Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation

Authors: Karim Belarbi, Timothy Jopson, David Tweedie, Carla Arellano, Weiming Luo, Nigel H Greig, Susanna Rosi

Published in: Journal of Neuroinflammation | Issue 1/2012

Login to get access

Abstract

Background

Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Activated microglia and secreted factors such as tumor necrosis factor (TNF)-α are key mediators of neuroinflammation and may contribute to neuronal dysfunction. Our study was aimed to evaluate the therapeutic potential of a novel analog of thalidomide, 3,6'-dithiothalidomide (DT), an agent with anti-TNF-α activity, in a model of chronic neuroinflammation.

Methods

Lipopolysaccharide or artificial cerebrospinal fluid was infused into the fourth ventricle of three-month-old rats for 28 days. Starting on day 29, animals received daily intraperitoneal injections of DT (56 mg/kg/day) or vehicle for 14 days. Thereafter, cognitive function was assessed by novel object recognition, novel place recognition and Morris water maze, and animals were euthanized 25 min following water maze probe test evaluation.

Results

Chronic LPS-infusion was characterized by increased gene expression of the proinflammatory cytokines TNF-α and IL-1β in the hippocampus. Treatment with DT normalized TNF-α levels back to control levels but not IL-1β. Treatment with DT attenuated the expression of TLR2, TLR4, IRAK1 and Hmgb1, all genes involved in the TLR-mediated signaling pathway associated with classical microglia activation. However DT did not impact the numbers of MHC Class II immunoreactive cells. Chronic neuroinflammation impaired novel place recognition, spatial learning and memory function; but it did not impact novel object recognition. Importantly, treatment with DT restored cognitive function in LPS-infused animals and normalized the fraction of hippocampal neurons expressing the plasticity-related immediate-early gene Arc.

