Top

Published in:

Open Access 01-12-2012 | Research

Time dependent neuroprotection of mycophenolate mofetil: effects on temporal dynamics in glial proliferation, apoptosis, and scar formation

Authors: Fahim Ebrahimi, Marco Koch, Philipp Pieroh, Chalid Ghadban, Constance Hobusch, Ingo Bechmann, Faramarz Dehghani

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Background

Immunosuppressants such as mycophenolate mofetil (MMF) have the capacity to inhibit microglial and astrocytic activation and to reduce the extent of cell death after neuronal injury. This study was designed to determine the effective neuroprotective time frame in which MMF elicits its beneficial effects, by analyzing glial cell proliferation, migration, and apoptosis.

Methods

Using organotypic hippocampal slice cultures (OHSCs), temporal dynamics of proliferation and apoptosis after N-methyl-D-aspartate (NMDA)-mediated excitotoxicity were analyzed by quantitative morphometry of Ki-67 or cleaved caspase-3 immunoreactive glial cells. Treatment on NMDA-lesioned OHSCs with mycophenolate mofetil (MMF)100 μg/mL was started at different time points after injury or performed within specific time frames, and the numbers of propidium iodide (PI)⁺ degenerating neurons and isolectin (I)B₄ ⁺ microglial cells were determined. Pre-treatment with guanosine 100 μmol/l was performed to counteract MMF-induced effects. The effects of MMF on reactive astrocytic scar formation were investigated in the scratch-wound model of astrocyte monolayers.

Results

Excitotoxic lesion induction led to significant increases in glial proliferation rates between 12 and 36 hours after injury and to increased levels of apoptotic cells between 24 and 72 hours after injury. MMF treatment significantly reduced glial proliferation rates without affecting apoptosis. Continuous MMF treatment potently reduced the extent of neuronal cell demise when started within the first 12 hours after injury. A crucial time-frame of significant neuroprotection was identified between 12 and 36 hours after injury. Pre-treatment with the neuroprotective nucleoside guanosine reversed MMF-induced antiproliferative effects on glial cells. In the scratch-wound model, gap closure was reached within 48 hours in controls, and was potently inhibited by MMF.

Conclusions

Our data indicate that immunosuppression by MMF significantly attenuates the extent of neuronal cell death when administered within a crucial time frame after injury. Moreover, long-lasting immunosuppression, as required after solid-organ transplantation, does not seem to be necessary. Targeting inosine 5-monophosphate dehydrogenase, the rate-limiting enzyme of purine synthesis, is an effective strategy to modulate the temporal dynamics of proliferation and migration of microglia and astrocytes, and thus to reduce the extent of secondary neuronal damage and scar formation.

Giulian D, Robertson C: Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord. Ann Neurol 1990, 27:33–42.CrossRefPubMed

Dusart I, Schwab ME: Secondary cell death and the inflammatory reaction after dorsal hemisection of the rat spinal cord. Eur J Neurosci 1994, 6:712–724.CrossRefPubMed

Bartholdi D, Schwab ME: Expression of pro-inflammatory cytokine and chemokine mRNA upon experimental spinal cord injury in mouse: an in situ hybridization study. Eur J Neurosci 1997, 9:1422–1438.CrossRefPubMed

Dumont RJ, Okonkwo DO, Verma S, Hurlbert RJ, Boulos PT, Ellegala DB, Dumont AS: Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 2001, 24:254–264.CrossRefPubMed

Horn K, Busch S, Hawthorne A, Van R, Silver J: Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. J Neurosci 2008, 28:9330–9341.CrossRefPubMedPubMedCentral

Popovich PG, Guan Z, Wei P, Huitinga I, Van R, Stokes BT: Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 1999, 158:351–365.CrossRefPubMed

Kitayama M, Ueno M, Itakura T, Yamashita T: Activated microglia inhibit axonal growth through RGMa. PLoS One 2011, 6:e25234.CrossRefPubMedPubMedCentral

Murai K, Pasquale E: Eph receptors and ephrins in neuron-astrocyte communication at synapses. Glia 2011, 59:1567–1578.CrossRefPubMed

Boje KM, Arora PK: Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res 1992, 587:250–256.CrossRefPubMed

10.

