641. https://doi.org/10.1016/j.bbrc.2017.07.151
Drisdel RC, Green WN (2000) Neuronal α-bungarotoxin receptors are α7 subunit homomers. J Neurosci 20:133–139. https://doi.org/10.1523/jneurosci.20-01-00133.2000
Dwivedi S, Rajasekar N, Hanif K, Nath C, Shukla R (2015) Sulforaphane ameliorates okadaic acid-induced memory impairment in rats by activating the Nrf2/HO-1 antioxidant pathway. Mol Neurobiol 53:5310–5323. https://doi.org/10.1007/s12035-015-9451-4
Eckert A, Keil U, Marques CA, Bonert A, Frey C, Schüssel K, Müller WE (2003) Mitochondrial dysfunction, apoptotic cell death, and Alzheimer’s disease. Biochem Pharmacol 66:1627–1634. https://doi.org/10.1016/s0006-2952(03)00534-3
Fiorani M, De Sanctis R, Menghinello P, Cucchiarini L, Cellini B, Dachà M (2001) Quercetin prevents glutathione depletion induced by dehydroascorbic acid in rabbit red blood cells. Free Radic Res 34:639–648. https://doi.org/10.1080/10715760100300531
Freitas AE, Egea J, Buendia I, Navarro E, Rada P, Cuadrado A (2015) Agmatine induces Nrf2 and protects against corticosterone effects in hippocampal neuronal cell line. Mol Neurobiol 51:1504–1519. https://doi.org/10.1007/s12035-014-8827-1
Fucile S, Renz M, Lax P, Euseb F (2003) Fractional Ca(2+) current through human neuronal alpha7 nicotinic acetylcholine receptors. Cell Calcium 34:205–209. https://doi.org/10.1016/S0143-4160(03)00071-X
Giacobini E (1996) New trends in cholinergic therapy for Alzheimer disease: nicotinic agonists or cholinesterase inhibitors? Prog Brain Res 109:311–323. https://doi.org/10.1016/s0079-6123(08)62114-7
Godoy JA, Lindsay CB, Quintanilla RA, Carvajal FJ, Cerpa W, Inestrosa NC (2016) Quercetin exerts differential neuroprotective effects against H2O2 and Aβ aggregates in hippocampal neurons: the role of mitochondria. Mol Neurobiol 54:7116–7128. https://doi.org/10.1007/s12035-016-0203-x
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138. https://doi.org/10.1016/0003-2697(82)90118-X
Grieb P (2016) Intracerebroventricular streptozotocin injections as a model of Alzheimer’s disease: in search of a relevant mechanism. Mol Neurobiol 53:1741–1752. https://doi.org/10.1007/s12035-015-9132-3
Guo X, Sun G, Zhou T, Wang Y, Xu X, Shi X, Zhu Z, Rukachaisirikul V, Hu L, Shen X (2017) LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy. Acta Pharmacol Sin 38:1104–1119. https://doi.org/10.1038/aps.2016.128
Gupta R, Shukla RK, Chandravanshi LP, Srivastava P, Dhuriya YK, Shanker J, Singh MP, Pant AB, Khanna VK (2017) Protective role of quercetin in cadmium-induced cholinergic dysfunctions in rat brain by modulating mitochondrial integrity and MAP kinase signaling. Mol Neurobiol 54:4560–4583. https://doi.org/10.1007/s12035-016-9950-y
Halawany AME, Sayed NSE, Abdallah HM, Dine RSE (2017) Protective effects of gingerol on streptozotocin-induced sporadic Alzheimer’s disease: emphasis on inhibition of β-amyloid, COX-2, alpha-, beta-secretases and APH1a. Sci Rep 7:1–11. https://doi.org/10.1038/s41598-017-02961-0
Hasselmo ME (2006) The role of acetylcholine in learning and memory. Curr Opin Neurobiol 16:710–715. https://doi.org/10.1016/j.conb.2006.09.002
Hellström-Lindahl E, Court J, Keverne J, Svedberg M, Lee M, Marutle A, Thomas A, Perry E, Bednar I, Nordberg A (2004) Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice. Eur J Neurosci 19:2703–2710. https://doi.org/10.1111/j.1460-9568.2004.03377.x
