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Graefe's Archive for Clinical and Experimental Ophthalmology

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01-09-2008 | Basic Science

The neuropeptide NAP provides neuroprotection against retinal ganglion cell damage after retinal ischemia and optic nerve crush

Authors: T. Jehle, C. Dimitriu, S. Auer, R. Knoth, M. Vidal-Sanz, I. Gozes, W. A. Lagrèze

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 9/2008

Abstract

Background

NAP, an 8-amino acid peptide (NAPVSIPQ=Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) derived from activity-dependent neuroprotective protein (ADNP), plays an important role in neuronal differentiation and the survival of neurons in different pathological situations. We already discovered that NAP increases the survival of retinal ganglion cells (RGC) in vitro, and supports neurite outgrowth in retinal explants at femtomolar concentrations. The aim of this study was to investigate the effects of NAP on RGC survival after transient retinal ischemia and optic nerve crush.

Methods

RGC of male Wistar rats were labelled retrogradely with 6 l FluoroGold injected stereotactically into both superior colliculi. Seven days later, retinal ischemia was induced by elevating the intraocular pressure to 120 mm Hg for 60 minutes or by crushing one optic nerve for 10 s after a partial orbitotomy. NAP was either injected intraperitoneally in the concentration of 100 mg/kg 1 day before, directly after, and on the first and the second days after damage, or intravitreally (0.05 or 0.5 μg/eye) directly after the optic nerve crush. Controls received the same concentrations of a control peptide. Densities of surviving RGC and activated microglial cells (AMC) were quantified in a masked fashion 10 days after damage by counting FluoroGold-labelled cells.

Results

After retinal ischemia, intraperitoneal injections of NAP increased the number of surviving RGC by 40% (p < 0.005) compared to the control group. After optic nerve crush, NAP raised the number of surviving RGC by 31% (p = 0.07) when injected intraperitoneally and by 54% (p < 0.05) when administered intravitreally.

Conclusions

NAP acts neuroprotectively in vivo after retinal ischemia and optic nerve crush, and may have potential in treating optic nerve diseases.

Ashur-Fabian O, Giladi E, Furman S, Steingart RA, Wollman Y, Fridkin M, Brenneman DE, Gozes I (2001) Vasoactive intestinal peptide and related molecules induce nitrite accumulation in the extracellular milieu of rat cerebral cortical cultures. Neurosci Lett 307:167–170PubMedCrossRef

Ashur-Fabian O, Segal-Ruder Y, Skutelsky E, Brenneman DE, Steingart RA, Giladi E, Gozes I (2003) The neuroprotective peptide NAP inhibits the aggregation of the beta-amyloid peptide. Peptides 24:1413–1423PubMedCrossRef

Bakalash S, Kipnis J, Yoles E, Schwartz M (2002) Resistance of retinal ganglion cells to an increase in intraocular pressure is immune-dependent. Invest Ophthalmol Vis Sci 43:2648–2653PubMed

Bassan M, Zamostiano R, Davidson A, Pinhasov A, Giladi E, Perl O, Bassan H, Blat C, Gibney G, Glazner G, Brenneman DE, Gozes I (1999) Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem 72:1283–1293PubMedCrossRef

Belokopytov M, Shulman S, Dubinsky G, Gozes I, Belkin M, Rozner M (2006) Neuroprotective treatment with NAP reduces laser-induced retinal damage in rats. Invest Ophthalmol Vis Sci 47:E-Abstract 4820

Beni-Adani L, Gozes I, Cohen Y, Assaf Y, Steingart RA, Brenneman DE, Eizenberg O, Trembolver V, Shohami E (2001) A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice. J Pharmacol Exp Ther 296:57–63PubMed

Bodeutsch N, Thanos S (2000) Migration of phagocytotic cells and development of the murine intraretinal microglial network: an in vivo study using fluorescent dyes. Glia 32:91–101PubMedCrossRef

Braun JS, Tuomanen EI, Cleveland JL (1999) Neuroprotection by caspase inhibitors. Expert Opin Investig Drugs 8:1599–1610PubMedCrossRef

Brenneman DE, Eiden LE (1986) Vasoactive intestinal peptide and electrical activity influence neuronal survival. Proc Natl Acad Sci USA 83:1159–1162PubMedCrossRef

10.