Rinner WA, Bauer J, Schmidts M, Lassmann H, Hickey WF: Resident microglia and hematogenous macrophages as phagocytes in adoptively transferred experimental autoimmune encephalomyelitis: an investigation using rat radiation bone marrow chimeras. Glia 1995, 14:257–266.CrossRefPubMed

11.

Flavin MP, Coughlin K, Ho LT: Soluble macrophage factors trigger apoptosis in cultured hippocampal neurons. Neuroscience 1997, 80:437–448.CrossRefPubMed

12.

Kim WK, Ko KH: Potentiation of N-methyl-D-aspartate-mediated neurotoxicity by immunostimulated murine microglia. J Neurosci Res 1998, 54:17–26.CrossRefPubMed

13.

Frade JM, Barde YA: Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 1998, 20:35–41.CrossRefPubMed

14.

Hailer NP, Wirjatijasa F, Roser N, Hischebeth GT, Korf HW, Dehghani F: Astrocytic factors protect neuronal integrity and reduce microglial activation in an in vitro model of N-methyl-D-aspartate-induced excitotoxic injury in organotypic hippocampal slice cultures. Eur J Neurosci 2001, 14:315–326.CrossRefPubMed

15.

Toulmond S, Rothwell NJ: Interleukin-1 receptor antagonist inhibits neuronal damage caused by fluid percussion injury in the rat. Brain Res 1995, 671:261–266.CrossRefPubMed

16.

Wakita H, Tomimoto H, Akiguchi I, Kimura J: Protective effect of cyclosporin A on white matter changes in the rat brain after chronic cerebral hypoperfusion. Stroke 1995, 26:1415–1422.CrossRefPubMed

17.

Zito MA, Koennecke LA, McAuliffe MJ, McNally B, van Rooijen N, Heyes MP: Depletion of systemic macrophages by liposome-encapsulated clodronate attenuates striatal macrophage invasion and neurodegeneration following local endotoxin infusion in gerbils. Brain Res 2001, 892:13–26.CrossRefPubMed

18.

Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings MG, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL, Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR, Young W: Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial. J Neurosurg 1998, 89:699–706.CrossRefPubMed

19.

Takami T, Oudega M, Bethea JR, Wood PM, Kleitman N, Bunge MB: Methylprednisolone and interleukin-10 reduce gray matter damage in the contused Fischer rat thoracic spinal cord but do not improve functional outcome. J Neurotrauma 2002, 19:653–666.CrossRefPubMed

20.

Hurlbert RJ: Strategies of medical intervention in the management of acute spinal cord injury. Spine 2006, 31:16–21. discussion S36CrossRef

21.

Teichner A, Morselli E, Buttarelli FR, Caronti B, Pontieri FE, Venturini G, Palladini G: Treatment with cyclosporine A promotes axonal regeneration in rats submitted to transverse section of the spinal cord. J Hirnforsch 1993, 34:343–349.PubMed

22.

Madsen JR, MacDonald P, Irwin N, Goldberg DE, Yao GL, Meiri KF, Rimm IJ, Stieg PE, Benowitz LI: Tacrolimus (FK506) increases neuronal expression of GAP-43 and improves functional recovery after spinal cord injury in rats. Exp Neurol 1998, 154:673–683.CrossRefPubMed

23.

Bavetta S, Hamlyn PJ, Burnstock G, Lieberman AR, Anderson PN: The effects of FK506 on dorsal column axons following spinal cord injury in adult rats: neuroprotection and local regeneration. Exp Neurol 1999, 158:382–393.CrossRefPubMed

24.

Klettner A, Herdegen T: FK506 and its analogs - therapeutic potential for neurological disorders. Curr Drug Targets CNS Neurol Disord 2003, 2:153–162.CrossRefPubMed

25.

Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C: Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation 1997, 63:39–47.PubMed

26.

