Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Excitotoxicity as a Target Against Neurodegenerative Processes

Author(s): Octavio Binvignat and Jordi Olloquequi*

Volume 26, Issue 12, 2020

Page: [1251 - 1262] Pages: 12

DOI: 10.2174/1381612826666200113162641

Price: $65


The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation.

Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms.

In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.

Keywords: Neurodegeneration, Alzheimer's disease, Parkinson's disease, oxidative stress, neuroinflammation, ER stress, glutamate, calcium.

Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech 499-502. England: The Company of Biologists Ltd 2017; 499-502
Heemels MT. Neurodegenerative diseases. Nature 2016; 539(7628): 179.
[] [PMID: 27830810]
GBD 2016 Dementia Collaborators. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(1): 88-106.
[] [PMID: 30497964]
GBD 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018; 17(11): 939-53.
[] [PMID: 30287051]
Rawlins MD, Wexler NS, Wexler AR, et al. The prevalence of Huntington’s disease. Neuroepidemiology 2016; 46(2): 144-53.
[] [PMID: 26824438]
Santiago JA, Bottero V, Potashkin JA. Dissecting the molecular mechanisms of neurodegenerative diseases through network biology. Front Aging Neurosci 2017; 9: 166.
[] [PMID: 28611656]
Ramanan VK, Saykin AJ. Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer’s disease, Parkinson’s disease, and related disorders. Am J Neurodegener Dis 2013; 2(3): 145-75.
[PMID: 24093081]
Olloquequi J, Cornejo-Córdova E, Verdaguer E, et al. Excitotoxicity in the pathogenesis of neurological and psychiatric disorders: Therapeutic implications. J Psychopharmacol (Oxford) 2018; 32(3): 265-75.
[] [PMID: 29444621]
Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 1969; 164(3880): 719-21.
[] [PMID: 5778021]
Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin 2009; 30(4): 379-87.
[] [PMID: 19343058]
Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 1999; 81(3): 163-221.
[] [PMID: 10334661]
Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 1999; 51(1): 7-61.
[PMID: 10049997]
Mayer ML. Glutamate receptor ion channels. Curr Opin Neurobiol 2005; 15(3): 282-8.
[] [PMID: 15919192]
Choi DW, Maulucci-Gedde M, Kriegstein AR. Glutamate neurotoxicity in cortical cell culture. J Neurosci 1987; 7(2): 357-68.
[] [PMID: 2880937]
Clapham DE. Calcium signaling. Cell 2007; 131(6): 1047-58.
[] [PMID: 18083096]
Bano D, Ankarcrona M. Beyond the critical point: An overview of excitotoxicity, calcium overload and the downstream consequences. Neurosci Lett 2018; 663: 79-85.
[] [PMID: 28843346]
Lee BK, Lee DH, Park S, et al. Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on glutamate-induced neuronal cell death and ischemia-induced cerebral infarct. Brain Res 2009; 1248: 22-30.
[] [PMID: 19022230]
Magi S, Castaldo P, Macrì ML, et al. Intracellular calcium dysregulation: implications for Alzheimer’s disease. BioMed Res Int 2016; 20166701324
[] [PMID: 27340665]
Hamada K, Miyata T, Mayanagi K, Hirota J, Mikoshiba K. Two-state conformational changes in inositol 1,4,5-trisphosphate receptor regulated by calcium. J Biol Chem 2002; 277(24): 21115-8.
[] [PMID: 11980893]
Santo-Domingo J, Demaurex N. Calcium uptake mechanisms of mitochondria. Biochim Biophys Acta 2010; 1797(6-7): 907-12.
[] [PMID: 20079335]
Mody I, MacDonald JF. NMDA receptor-dependent excitotoxicity: the role of intracellular Ca2+ release. Trends Pharmacol Sci 1995; 16(10): 356-9.
[] [PMID: 7491714]
Wang HG, Pathan N, Ethell IM, et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999; 284(5412): 339-43.
[] [PMID: 10195903]
Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 1999; 402(6762): 615-22.
[] [PMID: 10604467]
Saido TC, Sorimachi H, Suzuki K. Calpain: new perspectives in molecular diversity and physiological-pathological involvement. FASEB J 1994; 8(11): 814-22.
[] [PMID: 8070630]
Wu HY, Tomizawa K, Oda Y, et al. Critical role of calpain-mediated cleavage of calcineurin in excitotoxic neurodegeneration. J Biol Chem 2004; 279(6): 4929-40.
[] [PMID: 14627704]
Schubert D, Piasecki D. Oxidative glutamate toxicity can be a component of the excitotoxicity cascade. J Neurosci 2001; 21(19): 7455-62.
[] [PMID: 11567035]
Kritis AA, Stamoula EG, Paniskaki KA, Vavilis TD. Researching glutamate - induced cytotoxicity in different cell lines: a comparative/collective analysis/study. Front Cell Neurosci 2015; 9: 91.