Brenneman DE, Glazner G, Hill JM, Hauser J, Davidson A, Gozes I (1998) VIP neurotrophism in the central nervous system: multiple effectors and identification of a femtomolar-acting neuroprotective peptide. Ann N Y Acad Sci 865:207–212PubMedCrossRef

11.

Brenneman DE, Gozes I (1996) A femtomolar-acting neuroprotective peptide. J Clin Invest 97:2299–2307PubMedCrossRef

12.

Cellerino A, Arango-Gonzalez B, Pinzon-Duarte G, Kohler K (2003) Brain-derived neurotrophic factor regulates expression of vasoactive intestinal polypeptide in retinal amacrine cells. J Comp Neurol 467:97–104PubMedCrossRef

13.

Cheng B, Mattson MP (1994) NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res 640:56–67PubMedCrossRef

14.

Divinski I, Mittelman L, Gozes I (2004) A femtomolar acting octapeptide interacts with tubulin and protects astrocytes against zinc intoxication. J Biol Chem 279:28531–28538PubMedCrossRef

15.

Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Siren AL (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8:495–505PubMed

16.

Fischer D, Pavlidis M, Thanos S (2000) Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture. Invest Ophthalmol Vis Sci 41:3943–3954PubMed

17.

Gellrich NC, Schramm A, Rustemeyer J, Schon R, Theodor Eysel U (2002) Quantification of the neurodegenerative impact on the visual system following sudden retrobulbar expanding lesions—an experimental model. J Craniomaxillofac Surg 30:230–236PubMed

18.

Glazner GW, Boland A, Dresse AE, Brenneman DE, Gozes I, Mattson MP (1999) Activity- dependent neurotrophic factor peptide (ADNF9) protects neurons against oxidative stress- induced death. J Neurochem 73:2341–2347PubMedCrossRef

19.

Gozes I, Avidor R, Yahav Y, Katznelson D, Croce CM, Huebner K (1987) The gene encoding vasoactive intestinal peptide is located on human chromosome 6p21—-6qter. Hum Genet 75:41–44PubMed

20.

Gozes I, Steingart RA, Spier AD (2004) NAP mechanisms of neuroprotection. J Mol Neurosci 24:67–72PubMedCrossRef

21.

Heiduschka P, Thanos S (2000) Aurintricarboxylic acid promotes survival and regeneration of axotomised retinal ganglion cells in vivo. Neuropharmacology 39:889–902PubMedCrossRef

22.

Henderson CE, Camu W, Mettling C, Gouin A, Poulsen K, Karihaloo M, Rullamas J, Evans T, McMahon SB, Armanini MP et al (1993) Neurotrophins promote motor neuron survival and are present in embryonic limb bud. Nature 363:266–270PubMedCrossRef

23.

Jehle T, Kunze D, Wingert K, Bach M, Largreze WA (2007) Modulation of contrast depth and flash frequencies: Effects on visual evoked potentials recorded in awake, freely moving brown Norway rats. Invest Ophthalmol Vis Sci 48:E-Abstract 3756

24.

Jehle T, Lagreze WA, Blauth E, Knorle R, Schnierle P, Lucking CH, Feuerstein TJ (2000) Gabapentin-lactam (8-aza-spiro[5,4]decan-9-on; GBP-L) inhibits oxygen glucose deprivation- induced [3H]glutmate release and is a neuroprotective agent in amodel of acute retinal ischemia. Naunyn Schmiedebergs Arch Pharmacol 362:74–81PubMedCrossRef

25.

Kacza J, Mohr C, Pannicke T, Kuhrt H, Dietzel J, Fluss M, Richt JA, Vahlenkamp TW, Stahl T, Reichenbach A, Seeger J (2001) Changes of the organotypic retinal organization in Borna virus-infected Lewis rats. J Neurocytol 30:801–820PubMedCrossRef

26.