Eugui EM, Mirkovich A, Allison AC: Lymphocyte-selective antiproliferative and immunosuppressive effects of mycophenolic acid in mice. Scand J Immunol 1991, 33:175–183.CrossRefPubMed

27.

Allison AC, Eugui EM: Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000, 47:85–118.CrossRefPubMed

28.

Villarroel MC, Hidalgo M, Jimeno A: Mycophenolate mofetil: An update. Drugs Today 2009, 45:521–532.PubMed

29.

Carr SF, Papp E, Wu JC, Natsumeda Y: Characterization of human type I and type II IMP dehydrogenases. J Biol Chem 1993, 268:27286–27290.PubMed

30.

Dehghani F, Hischebeth GTR, Wirjatijasa F, Kohl A, Korf H, Hailer NP: The immunosuppressant mycophenolate mofetil attenuates neuronal damage after excitotoxic injury in hippocampal slice cultures. Eur J Neurosci 2003, 18:1061–1072.CrossRefPubMed

31.

Dehghani F, Sayan M, Conrad A, Evers J, Ghadban C, Blaheta R, Korf H, Hailer NP: Inhibition of microglial and astrocytic inflammatory responses by the immunosuppressant mycophenolate mofetil. Neuropathol Appl Neurobiol 2010, 36:598–611.CrossRefPubMed

32.

Miljkovic D, Cvetkovic I, Stosic-Grujicic S, Trajkovic V: Mycophenolic acid inhibits activation of inducible nitric oxide synthase in rodent fibroblasts. Clin Exp Immunol 2003, 132:239–246.CrossRefPubMedPubMedCentral

33.

Oest TM, Dehghani F, Korf H, Hailer NP: The immunosuppressant mycophenolate mofetil improves preservation of the perforant path in organotypic hippocampal slice cultures: a retrograde tracing study. Hippocampus 2006, 16:437–442.CrossRefPubMed

34.

Cottrell BL, Perez-Abadia G, Onifer SM, Magnuson DS, Burke DA, Grossi FV, Francois CG, Barker JH, Maldonado C: Neuroregeneration in composite tissue allografts: effect of low-dose FK506 and mycophenolate mofetil immunotherapy. Plast Reconstr Surg 2006, 118:615–623. discussion 624–5CrossRefPubMed

35.

Stoppini L, Buchs PA, Muller D: A simple method for organotypic cultures of nervous tissue. J Neurosci Methods 1991, 37:173–182.CrossRefPubMed

36.

Pozzo MLD, Mahanty NK, Connor JA, Landis DM: Spontaneous pyramidal cell death in organotypic slice cultures from rat hippocampus is prevented by glutamate receptor antagonists. Neuroscience 1994, 63:471–487.CrossRef

37.

Ebrahimi F, Hezel M, Koch M, Ghadban C, Korf H, Dehghani F: Analyses of neuronal damage in excitotoxically lesioned organotypic hippocampal slice cultures. Ann Anat 2010, 192:199–204.CrossRefPubMed

38.

Kohl A, Dehghani F, Korf H, Hailer NP: The bisphosphonate clodronate depletes microglial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol 2003, 181:1–11.CrossRefPubMed

39.

Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72:248–254.CrossRefPubMed

40.

Dehghani F, Conrad A, Kohl A, Korf H, Hailer NP: Clodronate inhibits the secretion of proinflammatory cytokines and NO by isolated microglial cells and reduces the number of proliferating glial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol 2004, 189:241–251.CrossRefPubMed

41.

Vijayan VK, Cotman CW: Hydrocortisone administration alters glial reaction to entorhinal lesion in the rat dentate gyrus. Exp Neurol 1987, 96:307–320.CrossRefPubMed

42.

Kitamura Y, Itano Y, Kubo T, Nomura Y: Suppressive effect of FK-506, a novel immunosuppressant, against MPTP-induced dopamine depletion in the striatum of young C57BL/6 mice. J Neuroimmunol 1994, 50:221–224.CrossRefPubMed

43.