[] [PMID: 25852482]
Brennan-Minnella AM, Won SJ, Swanson RA. NADPH oxidase-2: linking glucose, acidosis, and excitotoxicity in stroke. Antioxid Redox Signal 2015; 22(2): 161-74.
[] [PMID: 24628477]
Rego AC, Oliveira CR. Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases. Neurochem Res 2003; 28(10): 1563-74.
[] [PMID: 14570402]
Leaw B, Nair S, Lim R, Thornton C, Mallard C, Hagberg H. Mitochondria, bioenergetics and excitotoxicity: new therapeutic targets in perinatal brain injury. Front Cell Neurosci 2017; 11: 199.
[] [PMID: 28747873]
Szabo I, Zoratti M. Mitochondrial channels: ion fluxes and more. Physiol Rev 2014; 94(2): 519-608.
[] [PMID: 24692355]
Finkel T, Menazza S, Holmström KM, et al. The ins and outs of mitochondrial calcium. Circ Res 2015; 116(11): 1810-9.
[] [PMID: 25999421]
Di Lisa F, Bernardi P. A CaPful of mechanisms regulating the mitochondrial permeability transition. J Mol Cell Cardiol 2009; 46(6): 775-80.
[] [PMID: 19303419]
Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 2012; 13(9): 566-78.
[] [PMID: 22850819]
Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu Rev Biochem 2004; 73: 87-106.
[] [PMID: 15189137]
Adrain C, Creagh EM, Martin SJ. Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2. EMBO J 2001; 20(23): 6627-36.
[] [PMID: 11726499]
Yang S, Zhao X, Xu H, et al. AKT2 blocks nucleus translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) while promoting caspase activation during cardiac ischemia. Int J Mol Sci 2017; 18(3): 18.
[] [PMID: 28272306]
Mekahli D, Bultynck G, Parys JB, De Smedt H, Missiaen L. Endoplasmic-reticulum calcium depletion and disease. Cold Spring Harb Perspect Biol 2011; 3(6): 3.
[] [PMID: 21441595]
Kuznetsov G, Brostrom MA, Brostrom CO. Demonstration of a calcium requirement for secretory protein processing and export. Differential effects of calcium and dithiothreitol. J Biol Chem 1992; 267(6): 3932-9.
[PMID: 1740441]
Almanza A, Carlesso A, Chintha C, et al. Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. FEBS J 2019; 286(2): 241-78.
[] [PMID: 30027602]
Chuang YC, Chang AY, Lin JW, Hsu SP, Chan SH. Mitochondrial dysfunction and ultrastructural damage in the hippocampus during kainic acid-induced status epilepticus in the rat. Epilepsia 2004; 45(10): 1202-9.
[] [PMID: 15461674]
Racay P, Tatarkova Z, Chomova M, Hatok J, Kaplan P, Dobrota D. Mitochondrial calcium transport and mitochondrial dysfunction after global brain ischemia in rat hippocampus. Neurochem Res 2009; 34(8): 1469-78.
[] [PMID: 19252983]
Prentice H, Modi JP, Wu JY. Mechanisms of neuronal protection against excitotoxicity, endoplasmic reticulum stress, and mitochondrial dysfunction in stroke and neurodegenerative diseases. Oxid Med Cell Longev 2015; 2015964518
[] [PMID: 26576229]
Concannon CG, Ward MW, Bonner HP, et al. NMDA receptor-mediated excitotoxic neuronal apoptosis in vitro and in vivo occurs in an ER stress and PUMA independent manner. J Neurochem 2008; 105(3): 891-903.
[] [PMID: 18088354]
Sokka AL, Putkonen N, Mudo G, et al. Endoplasmic reticulum stress inhibition protects against excitotoxic neuronal injury in the rat brain. J Neurosci 2007; 27(4): 901-8.
[] [PMID: 17251432]
Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454(7203): 428-35.
[] [PMID: 18650913]
Hamanaka RB, Chandel NS. Mitochondrial reactive oxygen species regulate hypoxic signaling. Curr Opin Cell Biol 2009; 21(6): 894-9.
[] [PMID: 19781926]
Ungvari Z, Orosz Z, Labinskyy N, et al. Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 2007; 293(1): H37-47.
[] [PMID: 17416599]
Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther 2017; 2: 2.
[] [PMID: 29158945]
Palazon A, Goldrath AW, Nizet V, Johnson RS. HIF transcription factors, inflammation, and immunity. Immunity 2014; 41(4): 518-28.
[] [PMID: 25367569]
Voet S, Srinivasan S, Lamkanfi M, van Loo G. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med 2019; 11(6): 11.
