Next Article in Journal
Hypericins as Potential Leads for New Therapeutics
Next Article in Special Issue
3-Nitropropionic Acid as a Tool to Study the Mechanisms Involved in Huntington’s Disease: Past, Present and Future
Previous Article in Journal
The Measurement of Polymer Swelling Processes by an Interferometric Method and Evaluation of Diffusion Coefficients
Previous Article in Special Issue
Melatonin and Structurally-Related Compounds Protect Synaptosomal Membranes from Free Radical Damage
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 11
Issue 2
10.3390/ijms11020544
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Novel Neuroprotective Strategies in Ischemic Retinal Lesions

by
Krisztina Szabadfi
1,
Laszlo Mester
2,
Dora Reglodi
3,
Peter Kiss
3,
Norbert Babai
1,
Boglarka Racz
2,
Krisztina Kovacs
2,
Aliz Szabo
2,
Andrea Tamas
3,
Robert Gabriel
1 and
Tamas Atlasz
1,4,*
1
Department of Experimental Zoology and Neurobiology, University of Pecs, H-7624 Pecs, Hungary
2
Department of Biochemistry and Medical Chemistry, University of Pecs, H-7624 Pecs, Hungary
3
Department of Anatomy, University of Pecs, H-7624 Pecs, Hungary
4
Department of Sportbiology, University of Pecs, H-7624 Pecs, Hungary
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2010, 11(2), 544-561; https://doi.org/10.3390/ijms11020544
Submission received: 7 January 2010 / Revised: 27 January 2010 / Accepted: 27 January 2010 / Published: 3 February 2010
(This article belongs to the Special Issue Neuroprotective Strategies (special issue))
Browse Figures
Versions Notes

Abstract

:
Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review we summarize recent findings with different neuroprotective candidate molecules. We describe the protective effects of intravitreal treatment with: (i) urocortin 2; (ii) a mitochondrial ATP-sensitive K+ channel opener, diazoxide; (iii) a neurotrophic factor, pituitary adenylate cyclase activating polypeptide; and (iv) a novel poly(ADP-ribose) polymerase inhibitor (HO3089). The retinoprotective effects are demonstrated with morphological description and effects on apoptotic pathways using molecular biological techniques.

Graphical Abstract

1. Retinal Ischemia

The retina is supplied by two arterial systems: the chorocapillary layer supplies the outer retina, while the central retinal artery supplies the inner retina. The rich capillary networks provide an excellent blood supply suiting the high energy demand of the retinal light processing events. When the retinal circulation does not meet the requirements of the retina, the retina suffers an ischemic damage, present in numerous human conditions and leading to various degrees of visual impairment [1–6]. The pathways leading to ischemic retinal damage and the potential retinoprotective strategies have been reviewed in several excellent papers [1,7–10]. In the present review we focus on four recently proven retinoprotective agents in one type of animal model of retinal ischemia: in bilateral common carotid artery occlusion (BCCAO).
The main factors involved in ischemia-induced retinal degeneration are thought to be the excitatory neurotransmitter release, glial dysfunction, Ca2+ overload, formation of free radicals, elevation of nitric oxide and release of potentially toxic mediators by activated inflammatory cells such as tumor necrosis factor and interleukin-1 [1]. This complex cascade of events finally leads to degeneration of certain cell populations or the entire retina depending on the strength and duration of the ischemic event.
There are numerous animal models of retinal ischemia, including high intraocular pressure, ligation of the ophthalmic vessels and BCCAO with or without the occlusion of the vertebral arteries [1,11]. BCCAO leads to moderate reduction in the cerebral blood flow in rats leading to subtle changes in biochemical and behavioral measures. It has been shown that BCCAO causes long-lasting white matter lesion, neuronal degeneration, microglial activation, astrocytosis, behavioral deficits and changes in several biochemical parameters [12]. In the retina, the effects of chronic BCCAO depend on the rat strain and technique used. It produces varying degrees of retinal degeneration from subtle changes to severe degeneration, paralleling the retinopathy of carotid artery occlusive disease in humans [13,14]. Numerous electroretinographical, immunohistochemical, histological and functional studies show that BCCAO leads to varying degrees of ischemic damage of the retina [7,15,17–20].
Previously, we have found that permanent BCCAO leads to a severe retinal damage, with all retinal layers bearing the marks of deterioration [20,21]. The most marked reduction in thickness can be observed in the plexiform layers, and as a consequence, the distance between outer limiting membrane and inner limiting membrane is significantly less than in control preparations (Figures 1A, 1B and 2). The photoreceptor layer also suffers degeneration: the outer segments become shorter and the geometric arrangement is disturbed. Numerous photoreceptors and possibly the second- and third-order neurons belonging to the same retinal circuitry have been found to be damaged. This assumption is further justified by our observation of degenerating bipolar cell terminals in the inner plexiform layer.