Oudega M, Vargas CG, Weber AB, Kleitman N, Bunge MB: Long-term effects of methylprednisolone following transection of adult rat spinal cord. Eur J Neurosci 1999, 11:2453–2464.CrossRefPubMed

44.

Hailer NP: Immunosuppression after traumatic or ischemic CNS damage: it is neuroprotective and illuminates the role of microglial cells. Prog Neurobiol 2008, 84:211–233.CrossRefPubMed

45.

Adamchik Y, Frantseva MV, Weisspapir M, Carlen PL, Perez Velazquez JL: Methods to induce primary and secondary traumatic damage in organotypic hippocampal slice cultures. Brain Res Brain Res Protoc 2000, 5:153–158.CrossRefPubMed

46.

Hailer NP, Vogt C, Korf H, Dehghani F: Interleukin-1beta exacerbates and interleukin-1 receptor antagonist attenuates neuronal injury and microglial activation after excitotoxic damage in organotypic hippocampal slice cultures. Eur J Neurosci 2005, 21:2347–2360.CrossRefPubMed

47.

Kreutz S, Koch M, Böttger C, Ghadban C, Korf H, Dehghani F: 2-Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioned dentate gyrus granule cells via abnormal-cannabidiol-sensitive receptors on microglial cells. Glia 2009, 57:286–294.CrossRefPubMed

48.

Hailer NP, Jarhult JD, Nitsch R: Resting microglial cells in vitro: analysis of morphology and adhesion molecule expression in organotypic hippocampal slice cultures. Glia 1996, 18:319–331.CrossRefPubMed

49.

Martin LJ, Al-Abdulla NA, Brambrink AM, Kirsch JR, Sieber FE, Portera-Cailliau C: Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis. Brain Res Bull 1998, 46:281–309.CrossRefPubMed

50.

Qin ZH, Wang Y, Chase TN: Stimulation of N-methyl-D-aspartate receptors induces apoptosis in rat brain. Brain Res 1996, 725:166–176.PubMed

51.

Pohl D, Bittigau P, Ishimaru MJ, Stadthaus D, Hubner C, Olney JW, Turski L, Ikonomidou C: N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain. Proc Natl Acad Sci U S A 1999, 96:2508–2513.CrossRefPubMedPubMedCentral

52.

Vogt C, Hailer NP, Ghadban C, Korf H, Dehghani F: Successful inhibition of excitotoxic neuronal damage and microglial activation after delayed application of interleukin-1 receptor antagonist. J Neurosci Res 2008, 86:3314–3321.CrossRefPubMed

53.

Schmidt AP, Lara DR, Souza DO: Proposal of a guanine-based purinergic system in the mammalian central nervous system. Pharmacol Ther 2007, 116:401–416.CrossRefPubMed

54.

Baron BM, Dudley MW, McCarty DR, Miller FP, Reynolds IJ, Schmidt CJ: Guanine nucleotides are competitive inhibitors of N-methyl-D-aspartate at its receptor site both in vitro and in vivo. J Pharmacol Exp Ther 1989, 250:162–169.PubMed

55.

Porciuncula LO, Vinade L, Wofchuk S, Souza DO: Guanine based purines inhibit glutamate and AMPA binding at postsynaptic densities from cerebral cortex of rats. Brain Res 2002, 928:106–112.CrossRefPubMed

56.

Souza DO, Ramirez G: Effects of guanine nucleotides on kainic acid binding and on adenylate cyclase in chick optic tectum and cerebellum. J Mol Neurosci 1991, 3:39–45.CrossRefPubMed

57.

Dal-Cim T, Martins WC, Santos AR, Tasca CI: Guanosine is neuroprotective against oxygen/glucose deprivation in hippocampal slices via large conductance Ca(2+)-activated K(+) channels, phosphatidilinositol-3 kinase/protein kinase B pathway activation and glutamate uptake. Neuroscience 2011, 183:212–220.CrossRefPubMed

58.