[] [PMID: 31015277]
Al-Gayyar MM, Abdelsaid MA, Matragoon S, Pillai BA, El-Remessy AB. Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity. Br J Pharmacol 2011; 164(1): 170-80.
[] [PMID: 21434880]
Tsoka P, Barbisan PR, Kataoka K, et al. NLRP3 inflammasome in NMDA-induced retinal excitotoxicity. Exp Eye Res 2019; 181: 136-44.
[] [PMID: 30707890]
Olmos G, Lladó J. Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Mediators Inflamm 2014; 2014861231
[] [PMID: 24966471]
Viviani B, Bartesaghi S, Gardoni F, et al. Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 2003; 23(25): 8692-700.
[] [PMID: 14507968]
Fogal B, Li J, Lobner D, McCullough LD, Hewett SJ. System x(c)- activity and astrocytes are necessary for interleukin-1 beta-mediated hypoxic neuronal injury. J Neurosci 2007; 27(38): 10094-105.
[] [PMID: 17881516]
Bading H. Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations. J Exp Med 2017; 214(3): 569-78.
[] [PMID: 28209726]
Ribeiro FM, Vieira LB, Pires RG, Olmo RP, Ferguson SS. Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol Res 2017; 115: 179-91.
[] [PMID: 27872019]
Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 2010; 460(2): 525-42.
[] [PMID: 20229265]
Folch J, Busquets O, Ettcheto M, et al. Memantine for the Treatment of Dementia: a Review on its current and future applications. J Alzheimers Dis 2018; 62(3): 1223-40.
[] [PMID: 29254093]
Bickler PE, Hansen BM. Causes of calcium accumulation in rat cortical brain slices during hypoxia and ischemia: role of ion channels and membrane damage. Brain Res 1994; 665(2): 269-76.
[] [PMID: 7534604]
Silverstein FS, Buchanan K, Hudson C, Johnston MV. Flunarizine limits hypoxia-ischemia induced morphologic injury in immature rat brain. Stroke 1986; 17(3): 477-82.
[] [PMID: 3715946]
Takakura S, Sogabe K, Satoh H, et al. Nilvadipine as a neuroprotective calcium entry blocker in a rat model of global cerebral ischemia. A comparative study with nicardipine hydrochloride. Neurosci Lett 1992; 141(2): 199-202.
[] [PMID: 1436634]
Kopecky BJ, Liang R, Bao J. T-type calcium channel blockers as neuroprotective agents. Pflugers Arch 2014; 466(4): 757-65.
[] [PMID: 24563219]
Sendrowski K, Rusak M, Sobaniec P, et al. Study of the protective effect of calcium channel blockers against neuronal damage induced by glutamate in cultured hippocampal neurons. Pharmacol Rep 2013; 65(3): 730-6.
[] [PMID: 23950597]
Tran LT, Gentil BJ, Sullivan KE, Durham HD. The voltage-gated calcium channel blocker lomerizine is neuroprotective in motor neurons expressing mutant SOD1, but not TDP-43. J Neurochem 2014; 130(3): 455-66.
[] [PMID: 24716897]
Vallazza-Deschamps G, Fuchs C, Cia D, et al. Diltiazem-induced neuroprotection in glutamate excitotoxicity and ischemic insult of retinal neurons. Doc Ophthalmol 2005; 110(1): 25-35.
[] [PMID: 16249955]
Calzada JI, Jones BE, Netland PA, Johnson DA. Glutamate-induced excitotoxicity in retina: neuroprotection with receptor antagonist, dextromethorphan, but not with calcium channel blockers. Neurochem Res 2002; 27(1-2): 79-88.
[] [PMID: 11926279]
Biglan KM, Oakes D, Lang AE, et al. Parkinson Study Group STEADY‐PD III Investigators.A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY-PD III). Ann Clin Transl Neurol 2017; 4(6): 360-8.
[] [PMID: 28589163]
López-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 2002; (3): CD000147
[PMID: 12137606]
Paci A, Ottaviano P, Trenta A, et al. Nimodipine in acute ischemic stroke: a double-blind controlled study. Acta Neurol Scand 1989; 80(4): 282-6.
[] [PMID: 2683557]
Bailey I, Bell A, Gray J, et al. A trial of the effect of nimodipine on outcome after head injury. Acta Neurochir (Wien) 1991; 110(3-4): 97-105.
[] [PMID: 1927616]
The European Study Group on Nimodipine in Severe Head Injury.A multicenter trial of the efficacy of nimodipine on outcome after severe head injury. J Neurosurg 1994; 80(5): 797-804.
[] [PMID: 8169617]
Murray GD, Teasdale GM, Schmitz H. Nimodipine in traumatic subarachnoid haemorrhage: a re-analysis of the HIT I and HIT II trials. Acta Neurochir (Wien) 1996; 138(10): 1163-7.
