A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model

Munoz, Lenka; Ranaivo, Hantamalala Ralay; Roy, Saktimayee M; Hu, Wenhui; Craft, Jeffrey M; McNamara, Laurie K; Chico, Laura Wing; Van Eldik, Linda J; Watterson, D Martin

doi:10.1186/1742-2094-4-21

Cited by 226Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model

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Munoz, Lenka, Ranaivo, Hantamalala Ralay, Roy, Saktimayee M, Hu, Wenhui, Craft, Jeffrey M, McNamara, Laurie K, Chico, Laura Wing, Van Eldik, Linda J +1 more·2007·Journal of Neuroinflammation

DOI 10.1186/1742-2094-4-21PMC PMC2014744

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Abstract

BACKGROUND: An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38 alpha MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (A beta) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38 alpha MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes. METHODS: A novel synthetic small molecule based on a molecular scaffold used previously was designed, synthesized, and subjected to analyses to demonstrate its potential in vivo bioavailability, metabolic stability, safety and brain uptake. Testing for in vivo efficacy used an AD-relevant mouse model. RESULTS: A novel, CNS-penetrant, non-toxic, orally bioavailable, small molecule inhibitor of p38 alpha MAPK (MW01-2-069A-SRM) was developed. Oral administration of the compound at a low dose (2.5 mg/kg) resulted in attenuation of excessive proinflammatory cytokine production in the hippocampus back towards normal in the animal model. Animals with attenuated cytokine production had reductions in synaptic dysfunction and hippocampus-dependent behavioral deficits. CONCLUSION: The p38 alpha MAPK pathway is quantitatively important in the A beta-induced production of proinflammatory cytokines in hippocampus, and brain p38 alpha MAPK is a viable molecular target for future development of potential disease-modifying therapeutics in AD and related neurodegenerative disorders.