Heo HJ, Lee CY (2004) Protective effects of Quercetin and vitamin C against oxidative stress-induced neurodegeneration. J Agric Food Chem 52:7514–7517. https://doi.org/10.1021/jf049243r
Hernandez CM, Kayed R, Zheng H, Sweatt JD, Dineley KT (2010) Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer’s disease. J Neurosci 30:2442–2453. https://doi.org/10.1523/JNEUROSCI.5038-09.2010
Hindam MO, Sayed RH, Skalicka-Woźniak K, Budzynska B, Sayed EL (2020) Xanthotoxin and umbelliferone attenuate cognitive dysfunction in a streptozotocin-induced rat model of sporadic Alzheimer’s disease: the role of JAK2/STAT3 and Nrf2/HO-1 signalling pathway modulation. Phytother Res 34:2351–2365. https://doi.org/10.1002/ptr.6686
Huang SG (2002) Development of a high throughput screening assay for mitochondrial membrane potential in living cells. J Biomol Screen 7:383–389. https://doi.org/10.1177/108705710200700411
Ishisaka A, Ichikawa S, Sakakibara H, Piskula MK, Nakamura T, Kato Y, Ito M, Miyamoto K, Tsuji A, Kawai Y, Terao J (2011) Accumulation of orally administered Quercetin in brain tissue and its antioxidative effects in rats. Free Radic Biol Med 51:1329–1336. https://doi.org/10.1016/j.freeradbiomed.2011.06.017
Jiang S, Deng C, Lv J, Fan C, Hu W, Di S, Yan X, Ma Z, Liang Z, Yang Y (2017) Nrf2 weaves an elaborate network of neuroprotection against stroke. Mol Neurobiol 54:1440–1455. https://doi.org/10.1007/s12035-016-9707-7
Jonnala RR, Buccafusco JJ (2001) Relationship between the increased cell surface alpha 7 nicotinic receptor expression and neuroprotection induced by several nicotinic receptor agonists. J Neurosci Res 66:565–572. https://doi.org/10.1002/jnr.10022
Kakkar P, Das B, Viswanathan PN (1984) A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys 21:130–132
Kamalvand G, Pinard G, Ali-Khan Z (2003) Heme-oxygenase-1 response, a marker of oxidative stress, in a mouse model of AA amyloidosis. Amyloid 10:151–159. https://doi.org/10.3109/13506120308998997
Kamat PK (2015) Streptozotocin induced Alzheimer’s disease like changes and the underlying neural degeneration and regeneration mechanism. Neural Regen Res 10:1050–1052. https://doi.org/10.4103/1673-5374.160076
Kamat PK, Kalani A, Rai S, Tota SK, Kumar A, Ahmad AS (2016) Streptozotocin Intracerebroventricular-induced neurotoxicity and brain insulin resistance: a therapeutic intervention for treatment of sporadic Alzheimer’s disease (sAD)-like pathology. Mol Neurobiol 53:4548–4562. https://doi.org/10.1007/s12035-015-9384-y
Kamboj SS, Kumar V, Kamboj A, Sandhir R (2008) Mitochondrial oxidative stress and dysfunction in rat brain induced by carbofuran exposure. Cell Mol Neurobiol 28:961–969. https://doi.org/10.1007/s10571-008-9270-5
Kidd PM (2008) Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev 13:85–115
Kong Y, Li K, Fu T, Wan C, Zhang D, Song H, Zhang Y, Liu N, Gan Z, Yuan L (2016) Quercetin ameliorates Aβ toxicity in Drosophila AD model by modulating cell cycle-related protein expression. Oncotarget 7:67716–67731
Kumar M, Bansal N (2018) Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer’s disease: involvement of PI3-kinase, eNOS and NFκB. Behav Brain Res 351:4–16. https://doi.org/10.1016/j.bbr.2018.05.024
Kumar A, Sehgal N, Kumar P, Padi SS, Naidu PS (2008) Protective effect of Quercetin against ICV colchicine-induced cognitive dysfunctions and oxidative damage in rats. Phytother Res 22:1563–1569. https://doi.org/10.1002/ptr.2454