2. Potential Protective Strategies

Given the complexity of events leading to retinal cell death, a variety of pharmacological approaches has been shown to be protective in retinal ischemia. As glutamate-mediated excitotoxicity is one of the main factors in retinal ischemia, decreasing excitotoxicity is an important therapeutic approach [1]. Other strategies involve reducing the detrimental effects of free radicals and increased Ca2+ levels, counteracting mitochondrial failure, anti-inflammatory strategies and potentiating endogenous protective mechanisms [1,22]. Table 1 gives a brief overview of the protective strategies proven in animal models of retinal ischemia. In the following sections, we describe four novel neuroprotective strategies recently found to reduce ischemic retinal damage in the rat.

3. Urocortin 2

Urocortins (Ucn 1, 2 and 3) are paralogs of corticotropin-releasing factor (CRF) [52]. In terms of primary structure, Ucn 2 most resembles Ucn 3, with both peptides acting as a preferential or selective CRF2 agonist, leading to their designation as the selective CRF2 agonists, Ucn 2 and Ucn 3 [53]. Ucns have been proposed to participate in many physiological functions, including anxiety, learning and memory, osmoregulation, thermoregulation, feeding, reproductive and cardiovascular functions [52,54–58]. Ucns confer protection when added to post-ischemic/hypoxic cardiomyocytes or to isolated intact heart during reperfusion after regional ischemia, preventing necrotic and apoptotic cell death and reducing infarct size, respectively [52,59–62]. Ucn 1 and 2 are known to exert cardioprotective effects against ischemic/hypoxic insults via a CRF2 dependent mechanism [52]. The neuroprotective activity of Ucn 1 is mediated by CRF1 receptors via cAMP-dependent pathways [63]. Less is known about the neuroprotective functions of Ucns. Ucn 1 has been shown to protect hippocampal neurons against excitotoxic and oxidative injuries [64]. mRNA transcripts for both CRF receptor subtypes, class B G-protein coupled receptors [65,66], and the CRF peptides also have been reported in retina [67–72], so further studies are needed to determine the mediating receptor subtype. The downstream mechanisms underlying Ucn 2 retinoprotection also remain uncertain. CRF-like immunoreactivity is present in amacrine, horizontal, and ganglion cells, as well as inner and outer nuclear and plexiform layers. The presence of CRF, Ucns, POMC and mRNAs of prohormone convertases 1 and 2 also has been shown in the retinal pigment epithelium [66]. Based on the retinal distribution of the CRF peptide family, it has been suggested that ocular tissues express CRF/Ucn-driven signaling systems that may play multiple roles in retinal function [66]. We have provided evidence that acute intravitreal Ucn 2 administration attenuates the marked degeneration of retinal layers that otherwise is seen two weeks following permanent BCCAO in rats. The in vivo findings demonstrate that protective actions of Ucn 2 extend to sparing retina from ischemic injury (Figures 1C and 2) [73].

