Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson’s disease

Journal of Neuroinflammation

Eliezer Masliah²  Edward Rockenstein¹  Scott Anderson¹  Michael Mante¹  Elvira Valera¹ 

[1] Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla 92093-0624, CA, USA;Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla 92093-0624, CA, USA

关键词: Cytokines;    Microgliosis;    Neuroinflammation;    Parkinson’s disease;    Lenalidomide;   

Others  :  1222003
DOI  :  10.1186/s12974-015-0320-x

 received in 2015-03-16, accepted in 2015-05-05,  发布年份 2015

【 摘 要 】

Background

Parkinson’s disease (PD) is one of the most common causes of dementia and motor deficits in the elderly. PD is characterized by the abnormal accumulation of the synaptic protein alpha-synuclein (α-syn) and degeneration of dopaminergic neurons in substantia nigra, which leads to neurodegeneration and neuroinflammation. Currently, there are no disease modifying alternatives for PD; however, targeting neuroinflammation might be a viable option for reducing motor deficits and neurodegeneration. Lenalidomide is a thalidomide derivative designed for reduced toxicity and increased immunomodulatory properties. Lenalidomide has shown protective effects in an animal model of amyotrophic lateral sclerosis, and its mechanism of action involves modulation of cytokine production and inhibition of NF-κB signaling.

Methods

In order to assess the effect of lenalidomide in an animal model of PD, mThy1-α-syn transgenic mice were treated with lenalidomide or the parent molecule thalidomide at 100 mg/kg for 4 weeks.

Results

Lenalidomide reduced motor behavioral deficits and ameliorated dopaminergic fiber loss in the striatum. This protective action was accompanied by a reduction in microgliosis both in striatum and hippocampus. Central expression of pro-inflammatory cytokines was diminished in lenalidomide-treated transgenic animals, together with reduction in NF-κB activation.

Conclusion

These results support the therapeutic potential of lenalidomide for reducing maladaptive neuroinflammation in PD and related neuropathologies.

【 授权许可】

   
2015 Valera et al.; licensee BioMed Central.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

Fig. 7.