[] [PMID: 8955434]
Kim SJ, Park C, Han AL, et al. Ebselen attenuates cisplatin-induced ROS generation through Nrf2 activation in auditory cells. Hear Res 2009; 251(1-2): 70-82.
[] [PMID: 19286452]
Kawajiri S, Machida Y, Saiki S, Sato S, Hattori N. Zonisamide reduces cell death in SH-SY5Y cells via an anti-apoptotic effect and by upregulating MnSOD. Neurosci Lett 2010; 481(2): 88-91.
[] [PMID: 20600601]
Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 2009; 7(1): 65-74.
[] [PMID: 19721819]
Zaleska MM, Floyd RA. Regional lipid peroxidation in rat brain in vitro: possible role of endogenous iron. Neurochem Res 1985; 10(3): 397-410.
[] [PMID: 4000395]
Kim GH, Kim JE, Rhie SJ, Yoon S. The Role of oxidative stress in neurodegenerative diseases. Exp Neurobiol 2015; 24(4): 325-40.
[] [PMID: 26713080]
Rebec GV, Pierce RC. A vitamin as neuromodulator: ascorbate release into the extracellular fluid of the brain regulates dopaminergic and glutamatergic transmission. Prog Neurobiol 1994; 43(6): 537-65.
[] [PMID: 7816935]
Majewska MD, Bell JA, London ED. Regulation of the NMDA receptor by redox phenomena: inhibitory role of ascorbate. Brain Res 1990; 537(1-2): 328-32.
[] [PMID: 1964838]
Moretti M, Fraga DB, Rodrigues ALS. Preventive and therapeutic potential of ascorbic acid in neurodegenerative diseases. CNS Neurosci Ther 2017; 23(12): 921-9.
[] [PMID: 28980404]
Olajide OJ, Yawson EO, Gbadamosi IT, et al. Ascorbic acid ameliorates behavioural deficits and neuropathological alterations in rat model of Alzheimer’s disease. Environ Toxicol Pharmacol 2017; 50: 200-11.
[] [PMID: 28192749]
Sil S, Ghosh T, Gupta P, Ghosh R, Kabir SN, Roy A. Dual role of vitamin C on the neuroinflammation mediated neurodegeneration and memory impairments in colchicine induced rat model of alzheimer disease. J Mol Neurosci 2016; 60(4): 421-35.
[] [PMID: 27665568]
Wang C, Liu L, Zhang L, Peng Y, Zhou F. Redox reactions of the α-synuclein-Cu(2+) complex and their effects on neuronal cell viability. Biochemistry 2010; 49(37): 8134-42.
[] [PMID: 20701279]
Fernandes JT, Tenreiro S, Gameiro A, Chu V, Outeiro TF, Conde JP. Modulation of alpha-synuclein toxicity in yeast using a novel microfluidic-based gradient generator. Lab Chip 2014; 14(20): 3949-57.
[] [PMID: 25167219]
Nagano S, Ogawa Y, Yanagihara T, Sakoda S. Benefit of a combined treatment with trientine and ascorbate in familial amyotrophic lateral sclerosis model mice. Neurosci Lett 1999; 265(3): 159-62.
[] [PMID: 10327155]
Nagano S, Fujii Y, Yamamoto T, et al. The efficacy of trientine or ascorbate alone compared to that of the combined treatment with these two agents in familial amyotrophic lateral sclerosis model mice. Exp Neurol 2003; 179(2): 176-80.
[] [PMID: 12618124]
Gugliandolo A, Bramanti P, Mazzon E. Role of vitamin E in the treatment of Alzheimer’s disease: evidence from animal models. Int J Mol Sci 2017; 18(12): 18.
[] [PMID: 29168797]
Nakaso K, Horikoshi Y, Takahashi T, et al. Estrogen receptor-mediated effect of δ-tocotrienol prevents neurotoxicity and motor deficit in the MPTP mouse model of Parkinson’s disease. Neurosci Lett 2016; 610: 117-22.
[] [PMID: 26523792]
Schirinzi T, Martella G, Imbriani P, et al. Dietary vitamin E as a protective factor for Parkinson’s disease: clinical and experimental evidence. Front Neurol 2019; 10: 148.
[] [PMID: 30863359]
Dumont M, Kipiani K, Yu F, et al. Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis 2011; 27(1): 211-23.
[] [PMID: 21799249]
Elipenahli C, Stack C, Jainuddin S, et al. Behavioral improvement after chronic administration of coenzyme Q10 in P301S transgenic mice. J Alzheimers Dis 2012; 28(1): 173-82.
[] [PMID: 21971408]
Sharma SK, El Refaey H, Ebadi M. Complex-1 activity and 18F-DOPA uptake in genetically engineered mouse model of Parkinson’s disease and the neuroprotective role of coenzyme Q10. Brain Res Bull 2006; 70(1): 22-32.