Molz S, Dal-Cim T, Budni J, Martín-de-Saavedra M, Egea J, Romero A, del Barrio L, Rodrigues AL, López MG, Tasca CI: Neuroprotective effect of guanosine against glutamate-induced cell death in rat hippocampal slices is mediated by the phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase 3β pathway activation and inducible nitric oxide synthase inhibition. J Neurosci Res 2011, 89:1400–1408.CrossRefPubMed

59.

Oleskovicz SPB, Martins WC, Leal RB, Tasca CI: Mechanism of guanosine-induced neuroprotection in rat hippocampal slices submitted to oxygen-glucose deprivation. Neurochem Int 2008, 52:411–418.CrossRefPubMed

60.

Benfenati V, Caprini M, Nobile M, Rapisarda C, Ferroni S: Guanosine promotes the up-regulation of inward rectifier potassium current mediated by Kir4.1 in cultured rat cortical astrocytes. J Neurochem 2006, 98:430–445.CrossRefPubMed

61.

Volpini R, Marucci G, Buccioni M, Dal Ben D, Lambertucci C, Lammi C, Mishra RC, Thomas A, Cristalli G: Evidence for the Existence of a Specific G Protein-Coupled Receptor Activated by Guanosine. Chem. Med. Chem 2011, 6:1074–1080.CrossRefPubMed

62.

Kim JK, Rathbone MP, Middlemiss PJ, Hughes DW, Smith RW: Purinergic stimulation of astroblast proliferation: guanosine and its nucleotides stimulate cell division in chick astroblasts. J Neurosci Res 1991, 28:442–455.CrossRefPubMed

63.

Ciccarelli R, Di Iorio P, Giuliani P, D'Alimonte I, Ballerini P, Caciagli F, Rathbone MP: Rat cultured astrocytes release guanine-based purines in basal conditions and after hypoxia/hypoglycemia. Glia 1999, 25:93–98.CrossRefPubMed

64.

Middlemiss PJ, Gysbers JW, Rathbone MP: Extracellular guanosine and guanosine-5'-triphosphate increase: NGF synthesis and release from cultured mouse neopallial astrocytes. Brain Res 1995, 677:152–156.CrossRefPubMed

65.

Di Iorio P, Kleywegt S, Ciccarelli R, Traversa U, Andrew CM, Crocker CE, Werstiuk ES, Rathbone MP: Mechanisms of apoptosis induced by purine nucleosides in astrocytes. Glia 2002, 38:179–190.CrossRefPubMed

66.

Heinz C: Mycophenolate mofetil inhibits human Tenon fibroblast proliferation by guanosine depletion. Br J Ophthalmol 2003, 87:1397–1398.CrossRefPubMedPubMedCentral

67.

Raisanen-Sokolowski A, Vuoristo P, Myllarniemi M, Yilmaz S, Kallio E, Hayry P: Mycophenolate mofetil (MMF, RS-61443) inhibits inflammation and smooth muscle cell proliferation in rat aortic allografts. Transpl Immunol 1995, 3:342–351.CrossRefPubMed

68.

Waller J, Brook NR, Nicholson ML: Cardiac allograft vasculopathy: current concepts and treatment. Transplant. Int 2003, 16:367–375.CrossRef

69.

Ziswiler R, Steinmann-Niggli K, Kappeler A, Daniel C, Marti HP: Mycophenolic acid: a new approach to the therapy of experimental mesangial proliferative glomerulonephritis. J Am Soc Nephrol 1998, 9:2055–2066.PubMed

70.

Cohn RG, Mirkovich A, Dunlap B, Burton P, Chiu SH, Eugui E, Caulfield JP: Mycophenolic acid increases apoptosis, lysosomes and lipid droplets in human lymphoid and monocytic cell lines. Transplantation 1999, 68:411–418.CrossRefPubMed

71.

Lin JH, Weigel H, Cotrina ML, Liu S, Bueno E, Hansen AJ, Hansen TW, Goldman S, Nedergaard M: Gap-junction-mediated propagation and amplification of cell injury. Nat Neurosci 1998, 1:494–500.CrossRefPubMed

72.

Faber-Elman A, Lavie V, Schvartz I, Shaltiel S, Schwartz M: Vitronectin overrides a negative effect of TNF-alpha on astrocyte migration. FASEB J 1995, 9:1605–1613.PubMed

73.

Hou YJ, Yu AC, Garcia JM, Aotaki-Keen A, Lee YL, Eng LF, Hjelmeland LJ, Menon VK: Astrogliosis in culture. IV. Effects of basic fibroblast growth factor. J Neurosci Res 1995, 40:359–370.CrossRefPubMed

74.

Hassinger TD, Guthrie PB, Atkinson PB, Bennett MV, Kater SB: An extracellular signaling component in propagation of astrocytic calcium waves. Proc Natl Acad Sci U S A 1996, 93:13268–13273.CrossRefPubMedPubMedCentral

75.

Yu ACH, Lee Y, Eng LF: Astrogliosis in culture: I. The model and the effect of antisense oligonucleotides on glial fibrillary acidic protein synthesis. J Neurosci Res 1993, 34:295–303.CrossRefPubMed

76.

Toyooka T, Nawashiro H, Shinomiya N, Shima K: Down-regulation of glial fibrillary acidic protein and vimentin by RNA interference improves acute urinary dysfunction associated with spinal cord injury in rats. J Neurotrauma 2011, 28:607–618.CrossRefPubMed

77.

Ahrens N, Salama A, Haas J: Mycophenolate-mofetil in the treatment of refractory multiple sclerosis. J Neurol 2001, 248:713–714.CrossRefPubMed

78.

Frohman EM, Brannon K, Racke MK, Hawker K: Mycophenolate mofetil in multiple sclerosis. Clin Neuropharmacol 2004, 27:80–83.CrossRefPubMed

79.

Piepers S, van den Berg-Vos R, van der Pol W, Franssen H, Wokke J, van den Berg L: Mycophenolate mofetil as adjunctive therapy for MMN patients: a randomized, controlled trial. Brain 2007, 130:2004–2010.CrossRefPubMed

80.

Mowzoon N, Sussman A, Bradley WG: Mycophenolate (CellCept) treatment of myasthenia gravis, chronic inflammatory polyneuropathy and inclusion body myositis. J Neurol Sci 2001, 185:119–122.CrossRefPubMed

81.

Pourmand G, Salem S, Mehrsai A, Taherimahmoudi M, Ebrahimi R, Pourmand MR: Infectious complications after kidney transplantation: a single-center experience. Transpl Infect Dis 2007, 9:302–309.CrossRefPubMed

82.

Pourfarziani V, Panahi Y, Assari S, Moghani-Lankarani M, Saadat S: Changing treatment protocol from azathioprine to mycophenolate mofetil: decrease in renal dysfunction, increase in infections. Transplant Proc 2007, 39:1237–1240.CrossRefPubMed

83.

Sollinger HW: Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995, 60:225–232.CrossRefPubMed

84.

Hanvesakul R, Kubal C, Jham S, Sarkar E, Eardley K, Adu D, Cockwell P: Increased incidence of infections following the late introduction of mycophenolate mofetil in renal transplant recipients. Nephrol Dial Transplant 2008, 23:4049–4053.CrossRefPubMed

Title: Time dependent neuroprotection of mycophenolate mofetil: effects on temporal dynamics in glial proliferation, apoptosis, and scar formation
Authors: Fahim Ebrahimi
Marco Koch
Philipp Pieroh
Chalid Ghadban
Constance Hobusch
Ingo Bechmann
Faramarz Dehghani
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-89

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Time dependent neuroprotection of mycophenolate mofetil: effects on temporal dynamics in glial proliferation, apoptosis, and scar formation

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2012

Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation

Leukotrienes inhibit early stages of HIV-1 infection in monocyte-derived microglia-like cells

Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages

Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model

Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways

Prevention of methamphetamine-induced microglial cell death by TNF-α and IL-6 through activation of the JAK-STAT pathway