Conclusion

Our data demonstrate that the TNF-α synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-α is a critical mediator of chronic neuroinflammation-induced neuronal dysfunction and cognitive impairment and targeting its synthesis could provide an effective therapeutic approach to several human neurodegenerative diseases.
Literature
1.
Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB: In-vivo measurement of activated microglia in dementia. Lancet 2001, 358:461–467.CrossRefPubMed
2.
Garden GA: Microglia in human immunodeficiency virus-associated neurodegeneration. Glia 2002, 40:240–251.CrossRefPubMed
3.
McGeer PL, Itagaki S, Boyes BE, McGeer EG: Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 1988, 38:1285–1291.CrossRefPubMed
4.
Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S: Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999, 162:3749–3752.PubMed
5.
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T: Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA 2003, 100:8514–8519.CrossRefPubMedPubMedCentral
6.
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, et al.: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998, 282:2085–2088.CrossRefPubMed
7.
Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K: Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem 2007, 20:947–956.CrossRefPubMed
8.
Rogers J, Lue LF: Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int 2001, 39:333–340.CrossRefPubMed
9.
10.
Pocock JM, Liddle AC: Microglial signalling cascades in neurodegenerative disease. Prog Brain Res 2001, 132:555–565.CrossRefPubMed
11.
Rosi S, Ramirez-Amaya V, Vazdarjanova A, Worley PF, Barnes CA, Wenk GL: Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression. J Neurosci 2005, 25:723–731.CrossRefPubMed
12.
Rosi S, Ramirez-Amaya V, Vazdarjanova A, Esparza EE, Larkin PB, Fike JR, Wenk GL, Barnes CA: Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine. Brain 2009, 132:2464–2477.CrossRefPubMedPubMedCentral
13.
Belarbi K, Arellano C, Ferguson R, Jopson T, Rosi S: Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Brain Behav Immun 2012, 26:18–23.CrossRefPubMed
14.
15.
Hauss-Wegrzyniak B, Dobrzanski P, Stoehr JD, Wenk GL: Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer's disease. Brain Res 1998, 780:294–303.CrossRefPubMed
16.
Rosi S, Vazdarjanova A, Ramirez-Amaya V, Worley PF, Barnes CA, Wenk GL: Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience 2006, 142:1303–1315.CrossRefPubMed
17.
McCoy MK, Tansey MG: TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 2008, 5:45.CrossRefPubMedPubMedCentral
18.
Merrill JE: Effects of interleukin-1 and tumor necrosis factor-alpha on astrocytes, microglia, oligodendrocytes, and glial precursors in vitro. Dev Neurosci 1991, 13:130–137.CrossRefPubMed
19.
Pickering M, Cumiskey D, O'Connor JJ: Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol 2005, 90:663–670.CrossRefPubMed
20.
Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC: Control of synaptic strength by glial TNFalpha. Science 2002, 295:2282–2285.CrossRefPubMed
21.
Paganelli R, Di Iorio A, Patricelli L, Ripani F, Sparvieri E, Faricelli R, Iarlori C, Porreca E, Di Gioacchino M, Abate G: Proinflammatory cytokines in sera of elderly patients with dementia: levels in vascular injury are higher than those of mild-moderate Alzheimer's disease patients. Exp Gerontol 2002, 37:257–263.CrossRefPubMed
22.
Fillit H, Ding WH, Buee L, Kalman J, Altstiel L, Lawlor B, Wolf-Klein G: Elevated circulating tumor necrosis factor levels in Alzheimer's disease. Neurosci Lett 1991, 129:318–320.CrossRefPubMed
23.
Tarkowski E, Blennow K, Wallin A, Tarkowski A: Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol 1999, 19:223–230.CrossRefPubMed
24.
Alvarez A, Cacabelos R, Sanpedro C, Garcia-Fantini M, Aleixandre M: Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging 2007, 28:533–536.CrossRefPubMed
25.
Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T: Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 1994, 165:208–210.CrossRefPubMed
26.
Nagatsu T, Mogi M, Ichinose H, Togari A: Changes in cytokines and neurotrophins in Parkinson's disease. J Neural Transm Suppl 2000, 60:277–290.PubMed
27.
Wesselingh SL, Power C, Glass JD, Tyor WR, McArthur JC, Farber JM, Griffin JW, Griffin DE: Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann Neurol 1993, 33:576–582.CrossRefPubMed
28.
Frankola KA, Greig NH, Luo W, Tweedie D: Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS Neurol Disord Drug Targets 2011, 10:391–403.CrossRefPubMedPubMedCentral
29.
Tobinick E, Gross H, Weinberger A, Cohen H: TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. Med Gen Med 2006, 8:25.
30.
Tobinick EL, Gross H: Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation 2008, 5:2.CrossRefPubMedPubMedCentral
31.
Tobinick E: Perispinal etanercept for treatment of Alzheimer's disease. Curr Alzheimer Res 2007, 4:550–552.CrossRefPubMed
32.
Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G: Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 1993, 177:1675–1680.CrossRefPubMed
33.
Kruys V, Marinx O, Shaw G, Deschamps J, Huez G: Translational blockade imposed by cytokine-derived UA-rich sequences. Science 1989, 245:852–855.CrossRefPubMed
34.
Tweedie D, Luo W, Short RG, Brossi A, Holloway HW, Li Y, Yu QS, Greig NH: A cellular model of inflammation for identifying TNF-alpha synthesis inhibitors. J Neurosci Methods 2009, 183:182–187.CrossRefPubMedPubMedCentral
35.
Zhu X, Giordano T, Yu QS, Holloway HW, Perry TA, Lahiri DK, Brossi A, Greig NH: Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity. J Med Chem 2003, 46:5222–5229.CrossRefPubMed
36.
Greig NH, Giordano T, Zhu X, Yu QS, Perry TA, Holloway HW, Brossi A, Rogers JT, Sambamurti K, Lahiri DK: Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases. Acta Neurobiol Exp (Wars) 2004, 64:1–9.
37.
Baratz R, Tweedie D, Rubovitch V, Luo W, Yoon JS, Hoffer BJ, Greig NH, Pick CG: Tumor necrosis factor-alpha synthesis inhibitor, 3,6'-dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice. J Neurochem 2011, 118:1032–1042.CrossRefPubMedPubMedCentral
38.
Rosi S, Pert CB, Ruff MR, McGann-Gramling K, Wenk GL: Chemokine receptor 5 antagonist D-Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer's disease. Neuroscience 2005, 134:671–676.CrossRefPubMed
39.
Rosi S, Ramirez-Amaya V, Hauss-Wegrzyniak B, Wenk GL: Chronic brain inflammation leads to a decline in hippocampal NMDA-R1 receptors. J Neuroinflammation 2004, 1:12.CrossRefPubMedPubMedCentral
40.
Luo WM, Yu QS, Tweedie D, Deschamps J, Parrish D, Holloway HW, Li YZ, Brossi A, Greig NH: Syntheses of Aromatic Substituted 6 '-Thiothalidomides. Synthesis 2008, 2008:3415–3422.CrossRef
41.
Huang Y, Henry CJ, Dantzer R, Johnson RW, Godbout JP: Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiol Aging 2008, 29:1744–1753.CrossRefPubMed
42.
Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Sheridan JF, Godbout JP: Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 2008, 5:15.CrossRefPubMedPubMedCentral
43.
Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H: Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts. Learn Mem 2002, 9:49–57.CrossRefPubMedPubMedCentral
44.
Aggleton JP, Brown MW: Contrasting hippocampal and perirhinal cortex function using immediate early gene imaging. Q J Exp Psychol B 2005, 58:218–233.CrossRefPubMed
45.
Webster B, Hansen L, Adame A, Crews L, Torrance M, Thal L, Masliah E: Astroglial activation of extracellular-regulated kinase in early stages of Alzheimer disease. J Neuropathol Exp Neurol 2006, 65:142–151.CrossRefPubMed
46.
Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW: Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci USA 2004, 101:2173–2178.CrossRefPubMed
47.
Avison MJ, Nath A, Greene-Avison R, Schmitt FA, Bales RA, Ethisham A, Greenberg RN, Berger JR: Inflammatory changes and breakdown of microvascular integrity in early human immunodeficiency virus dementia. J Neurovirol 2004, 10:223–232.CrossRefPubMed
48.
Dean JL, Wait R, Mahtani KR, Sully G, Clark AR, Saklatvala J: The 3' untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol 2001, 21:721–730.CrossRefPubMedPubMedCentral
49.
Lai WS, Carballo E, Strum JR, Kennington EA, Phillips RS, Blackshear PJ: Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Mol Cell Biol 1999, 19:4311–4323.CrossRefPubMedPubMedCentral
50.
Zhang T, Kruys V, Huez G, Gueydan C: AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors. Biochem Soc Trans 2002, 30:952–958.CrossRefPubMed
51.
Jin SH, Kim TI, Yang KM, Kim WH: Thalidomide destabilizes cyclooxygenase-2 mRNA by inhibiting p38 mitogen-activated protein kinase and cytoplasmic shuttling of HuR. Eur J Pharmacol 2007, 558:14–20.CrossRefPubMed
52.
Ronkina N, Menon MB, Schwermann J, Tiedje C, Hitti E, Kotlyarov A, Gaestel M: MAPKAP kinases MK2 and MK3 in inflammation: complex regulation of TNF biosynthesis via expression and phosphorylation of tristetraprolin. Biochem Pharmacol 2010, 80:1915–1920.CrossRefPubMed
53.
Smith JA, Das A, Ray SK, Banik NL: Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull, in press.
54.
Kawai T, Adachi O, Ogawa T, Takeda K, Akira S: Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999, 11:115–122.CrossRefPubMed
55.