Kacza J, Seeger J (1997) Transcellular labelling of activated retinal microglia following transection of the optic nerve. Inflamm Res 46:430–433PubMedCrossRef

27.

Kaplan DR, Miller FD (2006) When a motor goes bad: a kinesin regulates neuronal survival. Cell 125:224–226PubMedCrossRef

28.

Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318PubMedCrossRef

29.

Lafuente MP, Villegas-Perez MP, Mayor S, Aguilera ME, Miralles de Imperial J, Vidal-Sanz M (2002) Neuroprotective effects of brimonidine against transient ischemia-induced retinal ganglion cell death: a dose response in vivo study. Exp Eye Res 74:181–189PubMedCrossRef

30.

Lafuente MP, Villegas-Perez MP, Sobrado-Calvo P, Garcia-Aviles A, Miralles de Imperial J, Vidal-Sanz M (2001) Neuroprotective effects of alpha(2)-selective adrenergic agonists against ischemia-induced retinal ganglion cell death. Invest Ophthalmol Vis Sci 42:2074–2084PubMed

31.

Lagreze WA (2001) [Neuroprotection. Bases and possibilities of a future clinical use]. Ophthalmologe 98:235–236PubMedCrossRef

32.

Lagreze WA, Knorle R, Bach M, Feuerstein TJ (1998) Memantine is neuroprotective in a rat model of pressure-induced retinal ischemia. Invest Ophthalmol Vis Sci 39:1063–1066PubMed

33.

Lagreze WA, Pielen A, Steingart R, Schlunck G, Hofmann HD, Gozes I, Kirsch M (2005) The peptides ADNF-9 and NAP increase survival and neurite outgrowth of rat retinal ganglion cells in vitro. Invest Ophthalmol Vis Sci 46:933–938PubMedCrossRef

34.

Leahy KM, Ornberg RL, Wang Y, Zhu Y, Gidday JM, Connor JR, Wax MB (2004) Quantitative ex vivo detection of rodent retinal ganglion cells by immunolabeling Brn-3b. Exp Eye Res 79:131–140PubMedCrossRef

35.

Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P, Thoenen H, Barde YA (1989) Molecular cloning and expression of brain-derived neurotrophic factor. Nature 341:149–152PubMedCrossRef

36.

Leker RR, Teichner A, Grigoriadis N, Ovadia H, Brenneman DE, Fridkin M, Giladi E, Romano J, Gozes I (2002) NAP, a femtomolar-acting peptide, protects the brain against ischemic injury by reducing apoptotic death. Stroke 33:1085–1092PubMedCrossRef

37.

Levi-Montalcini R, Angeletti PU (1968) Nerve growth factor. Physiol Rev 48:534–569PubMed

38.

Levkovitch-Verbin H, Quigley HA, Martin KR, Zack DJ, Pease ME, Valenta DF (2003) A model to study differences between primary and secondary degeneration of retinal ganglion cells in rats by partial optic nerve transection. Invest Ophthalmol Vis Sci 44:3388–3393PubMedCrossRef

39.

Lin LF, Mismer D, Lile JD, Armes LG, Butler ET 3rd, Vannice JL, Collins F (1989) Purification, cloning, and expression of ciliary neurotrophic factor (CNTF). Science 246:1023–1025PubMedCrossRef

40.

Midorikawa R, Takei Y, Hirokawa N (2006) KIF4 motor regulates activity-dependent neuronal survival by suppressing PARP-1 enzymatic activity. Cell 125:371–383PubMedCrossRef

41.

Naskar R, Wissing M, Thanos S (2002) Detection of early neuron degeneration and accompanying microglial responses in the retina of a rat model of glaucoma. Invest Ophthalmol Vis Sci 43:2962–2968PubMed

42.

Nickells RW (2004) The molecular biology of retinal ganglion cell death: caveats and controversies. Brain Res Bull 62:439–446PubMedCrossRef

43.

Osborne NN, Chidlow G, Layton CJ, Wood JP, Casson RJ, Melena J (2004) Optic nerve and neuroprotection strategies. Eye 18:1075–1084PubMedCrossRef

44.