Lakey-Beitia J, Berrocal R, Rao KS, Durant AA (2015) Polyphenols as therapeutic molecules in Alzheimer’s disease through modulating amyloid pathways. Mol Neurobiol 51:466–479. https://doi.org/10.1007/s12035-014-8722-9
Lee BH, Choi SH, Shin TJ, Pyo MK, Hwang SH, Kim BR, Lee SM, Lee JH, Kim HC, Park HY, Rhim H, Nah SY (2010) Quercetin enhances human α7 nicotinic acetylcholine receptor-mediated ion current through interactions with Ca(2+) binding sites. Mol Cells 30:245–253. https://doi.org/10.1007/s10059-010-0117-9
Lee BH, Choi SH, Kim HJ, Jung SW, Hwang SH, Pyo MK, Rhim H, Kim HC, Kim HK, Lee SM, Nah SY (2016) Differential effects of quercetin and quercetin glycosides on human α7 nicotinic acetylcholine receptor-mediated ion currents. Biomol Ther 24:410–417. https://doi.org/10.4062/biomolther.2015.153
Lee BH, Shin TJ, Hwang SH, Choi S, Kang J, Kim H, Kim HJ, Park CW, Lee SH, Nah SY (2011) Inhibitory effects of quercetin on muscle-type of nicotinic acetylcholine receptor-mediated ion currents expressed in Xenopus Oocytes. Korean J Physiol Pharmacol 15:195–201. https://doi.org/10.4196/kjpp.2011.15.4.195
Levin ED, Rezvani AH (2002) Nicotinic treatment for cognitive dysfunction. Curr Drug Targets CNS Neurol Disord 1:423–431. https://doi.org/10.2174/1568007023339102
Li W, Kong AN (2009) Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog 48:91–104. https://doi.org/10.1002/mc.20465
Li Y, Tian Q, Li Z, Dang M, Lin Y, Hou X (2019) Activation of Nrf2 signaling by sitagliptin and quercetin combination against β-amyloid induced Alzheimer’s disease in rats. Drug Dev Res 80:837–845. https://doi.org/10.1002/ddr.21567
Liaquat L, Batool Z, Sadir S, Rafiq S, Shahzad S, Perveen T, Haider S (2018) Naringenin-induced enhanced antioxidant defence system meliorates cholinergic neurotransmission and consolidates memory in male rats. Life Sci 194:213–223. https://doi.org/10.1016/j.lfs.2017.12.034
Liu J, Yu H, Ning X (2006) Effect of quercetin on chronic enhancement of spatial learning and memory of mice. Sci China Life Sci 49:583–590. https://doi.org/10.1007/s11427-006-2037-7
Liu P, Zou D, Yi L, Chen M, Gao Y, Zhou R, Zhang Q, Zhou Y, Zhu J, Chen K, Mi M (2015) Quercetin ameliorates hypobaric hypoxia-induced memory impairment through mitochondrial and neuron function adaptation via the PGC-1α pathway. Restor Neurol Neurosci 33:143–157. https://doi.org/10.3233/RNN-140446
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
Mahesh T, Menon VP (2004) Quercetin allievates oxidative stress in streptozotocin-induced diabetic rats. Phytother Res 18:123–127. https://doi.org/10.1002/ptr.1374
Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M (2010) Alzheimer’s disease: Clinical trials and drug development. Lancet Neurol 9:702–716. https://doi.org/10.1016/S1474-4422(10)70119-8
Mishra SK, Singh S, Shukla S, Shukla R (2018) Intracerebroventricular streptozotocin impairs adult neurogenesis and cognitive functions via regulating neuroinflammation and insulin signaling in adult rats. Neurochem Int 113:56–68. https://doi.org/10.1016/j.neuint.2017.11.012
Molaei A, Hatami H, Dehghan G, Sadeghian R, Khajehnasiri N (2020) Synergistic effects of quercetin and regular exercise on the recovery of spatial memory and reduction of parameters of oxidative stress in animal model of Alzheimer’s disease. Excli J 19:596–612