[] [PMID: 16750479]
Sikorska M, Lanthier P, Miller H, et al. Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson’s disease. Neurobiol Aging 2014; 35(10): 2329-46.
[] [PMID: 24775711]
Ferrante RJ, Andreassen OA, Dedeoglu A, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 2002; 22(5): 1592-9.
[] [PMID: 11880489]
Yang L, Calingasan NY, Wille EJ, et al. Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s diseases. J Neurochem 2009; 109(5): 1427-39.
[] [PMID: 19476553]
Müller T, Büttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson’s disease. Neurosci Lett 2003; 341(3): 201-4.
[] [PMID: 12697283]
Horstink MW, van Engelen BG. The effect of coenzyme Q10 therapy in Parkinson disease could be symptomatic. Arch Neurol United States . 2003; 1170-2.
Beal MF, Oakes D, Shoulson I, et al. Parkinson Study Group QE3 Investigators.A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol 2014; 71(5): 543-52.
[] [PMID: 24664227]
Parkinson Study Group.Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993; 328(3): 176-83.
[] [PMID: 8417384]
McBean GJ, López MG, Wallner FK. Redox-based therapeutics in neurodegenerative disease. Br J Pharmacol 2017; 174(12): 1750-70.
[] [PMID: 27477685]
Copple IM, Dinkova-Kostova AT, Kensler TW, Liby KT, Wigley WC. NRF2 as an emerging therapeutic target. Oxid Med Cell Longev 2017; 20178165458
[] [PMID: 28250892]
Johnson DA, Johnson JA. Nrf2--a therapeutic target for the treatment of neurodegenerative diseases. Free Radic Biol Med 2015; 88(Pt B): 253-67.
[] [PMID: 26281945]
Balogun E, Hoque M, Gong P, et al. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 2003; 371(Pt 3): 887-95.
[] [PMID: 12570874]
Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005; 280(7): 5892-901.
[] [PMID: 15590663]
Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem 2007; 102(4): 1095-104.
[] [PMID: 17472706]
Jiang H, Tian X, Guo Y, Duan W, Bu H, Li C. Activation of nuclear factor erythroid 2-related factor 2 cytoprotective signaling by curcumin protect primary spinal cord astrocytes against oxidative toxicity. Biol Pharm Bull 2011; 34(8): 1194-7.
[] [PMID: 21804205]
Dong H, Xu L, Wu L, et al. Curcumin abolishes mutant TDP-43 induced excitability in a motoneuron-like cellular model of ALS. Neuroscience 2014; 272: 141-53.
[] [PMID: 24785678]
Mohajeri M, Sadeghizadeh M, Najafi F, Javan M. Polymerized nano-curcumin attenuates neurological symptoms in EAE model of multiple sclerosis through down regulation of inflammatory and oxidative processes and enhancing neuroprotection and myelin repair. Neuropharmacology 2015; 99: 156-67.
[] [PMID: 26211978]
Azad N, Rasoolijazi H, Joghataie MT, Soleimani S. Neuroprotective effects of carnosic Acid in an experimental model of Alzheimer’s disease in rats. Cell J 2011; 13(1): 39-44.
[PMID: 23671826]
Wu CR, Tsai CW, Chang SW, Lin CY, Huang LC, Tsai CW. Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson’s disease: involvement of antioxidative enzymes induction. Chem Biol Interact 2015; 225: 40-6.
[] [PMID: 25446857]
Shimojo Y, Kosaka K, Noda Y, Shimizu T, Shirasawa T. Effect of rosmarinic acid in motor dysfunction and life span in a mouse model of familial amyotrophic lateral sclerosis. J Neurosci Res 2010; 88(4): 896-904.
[PMID: 19798750]
Ma T, Tan MS, Yu JT, Tan L. Resveratrol as a therapeutic agent for Alzheimer’s disease. BioMed Res Int 2014; 2014350516
[] [PMID: 25525597]
da Rocha Lindner G, Bonfanti Santos D, Colle D, et al. Improved neuroprotective effects of resveratrol-loaded polysorbate 80-coated poly(lactide) nanoparticles in MPTP-induced Parkinsonism. Nanomedicine (Lond) 2015; 10(7): 1127-38.
[] [PMID: 25929569]
Kim HV, Kim HY, Ehrlich HY, Choi SY, Kim DJ, Kim Y. Amelioration of Alzheimer’s disease by neuroprotective effect of sulforaphane in animal model. Amyloid 2013; 20(1): 7-12.
[] [PMID: 23253046]
Zhang R, Miao QW, Zhu CX, et al. Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid β deposits and peroxidation in mice with Alzheimer-like lesions. Am J Alzheimers Dis Other Demen 2015; 30(2): 183-91.
[] [PMID: 25024455]
Jazwa A, Rojo AI, Innamorato NG, Hesse M, Fernández-Ruiz J, Cuadrado A. Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal 2011; 14(12): 2347-60.