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p38α MAPK has been shown to mediate Aβ-induced expression of various proinflammatory cytokines/chemokines from microglial cells that causes neuroinflammation.
“First, p38α MAPK has been shown to mediate Aβ-induced expression of various proinflammatory cytokines/chemokines from microglial cells that causes neuroinflammation [25, 26, 29, 35].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [35]
The Background reports that Aβ activates p38 MAPK in glial cultures, followed by increased proinflammatory cytokines that p38 inhibitors block. The Results and Discussion report that a p38α inhibitor reduced Aβ-induced hippocampal cytokines in mice. The paper does not establish that those mouse cytokines came specifically from microglia, and the cited passages do not support the claim about chemokines. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Targeted inactivation of p38α MAPK with small molecule inhibitors prevents the production of proinflammatory cytokines, reduces neurodegeneration, and improves neuronal and cognitive functions in rodent models of amyloid pathology.
“Targeted inactivation of p38α MAPK with small molecule inhibitors prevents the production of proinflammatory cytokines, reduces neurodegeneration, and improves neuronal and cognitive functions in rodent models of amyloid pathology [25, 26, 29, 35].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [35]
In Results and Discussion, ‘In vivo efficacy in AD animal model’ (page not provided), the paper reports that a p38α MAPK inhibitor reduced Aβ-induced hippocampal cytokine increases, attenuated synaptophysin loss, and improved Y-maze performance in a mouse model. It reports reduction toward baseline, not prevention of cytokine production, and does not show reduced neurodegeneration or test multiple rodent models. (LLM, conf=0.87)
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Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Mammalian Mitogen-Activated Protein Kinase Signal Transduction Pathways Activated by Stress and Inflammation
Kyriakis, J. M., & Avruch, J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.807 · Cited by 3,369 · see citing works
The druggable genome
Hopkins, A. L., & Groom, C. R. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd892 · Cited by 3,305 · see citing works
Antiinflammatory Action of Glucocorticoids — New Mechanisms for Old Drugs
Rhen, T., & Cidlowski, J. A. (2005) · New England Journal of Medicine · doi:10.1056/nejmra050541 · Cited by 3,149 · see citing works
Mechanisms involved in the side effects of glucocorticoids
SCHACKE, H. (2002) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(02)00297-8 · Cited by 1,847 · see citing works
Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease.
Griffin, W. S., Stanley, L. C., Ling, C., White, L., MacLeod, V, Perrot, L. J., White, C. L., & Araoz, C. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.19.7611 · Cited by 1,777 · see citing works
MAPK signalling pathways as molecular targets for anti-inflammatory therapy—from molecular mechanisms to therapeutic benefits
Kaminska, B. (2005) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2005.08.017 · Cited by 1,285 · see citing works
p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases
Kumar, S., Boehm, J. C., & Lee, J. C. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1177 · Cited by 1,199 · see citing works
Blood–brain barrier delivery
Pardridge, W. M. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2006.10.013 · Cited by 1,191 · see citing works
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
Bhat, N. R., Zhang, P., Lee, J. C., & Hogan, E. L. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-05-01633.1998 · Cited by 714 · see citing works
Glial‐Neuronal Interactions in Alzheimer's Disease: The Potential Role of a ‘Cytokine Cycle’ in Disease Progression
Griffin, W. S. T., Sheng, J. G., Royston, M. C., Gentleman, S., McKenzie, J. E., Graham, D. I., Roberts, G. W., & Mrak, R. E. (1998) · Brain Pathology · doi:10.1111/j.1750-3639.1998.tb00136.x · Cited by 708 · see citing works
Interleukin 1 in the brain: biology, pathology and therapeutic target
Rothwell, N. J. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01661-1 · Cited by 671 · see citing works
Glia and their cytokines in progression of neurodegeneration
Mrak, R. E., & Griffin, W. S. T. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.05.010 · Cited by 592 · see citing works
Anti-TNF-α therapies: the next generation
Palladino, M. A., Bahjat, F. R., Theodorakis, E. A., & Moldawer, L. L. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1175 · Cited by 579 · see citing works
Interleukin-1 Mediates Pathological Effects of Microglia on Tau Phosphorylation and on Synaptophysin Synthesis in Cortical Neurons through a p38-MAPK Pathway
Li, Y., Liu, L., Barger, S. W., & Griffin, W. S. T. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-05-01605.2003 · Cited by 563 · see citing works
The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis
Minagar, A., Shapshak, P., Fujimura, R. K., Ownby, R., Heyes, M., & Eisdorfer, C. (2002) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(02)00207-1 · Cited by 538 · see citing works
Phenolic anti-inflammatory antioxidant reversal of AÎ²-induced cognitive deficits and neuropathology
Frautschy, S. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00300-1 · Cited by 514 · see citing works
The druggable genome: an update
Russ, A., & Lampel, S. (2005) · Drug Discovery Today · doi:10.1016/s1359-6446(05)03666-4 · Cited by 416 · see citing works
Inflammatory Process in Parkinsons Disease: Role for Cytokines
Nagatsu, T., & Sawada, M. (2005) · Current Pharmaceutical Design · doi:10.2174/1381612053381620 · Cited by 412 · see citing works
The p38 MAP kinase pathway as a therapeutic target in inflammatory disease
Saklatvala, J. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.03.009 · Cited by 408 · see citing works
Activation of p38 Kinase Links Tau Phosphorylation, Oxidative Stress, and Cell Cycle-Related Events in Alzheimer Disease
Zhu, X., Rottkamp, C. A., Boux, H., Takeda, A., Perry, G., & Smith, M. A. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.10.880 · Cited by 378 · see citing works
p38 Kinase Is Activated in the Alzheimer's Disease Brain
Hensley, K., Floyd, R. A., Zheng, N., Nael, R., Robinson, K. A., Nguyen, X., Pye, Q. N., Stewart, C. A., Geddes, J., Markesbery, W. R., et al. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0722053.x · Cited by 373 · see citing works
The Biology of p38 Kinase: A Central Role in Inflammation
Schieven, G. L. (2005) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026054985902 · Cited by 314 · see citing works
An inflammatory review of Parkinson's disease
Orr, C. F., Rowe, D. B., & Halliday, G. M. (2002) · Progress in Neurobiology · doi:10.1016/s0301-0082(02)00127-2 · Cited by 309 · see citing works
Current Advances on Different Kinases Involved in Tau Phosphorylation, and Implications in Alzheimers Disease and Tauopathies
Ferrer, I., Gómez‐Isla, T., Puig, B., Freixes, M., Ribé, E. M., Dalfó, E., & Ávila, J. (2005) · Current Alzheimer Research · doi:10.2174/1567205052772713 · Cited by 302 · see citing works
Activation of c-Jun N-Terminal Kinase and p38 in an Alzheimer's Disease Model Is Associated with Amyloid Deposition
Savage, M. J., Lin, Y.-G., Ciallella, J. R., Flood, D. G., & Scott, R. W. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-09-03376.2002 · Cited by 291 · see citing works
Role of p38 and p44/42 mitogen‐activated protein kinases in microglia
Koistinaho, M., & Koıstınaho, J. (2002) · Glia · doi:10.1002/glia.10151 · Cited by 283 · see citing works
TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study.
Tobinick, E. L., Gross, H., Weinberger, A., & Cohen, H. (2006) · PubMed Central · Cited by 271 · see citing works
In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis
Sheng, J. G., Ito, K., Skinner, R. D., Mrak, R. E., Rovnaghi, C. R., van Eldik, L. J., & Griffin, W. S. T. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00104-2 · Cited by 269 · see citing works
Interleukin-1 mediates Alzheimer and Lewy body pathologies
Griffin, W. S. T., Liu, L., Li, Y., Mrak, R. E., & Barger, S. W. (2006) · Journal of Neuroinflammation · doi:10.1186/1742-2094-3-5 · Cited by 262 · see citing works
β-Amyloid Fibrils Activate Parallel Mitogen-Activated Protein Kinase Pathways in Microglia and THP1 Monocytes
McDonald, D. R., Bamberger, M. E., Combs, C. K., & Landreth, G. E. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-12-04451.1998 · Cited by 259 · see citing works
Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1β production
Kim, S. H., Smith, C. J., & Eldik, L. J. V. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(03)00126-x · Cited by 234 · see citing works
MAP Kinase p38Inhibitors: Clinical Results and an Intimate Look at Their Interactions with p38α Protein
Lee, M. R., & Dominguez, C. (2005) · Current Medicinal Chemistry · doi:10.2174/092986705774462914 · Cited by 222 · see citing works
P38 MAP kinase is activated at early stages in Alzheimer's disease brain
Sun, A. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00180-8 · Cited by 219 · see citing works
Mitogen-activated protein kinases activated by lipopolysaccharide and β-amyloid in cultured rat microglia
Pyo, H., Jou, I., Jung, S., Hong, S., & Joe, E.-H. (1998) · Neuroreport · doi:10.1097/00001756-199803300-00020 · Cited by 217 · see citing works
Targeting IL-1 in inflammatory disease: new opportunities for therapeutic intervention
Braddock, M., & Quinn, A. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1342 · Cited by 214 · see citing works
β-Amyloid-Induced Inflammation and Cholinergic Hypofunction in the Rat Brain in Vivo: Involvement of the p38MAPK Pathway
Giovannini, M. G., Scali, C., Prosperi, C., Bellucci, A., Vannucchi, M. G., Rosi, S., Pepeu, G., & Casamenti, F. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0538 · Cited by 214 · see citing works
Neuronal–Glial Interactions Mediated by Interleukin-1 Enhance Neuronal Acetylcholinesterase Activity and mRNA Expression
Li, Y., Liu, L., Kang, J., Sheng, J. G., Barger, S. W., Mrak, R. E., & Griffin, W. S. T. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-01-00149.2000 · Cited by 209 · see citing works
Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis
Sargsyan, S. A., Monk, P. N., & Shaw, P. J. (2005) · Glia · doi:10.1002/glia.20210 · Cited by 203 · see citing works
Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation
Sheng, J. G., Jones, R. A., Zhou, X. Q., McGinness, J. M., Van Eldik, L. J., Mrak, R. E., & Griffin, W. S. T. (2001) · Neurochemistry International · doi:10.1016/s0197-0186(01)00041-9 · Cited by 176 · see citing works
MAPK-activated Protein Kinase 2 Deficiency in Microglia Inhibits Pro-inflammatory Mediator Release and Resultant Neurotoxicity
Culbert, A. A., Skaper, S. D., Howlett, D. R., Evans, N. A., Facci, L., Soden, P. E., Seymour, Z. M., Guillot, F., Gaestel, M., & Richardson, J. C. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513646200 · Cited by 170 · see citing works
Chromatographic Retention Parameters in Medicinal Chemistry and Molecular Pharmacology
Nasal, A., Siluk, D., & Kaliszan, R. (2003) · Current Medicinal Chemistry · doi:10.2174/0929867033368268 · Cited by 167 · see citing works
Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration
Pei, J.-J., Braak, E., Braak, H., Grundke-Iqbal, I., Iqbal, K., Winblad, B., & Cowburn, R. F. (2001) · Journal of Alzheimer's Disease · doi:10.3233/jad-2001-3107 · Cited by 165 · see citing works
1 p38 MAP Kinase: Molecular Target for the Inhibition of Pro-inflammatory Cytokines
Adams, J. L., Badger, A. M., Kumar, S., & Lee, J. C. (2001) · Progress in medicinal chemistry · doi:10.1016/s0079-6468(08)70091-2 · Cited by 165 · see citing works
Activation of MKK6, an upstream activator of p38, in Alzheimer's disease
Zhu, X.-W., Rottkamp, C., Hartzler, A., Sun, Z., Takeda, A., Boux, H., Shimohama, S., Perry, G., & Smith, M. A. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00597.x · Cited by 151 · see citing works
Interleukin-1 Promotes Expression and Phosphorylation of Neurofilament and tau Proteins in Vivo
Sheng, J. G., Zhu, S., Jones, R. A., Griffin, W. S. T., & Mrak, R. E. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7393 · Cited by 147 · see citing works
Innate immunity in amyotrophic lateral sclerosis
Moisse, K., & Strong, M. J. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2006.03.001 · Cited by 141 · see citing works
Glia as a Therapeutic Target: Selective Suppression of Human Amyloid-β-Induced Upregulation of Brain Proinflammatory Cytokine Production Attenuates Neurodegeneration
Ranaivo, H. R., Craft, J. M., Hu, W., Guo, L., Wing, L. K., Eldik, L. J. V., & Watterson, D. M. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4652-05.2006 · Cited by 137 · see citing works
Self-citation
Interlaboratory study of log {ce:inline-formula}P{/ce:inline-formula} determination by shake-flask and potentiometric methods
́k, K. T. ́.-N., & Avdeel, A. (1996) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/0731-7085(96)01773-6 · Cited by 137 · see citing works
New Approaches to the Treatment of Inflammatory Disorders Small Molecule inhibitors of p38 MAP Kinase
Peifer, C., Wagner, G. K., & Laufer, S. (2006) · Current Topics in Medicinal Chemistry · doi:10.2174/156802606775270323 · Cited by 127 · see citing works
Glial Activation Links Early‐Life Seizures and Long‐Term Neurologic Dysfunction: Evidence Using a Small Molecule Inhibitor of Proinflammatory Cytokine Upregulation
Somera-Molina, K., Robin, B., Somera, C. A., Anderson, C., Stine, C. D., Koh, S., Behanna, H. A., Eldik, L. J. V., Watterson, D. M., & Wainwright, M. S. (2007) · Epilepsia · doi:10.1111/j.1528-1167.2007.01135.x · Cited by 123 · see citing works
Self-citation
p38 MAP KINASE REGULATES TNF-α PRODUCTION IN HUMAN ASTROCYTES AND MICROGLIA BY MULTIPLE MECHANISMS
Lee, Y. B., Schrader, J. W., & Kim, S. U. (2000) · Cytokine · doi:10.1006/cyto.2000.0688 · Cited by 121 · see citing works
Neuroinflammation: a potential therapeutic target
Craft, J. M., Watterson, D. M., & Van Eldik, L. J. (2005) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.9.5.887 · Cited by 116 · see citing works
Self-citation
Human amyloid β‐induced neuroinflammation is an early event in neurodegeneration
Craft, J. M., Watterson, D. M., & Eldik, L. J. V. (2005) · Glia · doi:10.1002/glia.20306 · Cited by 108 · see citing works
Self-citation
The p38 MAP kinase signaling pathway in Alzheimer's disease
Johnson, G. (2003) · Experimental Neurology · doi:10.1016/s0014-4886(03)00268-1 · Cited by 106 · see citing works
Similarity in drugs: reflections on analogue design
Wermuth, C. G. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.02.006 · Cited by 96 · see citing works
Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human β-amyloid
Craft, J. M., Watterson, D. M., Hirsch, E., & Van Eldik, L. J. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-15 · Cited by 96 · see citing works
Self-citation
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Velentza, A. V., Wainwright, M. S., Zasadzki, M., Mirzoeva, S., Schumacher, A. M., Haiech, J., Focia, P. J., Egli, M., & Watterson, D. M. (2003) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(03)00733-9 · Cited by 93 · see citing works
Self-citation
Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo
Craft, J. M., Watterson, D. M., Frautschy, S. A., & Eldik, L. J. V. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.01.006 · Cited by 91 · see citing works
Self-citation
Drug discovery: selecting the optimal approach
Sams‐Dodd, F. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.03.015 · Cited by 81 · see citing works
Sodium ferulate prevents amyloid-beta-induced neurotoxicity through suppression of p38 MAPK and upregulation of ERK-1/2 and Akt/protein kinase B in rat hippocampus1
Jin, Y. H., Yan, E., Fan, Y., Zong, Z., Zhi-min, Q. I., & Li, Z. (2005) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2005.00158.x · Cited by 78 · see citing works
Small Molecule p38 Inhibitors: Novel Structural Features and Advances from 2002-2005
Hynes, J. J., & Leftheris, K. (2005) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026054985920 · Cited by 70 · see citing works
Neurodegenerative disease and the neuroimmune axis (Alzheimer's and Parkinson's disease, and viral infections)
Ringheim, G. E., & Conant, K. E. (2003) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2003.10.013 · Cited by 68 · see citing works
Broad-Spectrum Effects of 4-Aminopyridine to Modulate Amyloid β1–42-Induced Cell Signaling and Functional Responses in Human Microglia
Franciosi, S., Ryu, J. K., Choi, H. B., Radov, L. A., Kim, S. U., & McLarnon, J. G. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2490-06.2006 · Cited by 68 · see citing works
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Hu, W., Ranaivo, H. R., Roy, S. M., Behanna, H. A., Wing, L. K., Munoz, L., Guo, L., Eldik, L. J. V., & Watterson, D. M. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.10.028 · Cited by 66 · see citing works
Self-citation
Stress kinases involved inTau phosphorylation in alzheimer’s disease, tauopathies and APP transgenic mice
Ferrer, I. (2004) · Neurotoxicity Research · doi:10.1007/bf03033283 · Cited by 53 · see citing works
Enhanced susceptibility of S‐100B transgenic mice to neuroinflammation and neuronal dysfunction induced by intracerebroventricular infusion of human β‐amyloid
Craft, J. M., Watterson, D. M., Marks, A., & Eldik, L. J. V. (2005) · Glia · doi:10.1002/glia.20194 · Cited by 50 · see citing works
Self-citation
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Schumacher, A. M., Schavocky, J. P., Velentza, A. V., Mirzoeva, S., & Watterson, D. M. (2004) · Biochemistry · doi:10.1021/bi049589v · Cited by 46 · see citing works
Self-citation
New Methods in the Chemistry Pyridazones
Dury, K. (1965) · Angewandte Chemie International Edition in English · doi:10.1002/anie.196502921 · Cited by 43 · see citing works
Metabolic Stability Assessed by Liver Microsomes and Hepatocytes
Ackley, D. C., Rockich, K. T., & Baker, T. R. (2004) · Humana Press eBooks · doi:10.1385/1-59259-800-5:151 · Cited by 36 · see citing works
P4–428: Glia as a therapeutic target: Selective suppression of human amyloid–beta–induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration
Eldik, L. J. V., Ranaivo, H. R., Hu, W., Craft, J. M., Guo, L., Wing, L. K., & Watterson, D. M. (2006) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2006.05.2170 · Cited by 34 · see citing works
Self-citation
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Craft, J. M., Eldik, L. J. V., Zasadzki, M., Hu, W., & Watterson, D. M. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:24:1:115 · Cited by 31 · see citing works
Self-citation
p38 Mitogen Activated Protein Kinase as a Therapeutic Target for Alzheimer's Disease
Dalrymple, S. A. (2002) · Journal of Molecular Neuroscience · doi:10.1385/jmn:19:3:295 · Cited by 30 · see citing works
De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders
Wing, L., Behanna, H. A., Eldik, L. J. V., Watterson, D. M., & Ranaivo, H. R. (2006) · Current Alzheimer Research · doi:10.2174/156720506777632844 · Cited by 28 · see citing works
Self-citation
Physical chemical characterization of drug substances
Streng, W. H. (1997) · Drug Discovery Today · doi:10.1016/s1359-6446(97)01077-5 · Cited by 28 · see citing works
Pyridazine Derivatives, IX. Synthesis of 2H-Pyridazin-3-ones with Aroylpiperazinyl Groups
Raviña, E., Terán, C., Santana, L., GARCIA‐DOMINGUEZ, N., & Estévez, I. (1990) · Heterocycles · doi:10.3987/com-90-5493 · Cited by 27 · see citing works
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Sams‐Dodd, F. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.02.014 · Cited by 24 · see citing works
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Bhagwat, S. S., Manning, A. M., Hoekstra, M. F., & Lewis, A. J. (1999) · Drug Discovery Today · doi:10.1016/s1359-6446(99)01402-6 · Cited by 19 · see citing works
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Self-citation
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Guo, Y., & Shen, H. (2004) · Humana Press eBooks · doi:10.1385/1-59259-800-5:001 · Cited by 9 · see citing works
ChemInform Abstract: Pyridazine Derivatives. Part 9. Synthesis of 2H‐Pyridazin‐3‐ones with Aroylpiperazinyl Groups.
Raviña, E., Terán, C., Santana, L., GARCIA‐DOMINGUEZ, N., & Estévez, I. (1991) · ChemInform · doi:10.1002/chin.199114187 · Cited by 2 · see citing works