Morris R (1984) Developments of a Water-Maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60. https://doi.org/10.1016/0165-0270(84)90007-4
Motoshima S, Suemaru K, Kawasaki Y, Jin C, Kawasaki H, Gomita Y, Araki H (2005) Effects of α4β2 and α7 nicotinic acetylcholine receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats. Eur J Pharmacol 519:91–95. https://doi.org/10.1016/j.ejphar.2005.06.050
Mouri A, Noda Y, Hara H, Mizoguchi H, Tabira T, Nabeshima T (2007) Oral vaccination with a viral vector containing Aβ cDNA attenuates age-related Aβ accumulation and memory deficits without causing inflammation in a mouse Alzheimer model. The FASEB J 21:2135–2148. https://doi.org/10.1096/fj.06-7685com
Muthuraju S, Maiti P, Solanki P, Sharma AK, Amitabh SSB, Prasad D, Ilavazhagan G (2009) Acetylcholinesterase inhibitors enhance cognitive functions in rats following hypobaric hypoxia. Behav Brain Res 203:1–14. https://doi.org/10.1016/j.bbr.2009.03.026
Nakhate KT, Bharne AP, Verma VS, Aru DN, Kokare DM (2018) Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer’s disease via activation of Nrf2/ARE pathway and inhibition of β-secretase. Biomed Pharmacother 101:379–390. https://doi.org/10.1016/j.biopha.2018.02.052
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011) Guide for the care and use of laboratory animals, 8th edn. National Academies Press (US), Washington, DC
Navarro E, Gonzalez-Lafuente L, Pérez-Liébana I, Buendia I, López-Bernardo E, Sánchez-Ramos C, Prieto I, Cuadrado A, Satrustegui J, Cadenas S, Monsalve M, López MG (2017) Heme-oxygenase I and PCG-1α regulate mitochondrial biogenesis via microglial activation of alpha7 nicotinic acetylcholine receptors using PNU282987. Antioxid Redox Signal 27:93–105. https://doi.org/10.1089/ars.2016.6698
Nielsen BE, Bermudez I, Bouzat C (2019) Flavonoids as positive allosteric modulators of α7 nicotinic receptors. Neuropharm 160:107794. https://doi.org/10.1016/j.neuropharm.2019.107794
Nitti M, Piras S, Brondolo L, Marinari UM, Pronzato MA, Furfaro AL (2018) Heme oxygenase 1 in the nervous system: does it favor neuronal cell survival or induce neurodegeneration? Int J Mol Sci 19:1–20. https://doi.org/10.3390/ijms19082260
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358. https://doi.org/10.1016/0003-2697(79)90738-3
Paidi RK, Nthenge-ngumbau DN, Singh R, Kankanala T, Mehta H, Mohanakumar KP (2015) Mitochondrial deficits accompany cognitive decline following single bilateral intracerebroventricular streptozotocin. Curr Alzheimer Res 12:785–795. https://doi.org/10.2174/1567205012666150710112618
Parada E, Egea J, Buendia I, Negredo P, Cunha AC, Cardoso S, Soares MP, López MG (2013) The microglial α7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2. Antioxid Redox Signal 19:1135–1148. https://doi.org/10.1089/ars.2012.4671
Park HJ, Lee PH, Ahn YW, Choi YJ, Lee G, Lee D, Chung ES, Jin BK (2007) Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur J Neurosci 26:79–89. https://doi.org/10.1111/j.1460-9568.2007.05636.x
Parri HR, Hernandez CM, Dineley KT (2011) Research update : alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer’s disease. Biochem Pharmacol 82:931–942. https://doi.org/10.1016/j.bcp.2011.06.039
Patel H, Mcintire J, Ryan S, Dunah A, Loring R (2017) Anti-inflammatory effects of astroglial α7 nicotinic acetylcholine receptors are mediated by inhibition of the NF-κB pathway and activation of the Nrf2 pathway. J Neuroinflammation 14:1–15. https://doi.org/10.1186/s12974-017-0967-6