[] [PMID: 21254817]
Li B, Cui W, Liu J, et al. Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp Neurol 2013; 250: 239-49.
[] [PMID: 24120440]
Díaz A, Rojas K, Espinosa B, et al. Aminoguanidine treatment ameliorates inflammatory responses and memory impairment induced by amyloid-beta 25-35 injection in rats. Neuropeptides 2014; 48(3): 153-9.
[] [PMID: 24703968]
Sil S, Ghosh T, Ghosh R, Gupta P. Nitric oxide synthase inhibitor, aminoguanidine reduces intracerebroventricular colchicine induced neurodegeneration, memory impairments and changes of systemic immune responses in rats. J Neuroimmunol 2017; 303: 51-61.
[] [PMID: 28065581]
Han BH, Zhou ML, Johnson AW, et al. Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proc Natl Acad Sci USA 2015; 112(8): E881-90.
[] [PMID: 25675483]
Park L, Anrather J, Zhou P, et al. NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci 2005; 25(7): 1769-77.
[] [PMID: 15716413]
Ma MW, Wang J, Zhang Q, et al. NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 2017; 12(1): 7.
[] [PMID: 28095923]
Dowding JM, Song W, Bossy K, et al. Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death. Cell Death Differ 2014; 21(10): 1622-32.
[] [PMID: 24902900]
Rzigalinski BA, Carfagna CS, Ehrich M. Cerium oxide nanoparticles in neuroprotection and considerations for efficacy and safety. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2017; 9(4): 9.
[] [PMID: 27860449]
Li Y, Ganesh T, Diebold BA, et al. Thioxo-dihydroquinazolin-one compounds as novel inhibitors of myeloperoxidase. ACS Med Chem Lett 2015; 6(10): 1047-52.
[] [PMID: 26487910]
Jucaite A, Svenningsson P, Rinne JO, et al. Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson’s disease. Brain 2015; 138(Pt 9): 2687-700.
[] [PMID: 26137956]
Fiorito V, Chiabrando D, Tolosano E. Mitochondrial targeting in neurodegeneration: a heme perspective. Pharmaceuticals (Basel) 2018; 11(3): 11.
[] [PMID: 30231533]
Liao Y, Dong Y, Cheng J. The function of the mitochondrial calcium uniporter in neurodegenerative disorders. Int J Mol Sci 2017; 18(2): 18.
[] [PMID: 28208618]
Zhang SZ, Gao Q, Cao CM, Bruce IC, Xia Q. Involvement of the mitochondrial calcium uniporter in cardioprotection by ischemic preconditioning. Life Sci 2006; 78(7): 738-45.
[] [PMID: 16150463]
Soman S, Keatinge M, Moein M, et al. Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1-/- zebrafish. Eur J Neurosci 2017; 45(4): 528-35.
[] [PMID: 27859782]
McManus MJ, Murphy MP, Franklin JL. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci 2011; 31(44): 15703-15.
[] [PMID: 22049413]
Miquel E, Cassina A, Martínez-Palma L, et al. Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis. Free Radic Biol Med 2014; 70: 204-13.
[] [PMID: 24582549]
Yin X, Manczak M, Reddy PH. Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington’s disease. Hum Mol Genet 2016; 25(9): 1739-53.
[] [PMID: 26908605]
Solesio ME, Prime TA, Logan A, et al. The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson’s disease. Biochim Biophys Acta 2013; 1832(1): 174-82.
[] [PMID: 22846607]
Snow BJ, Rolfe FL, Lockhart MM, et al. Protect Study Group. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Mov Disord 2010; 25(11): 1670-4.
[] [PMID: 20568096]
Dolder M, Walzel B, Speer O, Schlattner U, Wallimann T. Inhibition of the mitochondrial permeability transition by creatine kinase substrates. Requirement for microcompartmentation. J Biol Chem 2003; 278(20): 17760-6.
[] [PMID: 12621025]
Sestili P, Martinelli C, Colombo E, et al. Creatine as an antioxidant. Amino Acids 2011; 40(5): 1385-96.
[] [PMID: 21404063]
Wallimann T, Tokarska-Schlattner M, Schlattner U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids 2011; 40(5): 1271-96.
[] [PMID: 21448658]
Chaturvedi RK, Flint Beal M. Mitochondrial diseases of the brain. Free Radic Biol Med 2013; 63: 1-29.
[] [PMID: 23567191]
Chaturvedi RK, Beal MF. Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 2008; 1147: 395-412.
[] [PMID: 19076459]
Bender A, Klopstock T. Creatine for neuroprotection in neurodegenerative disease: end of story? Amino Acids 2016; 48(8): 1929-40.