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Self-citation
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Borders, A. S., McNamara, L. K., Roy, S. M., Chico, L. W., Pishchulina, A., de Almeida, L. M., Eldik, L. J. V., & Watterson, D. M. (2008) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2008.05.1498
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Munoz, L., Ranaivo, H. R., Roy, S. M., Hu, W., Craft, J. M., McNamara, L. K., Eldik, L. J. V., & Watterson, D. M. (2013)
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Eldik, L. J. V. (2011) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2011.05.830
P4–428: Glia as a therapeutic target: Selective suppression of human amyloid–beta–induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration
Eldik, L. J. V., Ranaivo, H. R., Hu, W., Craft, J. M., Guo, L., Wing, L. K., & Watterson, D. M. (2006) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2006.05.2170 · Cited by 34 · see citing works
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Frazier, H. N., Braun, D. J., Davis, V. A., Coleman, M. J., Rogers, C. B., & Eldik, L. J. V. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.073093

Authors: Munoz, L., Ranaivo, H. R., Roy, S. M., Hu, W., Craft, J. M., McNamara, L. K., Chico, L. W., Van Eldik, L. J., & Watterson, D. M.
Affiliations: Northwestern University (US)
Corresponding author: Watterson, D Martin
ORCID: Munoz, Lenka
Ranaivo, Hantamalala Ralay
Roy, Saktimayee M
Hu, Wenhui
Watterson, D Martin
Venue: Journal of Neuroinflammation
Publisher: Springer Science and Business Media LLC
Published: 2007-09-04
Volume: 4
Issue: 1
Pages: 21-21
ISSN: 1742-2094 (ISSN-L)
DOI: 10.1186/1742-2094-4-21
PMC: PMC2014744
OpenAlex: W2029663297
Cited by: 224
References: 83
Citations by year: 2026: 4 · 2025: 4 · 2024: 11 · 2023: 10 · 2022: 9 · 2021: 12 · 2020: 11 · 2019: 13 · 2018: 9 · 2017: 20 · 2016: 15 · 2015: 13 · 2014: 10 · 2013: 14 · 2012: 21
FWCI: 6.26
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Journal of Neuroinflammation (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Northwestern University
National Institutes of Health
National Institute on Aging (R01AG031311)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: Alzheimer's disease, inflammatory cytokines, glial activation, synaptic dysfunction, amyloid-beta, small molecule inhibitors, blood-brain barrier penetration, orally bioavailable drugs, disease-modifying therapy, neuroinflammation
MeSH terms: Alzheimer Disease, Animals, Behavior, Animal, Brain, Disease Models, Animal, Humans, Mice, Inbred C57BL, Pyridazines, Pyrimidines, Synapses, Drugs, Investigational, Up-Regulation, Cytokines, Inflammation Mediators, MAP Kinase Signaling System, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 14, Mice

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A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model

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