Paxinos G, Watson C (1998) Rat brain in stereotaxic coordinates. Acad Press, New York
Pedersen PL, Greenawalt JW, Reynafarje B, Hullihen J, Decker GL, Soper JW, Bustamente E (1978) Preparation and characterization of mitochondria and submitochondrial particles of rat liver-derived tissues. Methods Cell Biol 20:411–481. https://doi.org/10.1016/s0091-679x(08)62030-0
Prakash A, Kalra JK, Kumar A (2015) Neuroprotective effect of N-acetyl cysteine against streptozotocin-induced memory dysfunction and oxidative damage in rats. J Basic Clin Physiol Pharmacol 26:13–23. https://doi.org/10.1515/jbcpp-2013-0150
Prasad J, Baitharu I, Sharma AK, Dutta R, Prasad D, Singh SB (2013) Quercetin reverses hypobaric hypoxia-induced hippocampal neurodegeneration and improves memory function in the rat. High Alt Med Biol 14:383–394. https://doi.org/10.1089/ham.2013.1014
Price DL, Whitehouse PJ, Struble RG (1985) Alzheimer’s Disease. Ann Rev Med 36:349–356. https://doi.org/10.1146/annurev.me.36.020185.002025
Pu F, Mishima K, Irie K, Motohashi K, Tanaka Y, Orito K, Egawa T, Kitamura Y, Egashira N, Iwasaki K, Fujiwara M (2007) Neuroprotective effects of Quercetin and rutin on spatial memory impairment in an 8-arm radial maze task and neuronal death induced by repeated cerebral ischemia in rats. J Pharmacol Sci 104:329–334. https://doi.org/10.1254/jphs.fp0070247
Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT, Kelly L, Jordan-Sciutto KL (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85. https://doi.org/10.1097/nen.0b013e31802d6da9
Rasheed NOA, Sayed NS, Khatib AS (2018) Targeting central β2 receptors ameliorates streptozotocin-induced neuroinflammation via inhibition of glycogen synthase kinase3 pathway in mice. Prog Neuropsychopharmacol Biol Psychiatry 86:65–75. https://doi.org/10.1016/j.pnpbp.2018.05.010
Ravelli KG, Rosário BDA, Camarini R, Hernandes MS, Britto LR (2017) Intracerebroventricular streptozotocin as a model of Alzheimer’s disease: neurochemical and behavioral characterization in Mice. Neurotox Res 31:327–333. https://doi.org/10.1007/s12640-016-9684-7
Re L, Barocci S, Capitani C, Vivani C, Ricci M, Rinaldi L, Paolucci G, Scarpantonio A, León-Fernández OS, Morales MA (1999) Effects of some natural extracts on the acetylcholine release at the mouse neuromuscular junction. Pharmacol Res 39:239–245. https://doi.org/10.1006/phrs.1998.0433
Reddy PH (2007) Mitochondrial dysfunction in aging and Alzheimer’s disease: strategies to protect neurons. Antioxid Redox Signal 9:1647–1658. https://doi.org/10.1089/ars.2007.1754
Reddy PH, Beal MF (2005) Are mitochondria critical in the pathogenesis of Alzheimer’s disease? Brain Res Rev 49:618–632. https://doi.org/10.1016/j.brainresrev.2005.03.004
Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med 14:45–53. https://doi.org/10.1016/j.molmed.2007.12.002
Sachdeva AK, Kuhad A, Chopra K (2014) Naringin ameliorates memory deficits in experimental paradigm of Alzheimer’s disease by attenuating mitochondrial dysfunction. Pharmacol Biochem Behav 127:101–110. https://doi.org/10.1016/j.pbb.2014.11.002
Santos TO, Henrique C, Mazucanti Y, Torraoa AS (2012) Early and late neurodegeneration and memory disruption after intracerebroventricular streptozotocin. Physiol Behav 107:401–413. https://doi.org/10.1016/j.physbeh.2012.06.019