[] [PMID: 26748651]
Udhayabanu T, Manole A, Rajeshwari M, Varalakshmi P, Houlden H, Ashokkumar B. Riboflavin responsive mitochondrial dysfunction in neurodegenerative diseases. J Clin Med 2017; 6(5): 6.
[] [PMID: 28475111]
Beal MF. Therapeutic approaches to mitochondrial dysfunction in Parkinson’s disease. Parkinsonism Relat Disord 2009; 15(Suppl. 3): S189-94.
[] [PMID: 20082988]
Fricker RA, Green EL, Jenkins SI, Griffin SM. The influence of nicotinamide on health and disease in the central nervous system. Int J Tryptophan Res 2018; 111178646918776658
[] [PMID: 29844677]
Molz P, Schröder N. Potential therapeutic effects of lipoic acid on memory deficits related to aging and neurodegeneration. Front Pharmacol 2017; 8: 849.
[] [PMID: 29311912]
Gomes ATPC, Neves MGPMS, Cavaleiro JAS. Cancer, photodynamic therapy and porphyrin-type derivatives. An Acad Bras Cienc 2018; 90(1)(Suppl. 2): 993-1026.
[] [PMID: 29873666]
Atamna H, Liu J, Ames BN. Heme deficiency selectively interrupts assembly of mitochondrial complex IV in human fibroblasts: revelance to aging. J Biol Chem 2001; 276(51): 48410-6.
[] [PMID: 11598132]
Omori C, Motodate R, Shiraki Y, et al. Facilitation of brain mitochondrial activity by 5-aminolevulinic acid in a mouse model of Alzheimer’s disease. Nutr Neurosci 2017; 20(9): 538-46.
[] [PMID: 27329428]
Wang X, Li H, Ding S. The effects of NAD+ on apoptotic neuronal death and mitochondrial biogenesis and function after glutamate excitotoxicity. Int J Mol Sci 2014; 15(11): 20449-68.
[] [PMID: 25387075]
Li PA, Hou X, Hao S. Mitochondrial biogenesis in neurodegeneration. J Neurosci Res 2017; 95(10): 2025-9.
[] [PMID: 28301064]
Tellone E, Galtieri A, Russo A, Giardina B, Ficarra S. Resveratrol: a focus on several neurodegenerative diseases. Oxid Med Cell Longev 2015; 2015392169
[] [PMID: 26180587]
Madeira JM, Schindler SM, Klegeris A. A new look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases. Neural Regen Res 2015; 10(3): 391-3.
[] [PMID: 25878586]
Rotermund C, Machetanz G, Fitzgerald JC. The therapeutic potential of metformin in neurodegenerative diseases. Front Endocrinol (Lausanne) 2018; 9: 400.
[] [PMID: 30072954]
Rappold PM, Cui M, Grima JC, et al. Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo. Nat Commun 2014; 5: 5244.
[] [PMID: 25370169]
Lutz AK, Exner N, Fett ME, et al. Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem 2009; 284(34): 22938-51.
[] [PMID: 19546216]
Ruiz A, Alberdi E, Matute C. Mitochondrial division inhibitor 1 (mdivi-1) protects neurons against excitotoxicity through the modulation of mitochondrial function and intracellular Ca2+ signaling. Front Mol Neurosci 2018; 11: 3.
[] [PMID: 29386996]
Bordt EA, Clerc P, Roelofs BA, et al. The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species. Dev Cell 2017; 40(6): 583-594.e6.
[] [PMID: 28350990]
Hetz C, Mollereau B. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 2014; 15(4): 233-49.
[] [PMID: 24619348]
Wiley JC, Pettan-Brewer C, Ladiges WC. Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice. Aging Cell 2011; 10(3): 418-28.
[] [PMID: 21272191]
Huang L, Xue Y, Feng D, et al. Blockade of RyRs in the ER attenuates 6-OHDA-induced calcium overload, cellular hypo-excitability and apoptosis in dopaminergic neurons. Front Cell Neurosci 2017; 11: 52.
[] [PMID: 28316566]
Bhardwaj A, Bhardwaj R, Dhawan DK, Kaur T. Exploring the effect of endoplasmic reticulum stress inhibition by 4-phenylbutyric acid on AMPA-induced hippocampal excitotoxicity in rat brain. Neurotox Res 2019; 35(1): 83-91.
[] [PMID: 30008047]
Kudo T, Kanemoto S, Hara H, et al. A molecular chaperone inducer protects neurons from ER stress. Cell Death Differ 2008; 15(2): 364-75.
[] [PMID: 18049481]
Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in disease. Nat Rev Drug Discov 2013; 12(9): 703-19.
[] [PMID: 23989796]
Hong Y, Wang X, Sun S, Xue G, Li J, Hou Y. Progesterone exerts neuroprotective effects against Aβ-induced neuroinflammation by attenuating ER stress in astrocytes. Int Immunopharmacol 2016; 33: 83-9.