Pinhasov A, Mandel S, Torchinsky A, Giladi E, Pittel Z, Goldsweig AM, Servoss SJ, Brenneman DE, Gozes I (2003) Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res Dev Brain Res 144:83–90PubMedCrossRef

45.

Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ (2003) Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 348:1333–1341PubMedCrossRef

46.

Selles-Navarro I, Villegas-Perez MP, Salvador-Silva M, Ruiz-Gomez JM, Vidal-Sanz M (1996) Retinal ganglion cell death after different transient periods of pressure-induced ischemia and survival intervals. A quantitative in vivo study. Invest Ophthalmol Vis Sci 37:2002–2014PubMed

47.

Sobrado-Calvo P, Vidal-Sanz M, Villegas-Perez MP (2007) Rat retinal microglial cells under normal conditions, after optic nerve section, and after optic nerve section and intravitreal injection of trophic factors or macrophage inhibitory factor. J Comp Neurol 501:866–878PubMedCrossRef

48.

Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt JC, Martone JF, Royall RM, Witt KA, Ezrine S (1991) Racial differences in the cause-specific prevalence of blindness in east Baltimore. N Engl J Med 325:1412–1417PubMed

49.

Thanos S (1992) Sick photoreceptors attract activated microglia from the ganglion cell layer: a model to study the inflammatory cascades in rats with inherited retinal dystrophy. Brain Res 588:21–28PubMedCrossRef

50.

Thanos S, Kacza J, Seeger J, Mey J (1994) Old dyes for new scopes: the phagocytosis- dependent long-term fluorescence labelling of microglial cells in vivo. Trends Neurosci 17:177–182PubMedCrossRef

51.

Thanos S, Mey J, Wild M (1993) Treatment of the adult retina with microglia-suppressing factors retards axotomy-induced neuronal degradation and enhances axonal regeneration in vivo and in vitro. J Neurosci 13:455–466PubMed

52.

Visochek L, Steingart RA, Vulih-Shultzman I, Klein R, Priel E, Gozes I, Cohen-Armon M (2005) PolyADP-ribosylation is involved in neurotrophic activity. J Neurosci 25:7420–7428PubMedCrossRef

53.

Vorwerk CK, Lipton SA, Zurakowski D, Hyman BT, Sabel BA, Dreyer EB (1996) Chronic low- dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. Invest Ophthalmol Vis Sci 37:1618–1624PubMed

54.

Watanabe M, Fukuda Y (2002) Survival and axonal regeneration of retinal ganglion cells in adult cats. Prog Retin Eye Res 21:529–553PubMedCrossRef

55.

Yoles E, Wheeler LA, Schwartz M (1999) Alpha2-adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration. Invest Ophthalmol Vis Sci 40:65–73PubMed

56.

Yuan L, Neufeld AH (2001) Activated microglia in the human glaucomatous optic nerve head. J Neurosci Res 64:523–532PubMedCrossRef

57.

Zaltzman R, Alexandrovich A, Trembovler V, Shohami E, Gozes I (2005) The influence of the peptide NAP on Mac-1-deficient mice following closed head injury. Peptides 26:1520–1527PubMedCrossRef

58.

Zemlyak I, Furman S, Brenneman DE, Gozes I (2000) A novel peptide prevents death in enriched neuronal cultures. Regul Pept 96:39–43PubMedCrossRef

59.

Zeng XX, Ng YK, Ling EA (2000) Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats. Vis Neurosci 17:463–471PubMedCrossRef

Title: The neuropeptide NAP provides neuroprotection against retinal ganglion cell damage after retinal ischemia and optic nerve crush
Authors: T. Jehle
C. Dimitriu
S. Auer
R. Knoth
M. Vidal-Sanz
I. Gozes
W. A. Lagrèze
Publication date: 01-09-2008
Publisher: Springer-Verlag
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 9/2008
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-007-0746-7

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The neuropeptide NAP provides neuroprotection against retinal ganglion cell damage after retinal ischemia and optic nerve crush

Abstract

Background

Methods

Results

Conclusions

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Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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