Schoonheim MM, Popescu V, Lopes FCR, Wiebenga OT, Vrenken H, Douw L, Polman CH, Geurts JJ, Barkhof F (2012) Subcortical atrophy and cognition: sex effects in multiple sclerosis. Neurology 79:1754–1761. https://doi.org/10.1212/WNL.0b013e3182703f46
Shen H, Kihara T, Hongo H, Wu X, Kem WR, Shimohama S, Akaike A, Niidome T, Sugimoto H (2010) Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of alpha7 nicotinic receptors and internalization of NMDA receptors. Br J Pharmacol 161:127–139. https://doi.org/10.1111/j.1476-5381.2010.00894.x
Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23:3394–3406. https://doi.org/10.1523/JNEUROSCI.23-08-03394.2003
Singh A, Naidu PS, Kulkarni SK (2003) Reversal of aging and chronic ethanol-induced cognitive dysfunction by quercetin a bioflavonoid. Free Radic Res 37:1245–1252. https://doi.org/10.1080/10715760310001616014
Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, Perry G (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:2212–2215. https://doi.org/10.1046/j.1471-4159.1998.70052212.x
Sodhi RK, Singh N (2013) Defensive effect of lansoprazole in dementia of AD type in mice exposed to streptozotocin and cholesterol enriched diet. PLoS ONE 8:e70487. https://doi.org/10.1371/journal.pone.0070487
Sonkusare S, Srinivasan K, Kaul C, Ramarao P (2005) Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats. Life Sci 77:1–14. https://doi.org/10.1016/j.lfs.2004.10.036
Sorial ME, Sayed NSED (2017) Protective effect of valproic acid in streptozotocin-induced sporadic Alzheimer’s disease mouse model: possible involvement of the cholinergic system. Naunyn Schmiedebergs Arch Pharmacol 390:581–593. https://doi.org/10.1007/s00210-017-1357-4
Sriraksa N, Wattanathorn J, Muchimapura S, Tiamkao S, Brown K, Chaisiwamongkol K (2012) Cognitive-enhancing effect of Quercetin in a rat model of Parkinson’s disease induced by 6-hydroxydopamine. Evid Based Complement Alternat Med 2012:1–9. https://doi.org/10.1155/2012/823206
Sun SW, Yu HQ, Zhang H, Zheng YL, Wang JJ, Luo L (2007) Quercetin attenuates spontaneous behavior and spatial memory impairment in dgalactose-treated mice by increasing brain antioxidant capacity. Nutr Res 27:169–175. https://doi.org/10.1016/j.nutres.2007.01.010
Takata K, Amamiya T, Mizoguchi H, Kawanishi S, Kuroda E, Kitamura R, Ito A, Saito Y, Tawa M, Nagasawa T, Okamoto H, Sugino Y, Takegami S, Kitade T, Toda Y, Kem WR, Kitamura Y, Shimohama S, Ashihara E (2018) Alpha7 nicotinic acetylcholine receptor-specific agonist DMXBA (GTS-21) attenuates Aβ accumulation through suppression of neuronal γ-secretase activity and promotion of microglial amyloid-β phagocytosis and ameliorates cognitive impairment in a mouse model of Alzheimer’s disease. Neurobiol Aging 62:197–209. https://doi.org/10.1016/j.neurobiolaging.2017.10.021
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. https://doi.org/10.1002/ana.410300410
Tota S, Awasthi H, Kamat PK, Nath C, Hanif K (2010) Protective effect of Quercetin against intracerebral streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice. Behav Brain Res 209:73–79. https://doi.org/10.1016/j.bbr.2010.01.017
Vomhof-DeKrey EE, Picklo MJ (2012) The Nrf2-antioxidant response element pathway: a target for regulating energy metabolism. J Nutr Biochem 23:1201–1206. https://doi.org/10.1016/j.jnutbio.2012.03.005