[] [PMID: 26878478]
Vieira FG, Ping Q, Moreno AJ, et al. Guanabenz treatment accelerates disease in a mutant sod1 mouse model of ALS. PLoS One 2015; 10(8)e0135570
[] [PMID: 26288094]
Ning B, Deng M, Zhang Q, Wang N, Fang Y. β-Asarone inhibits IRE1/XBP1 endoplasmic reticulum stress pathway in 6-OHDA-induced Parkinsonian rats. Neurochem Res 2016; 41(8): 2097-101.
[] [PMID: 27097550]
Ning B, Zhang Q, Wang N, Deng M, Fang Y. β-Asarone regulates ER stress and autophagy Via inhibition of the PERK/CHOP/Bcl-2/Beclin-1 Pathway in 6-OHDA-induced Parkinsonian rats. Neurochem Res 2019; 44(5): 1159-66.
[] [PMID: 30796752]
Zhang S, Gui XH, Huang LP, et al. Neuroprotective effects of β-asarone against 6-hydroxy dopamine-induced Parkinsonism via JNK/Bcl-2/Beclin-1 pathway. Mol Neurobiol 2016; 53(1): 83-94.
[] [PMID: 25404088]
Celardo I, Costa AC, Lehmann S, et al. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson’s disease. Cell Death Dis 2016; 7(6)e2271
[] [PMID: 27336715]
Halliday M, Radford H, Sekine Y, et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis 2015; 6e1672
[] [PMID: 25741597]
Halliday M, Radford H, Zents KAM, et al. Repurposed drugs targeting eIF2&α;-P-mediated translational repression prevent neurodegeneration in mice. Brain 2017; 140(6): 1768-83.
[] [PMID: 28430857]
Zhu YF, Li XH, Yuan ZP, et al. Allicin improves endoplasmic reticulum stress-related cognitive deficits via PERK/Nrf2 antioxidative signaling pathway. Eur J Pharmacol 2015; 762: 239-46.
[] [PMID: 26049013]
Remondelli P, Renna M. The endoplasmic reticulum unfolded protein response in neurodegenerative disorders and its potential therapeutic significance. Front Mol Neurosci 2017; 10: 187.
[] [PMID: 28670265]
Ettcheto M, Sánchez-López E, Pons L, et al. Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways. Redox Biol 2017; 13: 345-52.
[] [PMID: 28646794]
McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 2008; 5: 45.
[] [PMID: 18925972]
Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation 2008; 5: 2.
[] [PMID: 18184433]
Coll RC, Robertson AA, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 2015; 21(3): 248-55.
[] [PMID: 25686105]
Dempsey C, Rubio Araiz A, Bryson KJ, et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav Immun 2017; 61: 306-16.
[] [PMID: 28003153]
Daniels MJ, Rivers-Auty J, Schilling T, et al. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat Commun 2016; 7: 12504.
[] [PMID: 27509875]
Yulug B, Hanoglu L, Ozansoy M, et al. Therapeutic role of rifampicin in Alzheimer’s disease. Psychiatry Clin Neurosci 2018; 72(3): 152-9.
[] [PMID: 29315976]
Santa-Cecília FV, Leite CA, Del-Bel E, Raisman-Vozari R. The neuroprotective effect of doxycycline on neurodegenerative diseases. Neurotox Res 2019; 35(4): 981-6.
[] [PMID: 30798507]
Balducci C, Forloni G. Doxycycline for Alzheimer’s disease: fighting β-amyloid oligomers and neuroinflammation. Front Pharmacol 2019; 10: 738.
[] [PMID: 31333460]
Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer’s Disease. J Neurogastroenterol Motil 2019; 25(1): 48-60.
[] [PMID: 30646475]
Friedland RP, Chapman MR. The role of microbial amyloid in neurodegeneration. PLoS Pathog 2017; 13(12)e1006654
[] [PMID: 29267402]
Stoilova T, Colombo L, Forloni G, Tagliavini F, Salmona M. A new face for old antibiotics: tetracyclines in treatment of amyloidoses. J Med Chem 2013; 56(15): 5987-6006.
[] [PMID: 23611039]
Fasano A, Bove F, Gabrielli M, et al. The role of small intestinal bacterial overgrowth in Parkinson’s disease. Mov Disord 2013; 28(9): 1241-9.
[] [PMID: 23712625]
Loeb MB, Molloy DW, Smieja M, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease. J Am Geriatr Soc 2004; 52(3): 381-7.
[] [PMID: 14962152]
Molloy DW, Standish TI, Zhou Q, Guyatt G. DARAD Study Group. A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer’s disease: the DARAD trial. Int J Geriatr Psychiatry 2013; 28(5): 463-70.
[] [PMID: 22718435]
Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 2016; 315(17): 1864-73.
[] [PMID: 27139059]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy