Abstract
A combinatorial cocktail approach is suggested as a rationale intervention to attenuate chronic inflammation and confer neuroprotection in Alzheimer’s disease (AD). The requirement for an assemblage of pharmacological compounds follows from the host of pro-inflammatory pathways and mechanisms present in activated microglia in the disease process. This article suggests a starting point using four compounds which present some differential in anti-inflammatory targets and actions but a commonality in showing a finite permeability through Blood-brain Barrier (BBB). A basis for firstchoice compounds demonstrated neuroprotection in animal models (thalidomide and minocycline), clinical trial data showing some slowing in the progression of pathology in AD brain (ibuprofen) and indirect evidence for putative efficacy in blocking oxidative damage and chemotactic response mediated by activated microglia (dapsone). It is emphasized that a number of candidate compounds, other than ones suggested here, could be considered as components of the cocktail approach and would be expected to be examined in subsequent work. In this case, systematic testing in AD animal models is required to rigorously examine the efficacy of first-choice compounds and replace ones showing weaker effects. This protocol represents a practical approach to optimize the reduction of microglial-mediated chronic inflammation in AD pathology. Subsequent work would incorporate the anti-inflammatory cocktail delivery as an adjunctive treatment with ones independent of inflammation as an overall preventive strategy to slow the progression of AD.
Keywords: Combinatorial pharmacology, chronic inflammation, microglia, minocycline, thalidomide, ibuprofen, dapsone.
[1]
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’ disease. Neurobiol Aging 21: 383-421.(2000);
[2]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297: 353-6.(2002);
[3]
Rogers J, Webster S, Lue LF, Brachova L, Civin WH, et al. Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging 17: 681-6.(1996);
[4]
Grammas P. Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer’s disease. J Neuroinflammation 8: 26.(2011);
[5]
Combs CK, Johnson DE, Cannady SB, Lehman TM, Landreth GE. Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins. J Neurosci 19: 928-39.(1999);
[6]
Mrak RE, Griffin WS. Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26: 349-54.(2005);
[7]
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseran F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14: 388-405.(2015);
[8]
Ryu JK, McLarnon JG. A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brain. J Cell Mol Med 13: 2911-25.(2009);
[9]
Eikelenboom P, van Gool WA. Neuroinflammatory perspectives on the two faces of Alzheimer’s disease. J Neural Transm 111: 281-94.(2004);
[10]
McGeer PL, McGeer EG. NSAIDS and Alzheimer’s disease: epidemiological, animal model and clinical studies. Neurobiol Aging 28: 639-47.(2006);
[11]
Galimberti D, Scarpini E. Disease-modifying treatments for Alzheimer’s disease. Ther Adv Neurol Disorder 4: 203-16.(2011);
[12]
Piton M, Hirtz C, Desmetz C, Milhau J, Dominique A, et al. Alzheimer’s disease: Advances in drug development. J Alzheimers Dis 65: 3-13.(2018);
[13]
Ransohoff RM. All (animal) models (of neurodegeneration) are wrong. Are they also useful? J Exp Med 215: 2955-8.(2018);
[14]
Montagne A, Zhao Z, Zlokovic BV. Alzheimer’s disease: a matter of blood-brain barrier dysfunction. J Exp Med 214: 3151-60.(2017);
[15]
Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85: 296-302.(2015);
[16]
Cortes-Canteli M, Zamolodchikov D, Ahn HJ, Strickland S, Norris EH. Fibrinogen and altered hemostasis in Alzheimer’s disease. J Alzheimers Dis 32: 599-608.(2012);
[17]
Strickland S. Blood will out: vascular contributions to Alzheimer’s disease. J Clin Invest 128: 556-63.(2018);
[18]
Ryu JK, Cho T, Choi HB, Jantaratnotai N, McLarnon JG. Pharmacological antagonism of interleukin-8 receptor CXCR2 inhibits inflammatory reactivity and is neuroprotective in an animal model of Alzheimer’s disease. J Neuroinflammation 12: 144.(2015);
[19]
McLarnon JG, Ryu JK. Relevance of Aβ1-42 intrahippocampal injection as an animal model of inflamed Alzheimer’s disease brain. Curr Alzheimer Res 5: 475-80.(2008);
[20]
Pogue AI, Lukiw WJ. Angiogenic signaling in Alzheimer’s disease. Neuroreport 15: 1507-10.(2004);
[21]
Ryu JK, McLarnon JG. Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-α in an animal model of inflamed Alzheimer’s disease brain. Neurobiol Dis 29: 254-66.(2008);
[22]
Jantaratnotal N, Ryu JK, Schwab C, McGeer PL, McLarnon JG. Comparison of vascular perturbations in an Aβ-injected animal model and in AD brain. Int J Alz Dis (2011).
[http://dx.doi.org/10.4061/2011/918280]
[http://dx.doi.org/10.4061/2011/918280]
[23]
Desai BS, Schneider JA, Li JL, Carvey PM, Hendey B. Evidence of angiogenic vessels in Alzheimer’s disease. J Neural Transm 116: 587-97.(2009);
[24]
Jantaratnotai N, Schwab C, Ryu JK, McGeer PL, McLarnon JG. Converging perturbed vasculature and microglial clusters characterize Alzheimer disease brain. Curr Alzheimer Res 7: 1-12.(2010);
[25]
Biron KE, Dickstein DL, Gopaul R, Jefferies WA. Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer’s disease. PLoS One 6 e23789(2011);
[26]
Ujiie M, Dickstein D, Carlow D, Jefferies WA. Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10: 463-70.(2003);
[27]
Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer’s disease-like amyloid pathology. J Neuroinflammation 9: 62.(2012);
[28]
Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, et al. Minocycline prevents nigtostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. PNAS 90: 14669-74.(2001);
[29]
Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseh C, et al. Ischiropoulos H, Przedborski S. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. J Neurosci 22: 1763-71.(2002);
[30]
Tomas-Camardiel M, Rite I, Herrera AJ, et al. Minocycline reduces the lipopolysaccharide-induced inflammatory reaction, peroxynitrite-mediated nitration of proteins, disruption of the blood-brain barrier and damage in the nigral dopaminergic system. Neurobiol Dis 16: 190-201.(2004);
[31]
Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington’s disease. Nat Med 6: 797-801.(2000);
[32]
Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 96: 13496-500.(1999);
[33]
Ryu JK, Franciosi S, Sattayaprasert P, Kim SU, McLarnon JG. Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia 48: 85-90.(2004);
[34]
Ryu JK, McLarnon JG. Minocycline or iNOS inhibition block 3-nitrotyrosine increases and blood-brain barrier leakiness in amyloid beta-peptide-injected rat hippocampus. Exp Neurol 198: 552-7.(2006);
[35]
Seabrook TJ, Jiang L, Maier M, Lemere CA. Minocycline affects microglial activation, Abeta deposition, and behavior in APP-tg mice. Glia 5: 776-82.(2006);
[36]
Noble W, Garwood C, Stephenson J, Kinsey AM, Hanger DP, Anderton BH. Minocycline reduces the development of abnormal tau species in models of Alzheimer’s disease. FASEB J 23: 739-50.(2009);
[37]
Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS, et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models. Neuropsychopharmacol 32: 2393-404.(2007);
[38]
D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91: 4082-5.(1994);
[39]
Calabrese L, Fleischer AB. Thalidomide: current and potential clinical applications. Am J Med 108: 487-95.(2000);
[40]
Kiaei M, Petri S, Kipiani K, Gardian G, Choi DK, Chen J, et al. Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis. Nat Neurosci 26: 2467-73.(2006);
[41]
Neymotin A, Petri S, Calingasan NY, Wille E, Schafer P, Stewart C, et al. Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 220: 191-7.(2009);
[42]
Valera E, Mante M, Anderson S, Rockenstein E, Masliah E. Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson’s disease. J Neuroinflamm 12: 93.(2015);
[http://dx.doi.org/10.1186]
[http://dx.doi.org/10.1186]
[43]
Teo SK, Stirling DI, Zeldis JB. Thalidomide as a novel therapeutic agent: new uses for an old product. Drug Discov Today 10: 107-14.(2005);
[44]
Tweedie D, Ferguson RA, Fishman K, Frankola KA, Van Praag H, Holloway HW, et al. Tumor necrosis factor-α synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer’s pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease. J Neuroinflammation 9: 106.(2012);
[45]
He P, Cheng X, Staufenbiel M, Li R, Shen Y. Long-term treatment of thalidomide ameliorates amyloid-like pathology through inhibition of β-secretase in a mouse model of Alzheimer’s disease. PLoS One 8 e55091(2013);
[46]
Decourt B, Drumm-Gurnee D, Wilson J, Jacobson S, Belden C, et al. Poor safety and tolerability hamper reaching a potentially therapeutic dose in the use of thalidomide: Results from a double-blind, placebo-controlled trial. Curr Alzheimer Res 14: 403-11.(2017);
[47]
Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk of Parkinson disease. Neurology 76: 863-9.(2011);
[48]
Breitner JC, Welsh KA, Helms MJ, Gaskell PC, Gau BA, Roses AD, et al. Delayed onset of Alzheimer’s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging 16: 523-30.(1995);
[49]
Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer L, Breitner JC. Reduced incidence of AD with NSAID but not H2 receptor antagonist: the Cache County study. Neurology 59: 880-6.(2002);
[50]
Veld SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDS on the development of Alzheimer’s disease. Neurology 70: 1672-7.(2008);
[51]
Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48: 626-32.(1997);
[52]
Int Veldt BA, Ruttenburg A, Hofman A. Nonsteroidal anti-inflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 345: 1515-21.(2001);
[53]
McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 126: 479-97.(2013);
[54]
Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 20: 5709-14.(2000);
[55]
Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, et al. NSAIDS and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo. J Clin Invest 112: 440-9.(2003);
[56]
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, et al. Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1-42 levels in APPV7171 transgenic mice. Brain 128: 1442-53.(2005);
[57]
Cohen PR. Neutrophilic dermatoses: a review of current treatment options. Am J Clin Dermatol 10: 301-12.(2009);
[58]
Hong TM, Teng LJ, Shun CT, Peng MC, Tsai JC. Induced interleukin-8 expression in gliomas by tumor-associated macrophages. J Neurooncol 93: 289-301.(2009);
[59]
Kast RE, Scheuerle A, Wirtz CR, Karpel-Massler G, Halatsch ME. The rationale of targeting neutrophils with dapsone during glioblastoma treatment. Anticancer Agents Med Chem 11(8): 756-61.(2011);
[60]
McGeer PL, Harada N, Kimura H, McGeer EG, Schulzer M. Prevalence of dementia amongst elderly Japanese with leprosy: apparent effect of chronic drug therapy. Dement Geriatr Cogn Disord 3: 146-9.(1992);
[61]
Goto M, Kimura T, Hagio S, Ueda K, Kitajima S. Neuropathological analysis of dementia in a Japanese leprosarum. Dementia 6: 157-61.(1995);
[62]
Zhan R, Zhao M, Zhou T, Chen Y, Yu W, Zhao L, et al. Dapsone protects brain microvascular integrity from high-fat diet induced LDL oxidation. Cell Death Dis 9: 680.(2018);
[63]
Grammas P, Ovase R. Inflammatory factors are elevated in brain microvessels in Alzheimer’s disease. Neurobiol Aging 22: 837-42.(2001);
[64]
Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14: 133-50.(2018);
[65]
Galimberti D, Schoonenboom N, Scarpini E, Scheltens P. Chemokines in serum and cerebrospinal fluid of Alzheimer’s disease patients. Ann Neurol 53: 547-8.(2003);
[66]
Xia M, Qin S, McNamara M, Mackay C, Hyman BT. Interleukin-8 receptor B immunoreactivity in brain and neuritic plaques of Alzheimer’s disease. Am J Pathol 150: 1267-74.(1997);
[67]
Walker DG, Lue LF, Beach TG. Gene expression profiling of amyloid beta peptide-stimulated human post-mortem brain microglia. Neurobiol Aging 22: 957-66.(2001);
[68]
Franciosi S, Choi HB, Kim SU, McLarnon JG. IL-8 enhancement of amyloid-beta (Aβ1-42)-induced expression and production of pro-inflammatory cytokines and COX-2 in cultured human microglia. J Neuroimmunol 159: 66-74.(2005);
[69]
Herrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18: 794-9.(2015);
[70]
Mehta D, Jackson R, Paul G, Shi J, Sabbagh M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs 26: 735-9.(2017);
[71]
Brogden RN, Speight TM, Avery GS. Minocycline: a review of its antibacterial and pharmacokinetic properties and therapeutic use. Drugs 9: 251-91.(1975);
[72]
Garrido-Mesa N, Zarzuelo A, Galvez J. Minocycline: far beyond an antibiotic. Br J Pharmacol 169: 337-52.(2013);
[73]
Muscal JA, Sun Y, Nuchtern JG, Dauser RC, McGuffey LH, Gibson BW, et al. Plasma and cerebrospinal fluid pharmacokinetics of thalidomide and lenalidomide in nonhuman primates. Cancer Chemother Pharmacol 69: 943-7.(2012);
[74]
Palumbo A, Facon T, Sonneveld P, Bladè J, Offidani M, Gay F, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood 111: 3968-77.(2008);
[75]
Parepally JM, Mandula H, Smith QK. Brain uptake of nonsteroidal anti-inflammatory drugs: ibuprofen, flurbiprofen and indomethacin. Pharm Res 23: 873-81.(2006);
[76]
Adams SS, Bough RG, Cliffe EE, Lessel B, Mills RFN. Absorption, distribution and toxicity of ibuprofen. Toxicol Appl Pharmacol 15: 310-30.(1969);
[77]
Murray JF Jr, Gordon GR, Peters JH. Tissue levels of dapsone and monoacetyl-dapsone in Lewis rats receiving dietary dapsone. Proc West Pharmacol Soc 17: 150-4.(1974);
[78]
Coleman MD. Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance. Br J Dermatol 129: 507-13.(1993);
[79]
Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ. Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer’s disease mice. J Neuroinflammation 2: 23.(2005);
[80]
Moir RD, Lathe R. T RE. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement 14: 1602-14.(2018);
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