【 参考文献 】

• [1]McKeith IG: Spectrum of Parkinson’s disease, Parkinson’s dementia, and Lewy body dementia. Neurol Clin 2000, 18(4):865-902.
• [2]Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, et al.: DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 2007, 68(11):812-9.
• [3]Burn DJ: Cortical Lewy body disease and Parkinson’s disease dementia. Curr Opin Neurol 2006, 19(6):572-9.
• [4]Dickson DW: Alpha-synuclein and the Lewy body disorders. Curr Opin Neurol 2001, 14(4):423-32.
• [5]Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M: Alpha-synuclein in Lewy bodies. Nature 1997, 388(6645):839-40.
• [6]Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E: Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol 1998, 152(2):367-72.
• [7]Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, et al.: Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 2002, 22(20):8797-807.
• [8]Kubo S, Nemani VM, Chalkley RJ, Anthony MD, Hattori N, Mizuno Y, et al.: A combinatorial code for the interaction of alpha-synuclein with membranes. J Biol Chem 2005, 280(36):31664-72.
• [9]Lashuel HA, Overk CR, Oueslati A, Masliah E: The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 2012, 14(1):38-48.
• [10]Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, et al.: In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 2011, 108(10):4194-9.
• [11]Jang A, Lee HJ, Suk JE, Jung JW, Kim KP, Lee SJ: Non-classical exocytosis of alpha-synuclein is sensitive to folding states and promoted under stress conditions. J Neurochem 2010, 113(5):1263-74.
• [12]Danzer KM, Ruf WP, Putcha P, Joyner D, Hashimoto T, Glabe C, et al.: Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. Faseb J 2011, 25(1):326-36.
• [13]Lee SJ: Origins and effects of extracellular alpha-synuclein: implications in Parkinson’s disease. J Molecular Neurosci: MN 2008, 34(1):17-22.
• [14]Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, et al.: Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A 2009, 106(31):13010-5.
• [15]Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, et al.: Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 2010, 285(12):9262-72.
• [16]Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al.: Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 2005, 19(6):533-42.
• [17]Chesselet MF, Richter F, Zhu C, Magen I, Watson MB, Subramaniam SR: A progressive mouse model of Parkinson’s disease: the Thy1-aSyn (“Line 61”) mice. Neurotherapeutics 2012, 9(2):297-314.
• [18]Kim C, Ho DH, Suk JE, You S, Michael S, Kang J, et al.: Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun. 2013, 4:1562.
• [19]Beraud D, Maguire-Zeiss KA. Misfolded alpha-synuclein and Toll-like receptors: therapeutic targets for Parkinson’s disease. Parkinsonism Relat Disord. 2012;18 Suppl 1:S17-20. doi:10.1016/S1353-8020(11)70008-6.
• [20]Beraud D, Twomey M, Bloom B, Mittereder A, Ton V, Neitzke K, et al.: Alpha-synuclein alters Toll-like receptor expression. Front Neurosci. 2011, 5:80.
• [21]Flood PM, Qian L, Peterson LJ, Zhang F, Shi JS, Gao HM, et al.: Transcriptional factor NF-kappaB as a target for therapy in Parkinson’s disease. Parkinsons Dis. 2011, 2011:216298.
• [22]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(6):1675-80.
• [23]Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G: Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991, 173(3):699-703.
• [24]Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, et al.: Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 1999, 163(1):380-6.
• [25]Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, et al.: Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 2002, 68(5):568-78.
• [26]Ubhi K, Rockenstein E, Mante M, Inglis C, Adame A, Patrick C, et al.: Neurodegeneration in a transgenic mouse model of multiple system atrophy is associated with altered expression of oligodendroglial-derived neurotrophic factors. J Neurosci 2010, 30(18):6236-46.
• [27]Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F: Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 1990, 27(2–3):229-37.
• [28]Spencer B, Emadi S, Desplats P, Eleuteri S, Michael S, Kosberg K, et al.: ESCRT-mediated uptake and degradation of brain-targeted alpha-synuclein single chain antibody attenuates neuronal degeneration in vivo. Mol Ther 2014, 22(10):1753-67.
• [29]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 2012, 69(4):943-7.
• [30]Rozewski DM, Herman SE, Towns WH 2nd, Mahoney E, Stefanovski MR, Shin JD, et al.: Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J 2012, 14(4):872-82.
• [31]Muller GW, Corral LG, Shire MG, Wang H, Moreira A, Kaplan G, et al.: Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity. J Med Chem 1996, 39(17):3238-40.
• [32]Corral LG, Muller GW, Moreira AL, Chen Y, Wu M, Stirling D, et al.: Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity. Mol Med 1996, 2(4):506-15.
• [33]Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A, et al.: Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J Neurosci 2014, 34(28):9441-54.
• [34]Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, Adame A, et al.: Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol 2014, 127(6):861-79.
• [35]Halliday G. Clinicopathological aspects of motor parkinsonism. Parkinsonism Relat Disord. 2007;13 Suppl 3:S208-10. doi:10.1016/S1353-8020(08)70003-8.