Wang H, Liao H, Ochani M, Justiniani X, Lin L, Yang Y, Al-Abed H, Wang C, Metz E, Miller J, Tracey KJ, Ulloa L (2004) Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 10:1216–1221. https://doi.org/10.1038/nm1124
Wang DM, Li SQ, Wu WL, Zhu XY, Wang Y, Yuan HY (2014) Effects of long-term treatment with quercetin on cognition and mitochondrial function in a mouse model of Alzheimer’s disease. Neurochem Res 39:1533–1543. https://doi.org/10.1007/s11064-014-1343-x
Wilson B, Geetha KM (2020) Neurotherapeutic applications of nanomedicine for treating Alzheimer’s disease. J Control Release 325:25–37. https://doi.org/10.1016/j.jconrel.2020.05.044
Xue R, Wan Y, Sun X, Zhang X, Gao W, Wu W (2019) Nicotinic mitigation of neuroinflammation and oxidative stress after chronic sleep deprivation. Front Immunol 10:1–12. https://doi.org/10.3389/fimmu.2019.02546
Yao Y, Han DD, Zhang T, Yang Z (2010) Quercetin improves cognitive deficits in rats with chronic cerebral ischemia and inhibits voltage-dependent sodium channels in hippocampal CA1 pyramidal neurons. Phytother Res 24:136–140. https://doi.org/10.1002/ptr.2902
Yiannopoulou KG, Papageorgiou SG (2013) Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord 6:19–33. https://doi.org/10.1177/1756285612461679
Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ (2014) Flavonoid permeability across an in-situ model of the blood-brain barrier. Free Radic Biol Med 36:592–604. https://doi.org/10.1016/j.freeradbiomed.2003.11.023
Zafeer MF, Firdaus F, Anis E, Hossain MM (2019) Neurotoxicology prolong treatment with trans-ferulic acid mitigates bioenergetics loss and restores mitochondrial dynamics in streptozotocin-induced sporadic dementia of Alzheimer’s type. Neurotoxicology 73:246–257. https://doi.org/10.1016/j.neuro.2019.04.006
Zeevalk G, Bernard L, Song C, Gluck M, Ehrhart J (2005) Mitochondrial inhibition and oxidative stress: reciprocating players in neurodegeneration. Antioxid Redox Signal 7:1117–1139. https://doi.org/10.1089/ars.2005.7.1117
Zhang H, Liu YY, Jiang Q, Li K, Zhao Y (2014) Salvianolic acid A protects RPE cells against oxidative stress through activation of Nrf2/HO-1 signaling. Free Radic Biol Med 69:219–228. https://doi.org/10.1016/j.freeradbiomed.2014.01.025
Zhang R, Xu M, Wang Y, Xie F, Zhang G, Qin X (2016) Nrf2-a promising therapeutic target for defensing against oxidative stress in stroke. Mol Neurobiol 54:6006–6017. https://doi.org/10.1007/s12035-016-0111-0
Zhu Z, Yan J, Jiang W, Yao XG, Chen J, Chen L, Li C, Hu L, Jiang H, Shen X (2013) Arctigenin effectively ameliorates memory impairment in Alzheimer’s disease model mice targeting both β-amyloid production and clearance. J Neurosci 33:13138–13149. https://doi.org/10.1523/JNEUROSCI.4790-12.2013.22
Zoukhri D, Kublin CL (2001) Impaired neurotransmitter release from lacrimal and salivary gland nerves of a murine model of Sjögren’s syndrome. Invest Ophthalmol vis Sci 42:925–932
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NKS is thankful to GLA University, Mathura, UP, India for the financial assistantship.
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Singh, N.K., Garabadu, D. Quercetin Exhibits α7nAChR/Nrf2/HO-1-Mediated Neuroprotection Against STZ-Induced Mitochondrial Toxicity and Cognitive Impairments in Experimental Rodents. Neurotox Res 39, 1859–1879 (2021). https://doi.org/10.1007/s12640-021-00410-5
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DOI: https://doi.org/10.1007/s12640-021-00410-5