Barker GR, Warburton EC: When is the hippocampus involved in recognition memory? J Neurosci 2011, 31:10721–10731.CrossRefPubMed
56.
Morris RG, Garrud P, Rawlins JN, O'Keefe J: Place navigation impaired in rats with hippocampal lesions. Nature 1982, 297:681–683.CrossRefPubMed
57.
Aggleton JP, Brown MW: Episodic memory, amnesia, and the hippocampal-anterior thalamic axis. Behav Brain Sci 1999, 22:425–444. discussion 444–489PubMed
58.
Steckler T, Drinkenburg WH, Sahgal A, Aggleton JP: Recognition memory in rats-II. Neuroanatomical substrates. Prog Neurobiol 1998, 54:313–332.CrossRefPubMed
59.
Steward O, Schuman EM: Compartmentalized synthesis and degradation of proteins in neurons. Neuron 2003, 40:347–359.CrossRefPubMed
60.
Bramham CR, Wells DG: Dendritic mRNA: transport, translation and function. Nat Rev Neurosci 2007, 8:776–789.CrossRefPubMed
61.
Lee PR, Cohen JE, Becker KG, Fields RD: Gene expression in the conversion of early-phase to late-phase long-term potentiation. Ann N Y Acad Sci 2005, 1048:259–271.CrossRefPubMed
62.
Wibrand K, Messaoudi E, Havik B, Steenslid V, Lovlie R, Steen VM, Bramham CR: Identification of genes co-upregulated with Arc during BDNF-induced long-term potentiation in adult rat dentate gyrus in vivo. Eur J Neurosci 2006, 23:1501–1511.CrossRefPubMed
63.
Frey U, Krug M, Reymann KG, Matthies H: Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro. Brain Res 1988, 452:57–65.CrossRefPubMed
64.
Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes CA: Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 2000, 20:3993–4001.PubMed
65.
Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Gilbert DJ, Jenkins NA, Lanahan AA, Worley PF: Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 1995, 14:433–445.CrossRefPubMed
66.
Stellwagen D, Beattie EC, Seo JY, Malenka RC: Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 2005, 25:3219–3228.CrossRefPubMed
67.
Santos SD, Carvalho AL, Caldeira MV, Duarte CB: Regulation of AMPA receptors and synaptic plasticity. Neuroscience 2009, 158:105–125.CrossRefPubMed
68.
Cunningham AJ, Murray CA, O'Neill LA, Lynch MA, O'Connor JJ: Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci Lett 1996, 203:17–20.CrossRefPubMed
69.
Tancredi V, D'Arcangelo G, Grassi F, Tarroni P, Palmieri G, Santoni A, Eusebi F: Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett 1992, 146:176–178.CrossRefPubMed
70.
Rosi S, Belarbi K, Ferguson RA, Fishman K, Obenaus A, Raber J, Fike JR: Trauma-induced alterations in cognition and arc expression are reduced by previous exposure to (56)Fe irradiation. Hippocampus, in press.
71.
Guzowski JF, McNaughton BL, Barnes CA, Worley PF: Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nat Neurosci 1999, 2:1120–1124.CrossRefPubMed
72.
Ramirez-Amaya V, Vazdarjanova A, Mikhael D, Rosi S, Worley PF, Barnes CA: Spatial exploration-induced Arc mRNA and protein expression: evidence for selective, network-specific reactivation. J Neurosci 2005, 25:1761–1768.CrossRefPubMed
73.
Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, Kuhl D, Huganir RL, Worley PF: Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 2006, 52:445–459.CrossRefPubMedPubMedCentral
74.
Hunsaker MR, Kesner RP: Evaluating the differential roles of the dorsal dentate gyrus, dorsal CA3, and dorsal CA1 during a temporal ordering for spatial locations task. Hippocampus 2008, 18:955–964.CrossRefPubMedPubMedCentral
75.
Rolls ET, Kesner RP: A computational theory of hippocampal function, and empirical tests of the theory. Prog Neurobiol 2006, 79:1–48.CrossRefPubMed
76.
Rao VR, Pintchovski SA, Chin J, Peebles CL, Mitra S, Finkbeiner S: AMPA receptors regulate transcription of the plasticity-related immediate-early gene Arc. Nat Neurosci 2006, 9:887–895.CrossRefPubMed
Metadata
Title
TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation
Authors
Karim Belarbi
Timothy Jopson
David Tweedie
Carla Arellano
Weiming Luo
Nigel H Greig
Susanna Rosi
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-23

Other articles of this Issue 1/2012

Journal of Neuroinflammation 1/2012 Go to the issue

Erratum

Erratum to: Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats

Research

Evaluation of age-related changes in translocator protein (TSPO) in human brain using 11C-[R]-PK11195 PET

Research

Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice

Research

Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release, which is inhibited by luteolin

Short report

Preserved vascular integrity and enhanced survival following neuropilin-1 inhibition in a mouse model of CD8 T cell-initiated CNS vascular permeability

Research

TGFβ signalling plays an important role in IL4-induced alternative activation of microglia