• [36]Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, et al.: Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A 1998, 95(18):10896-901.
• [37]Hughes PM, Botham MS, Frentzel S, Mir A, Perry VH: Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. Glia 2002, 37(4):314-27.
• [38]Sheridan GK, Murphy KJ: Neuron-glia crosstalk in health and disease: fractalkine and CX3CR1 take centre stage. Open Biol 2013, 3(12):130181.
• [39]Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, et al.: Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 2006, 9(7):917-24.
• [40]Su X, Federoff HJ: Immune responses in Parkinson’s disease: interplay between central and peripheral immune systems. BioMed Res Int. 2014, 2014:275178.
• [41]Lee SJ, Desplats P, Lee HJ, Spencer B, Masliah E: Cell-to-cell transmission of α-synuclein aggregates. Methods Mol Biol. 2012, 849:347-59.
• [42]Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Arumugam TV: Toll-like receptors in neurodegeneration. Brain Res Rev 2009, 59(2):278-92.
• [43]Stefanova N, Fellner L, Reindl M, Masliah E, Poewe W, Wenning GK: Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons. Am J Pathol 2011, 179(2):954-63.
• [44]Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, et al.: Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 2013, 61(3):349-60.
• [45]Drouin-Ouellet J, St-Amour I, Saint-Pierre M, Lamontagne-Proulx J, Kriz J, Barker RA, et al.: Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson’s disease. Int J Neuropsychopharmacol 2014.
• [46]Doty KR, Guillot-Sestier MV, Town T: The role of the immune system in neurodegenerative disorders: adaptive or maladaptive? Brain Res 2014.
• [47]Gao X, Chen H, Schwarzschild MA, Ascherio A: Use of ibuprofen and risk of Parkinson disease. Neurology 2011, 76(10):863-9.
• [48]Rees K, Stowe R, Patel S, Ives N, Breen K, Clarke CE, et al.: Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson’s disease: evidence from observational studies. Cochrane Database Syst Rev. 2011, 11:CD008454.
• [49]Swiatkiewicz M, Zaremba M, Joniec I, Czlonkowski A, Kurkowska-Jastrzebska I: Potential neuroprotective effect of ibuprofen, insights from the mice model of Parkinson’s disease. Pharmacol Reports 2013, 65(5):1227-36.
• [50]Watson MB, Richter F, Lee SK, Gabby L, Wu J, Masliah E, et al.: Regionally-specific microglial activation in young mice over-expressing human wildtype alpha-synuclein. Exp Neurol 2012, 237(2):318-34.
• [51]Valera E, Ubhi K, Mante M, Rockenstein E, Masliah E: Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia 2014, 62(2):317-37.
• [52]Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A, Ciborowski P, et al.: Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J Neurochem 2008, 104(6):1504-25.
• [53]Martiniani R, Di Loreto V, Di Sano C, Lombardo A, Liberati AM: Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma. Adv Hematol. 2012, 2012:842945.
• [54]Galustian C, Meyer B, Labarthe MC, Dredge K, Klaschka D, Henry J, et al.: The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother 2009, 58(7):1033-45.
• [55]Teo SK: Properties of thalidomide and its analogues: implications for anticancer therapy. AAPS J 2005, 7(1):E14-9.
• [56]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 2009, 220(1):191-7.
• [57]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. J Neurosci 2006, 26(9):2467-73.
• [58]Kotla V, Goel S, Nischal S, Heuck C, Vivek K, Das B, et al.: Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009, 2:36. BioMed Central Full Text
• [59]Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, et al.: Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol 2014, 164(6):811-21.
• [60]Zhu YX, Kortuem KM, Stewart AK: Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma 2013, 54(4):683-7.
• [61]Galustian C, Labarthe MC, Bartlett JB, Dalgleish AG: Thalidomide-derived immunomodulatory drugs as therapeutic agents. Expert Opin Biol Ther 2004, 4(12):1963-70.
• [62]Muller GW, Chen R, Huang SY, Corral LG, Wong LM, Patterson RT, et al.: Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett 1999, 9(11):1625-30.
• [63]Stommel EW, Cohen JA, Fadul CE, Cogbill CH, Graber DJ, Kingman L, et al.: Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotrophic lateral sclerosis 2009, 10(5–6):393-404.
• [64]Crystal SC, Leonidas J, Jakubowski A, Di Rocco A: Thalidomide induced acute worsening of Parkinson’s disease. Mov Disord 2009, 24(12):1863-4.
• [65]Moncada B, Baranda ML, Gonzalez-Amaro R, Urbina R, Loredo CE: Thalidomide–effect on T cell subsets as a possible mechanism of action. Int J Leprosy Mycobacterial dis 1985, 53(2):201-5.
• [66]Rocha NP, Scalzo PL, Barbosa IG, Souza MS, Morato IB, Vieira EL, et al.: Cognitive status correlates with CXCL10/IP-10 levels in Parkinson’s disease. Parkinsons Dis. 2014, 2014:903796.
• [67]Lorenzl S, Albers DS, Narr S, Chirichigno J, Beal MF: Expression of MMP-2, MMP-9, and MMP-1 and their endogenous counterregulators TIMP-1 and TIMP-2 in postmortem brain tissue of Parkinson’s disease. Exp Neurol 2002, 178(1):13-20.
• [68]Kalkonde YV, Morgan WW, Sigala J, Maffi SK, Condello C, Kuziel W, et al.: Chemokines in the MPTP model of Parkinson’s disease: absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration. Brain Res 2007, 1128(1):1-11.