4. Diazoxide

Mitochondrial dysfunction is involved in many key events of neuronal cell death in the retina [1]. ATP-sensitive K+ channels are located in different parts of the cell, including the inner mitochondrial membrane. 7-chloro-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide, diazoxide (DIAZ), a selective mitochondrial, ATP-dependent K+ channel opener that has been implicated in cytoprotection in cardiac and cerebral ischemia [12]. The cardio- and neuroprotective effects of various agents are attributed to the activation of these channels [74,75]. This type of neuroprotection represents a new mechanism of protection which is not dependent on blocking glutamatergic receptors or scavanging free radicals [74]. DIAZ is usually applied as pretreatment before CNS insults because the drug is known to mimic the effects of ischemic preconditioning [76–79]. When DIAZ is used prior to the insult in vitro, it protects against neuronal cell death induced by oxidative stress or glutamate [80,81]. DIAZ can target both mitochondrial and surface cation channels on the astrocytes, thereby modulating the astrocytic function [82]. DIAZ has mostly been applied in neuronal cell cultures exposed to oxygen–glucose deprivation [74,81,83–86]. In vivo, it has neuroprotective effects in various cerebral ischemic experimental conditions [74,83,87,88–90]. The protective effects of DIAZ have also been described both using pre- and postischemic administration in BCCAO [88,89,91,92], but relatively little is known about its putative protective effects in the retina. The mitochondrial ATP-sensitive K+ channels are also present in the retina, where the stimulatory effects of DIAZ have been reported [93]. It has been shown that DIAZ enhances survival of retinal ganglion cells, protects retinal neurons against excitotoxicity and inhibits the glutamate-induced mitochondrial depolarization in vitro [75,94]. DIAZ has also been reported to block the hypoxia-induced horizontal cell depolarization and the reduction of the light-evoked hyperpolarization in vitro [95]. In vivo, ischemic preconditioning can effectively be mimicked by DIAZ [96]. In an in vitro system, opening the mitochondrial K+ channels has been shown to inhibit the oxygen/glucose deprivation-induced glutamate release and to be protective in a model of retinal ischemia [97]. In a superfused retinal system, DIAZ has blocked the hypoxia-induced horizontal cell depolarization and the reduction of the light-evoked hyperpolarization [95]. We have recently reported that local administration of DIAZ is protective in retinal degeneration induced by neonatal monosodium-glutamate treatment or by BCCAO-induced ischemic damage of the retina (Figures 1D and 2) [98]. The mechanism could be multiple, including acute cytoprotective effects of the drug as well as early and late preconditioning. If DIAZ is available for the cells at the time of the ischemia/hypoxia or other kind of depolarization, its protective mechanism can be mediated by reduction of the mitochondrial calcium load [83].

5. Pituitary Adenylate Cyclase Activating Polypeptide

An important approach in neuroprotection is to potentiate or mimic endogenous protective mechanisms [1,96]. Several trophic factors have protective effects against retinal ischemia. Intravitreal injections of brain-derived neurotrophic factor, ciliary neurotrophic factor, basic fibroblast growth factor, hepatocyte growth factor and pigment epithelium derived factor result in significantly less damage in the inner retinal layers [99–101]. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophic and neuroprotective peptide that has been shown to exert protective effects in different neuronal injuries, such as traumatic brain and spinal cord injury, models of neurodegenerative diseases and cerebral ischemia [102–104]. PACAP and its receptors are present in the retina [105,106]. PACAP is also a trophic factor in the nervous system and retina [107–109]. Increasing body of evidence shows that PACAP is an effective protective agent in retinal injuries. In vitro, the peptide has been shown to counteract the excitotoxic lesion induced by glutamate [110], cell death induced by anisomycin [111] and electrophysiological changes induced by anoxia [112]. In vivo, PACAP protects the retina against glutamate and kainate toxicity and optic nerve transection [113–118].
The neuroprotective effects of PACAP seem to be mediated predominantly by PAC1 receptors, involving protein kinase A and C (PKA and PKC) pathways. A major contribution to this effect has been shown to come from the PKA/MAPK (mitogen activated protein kinase) pathway and downstream, the inhibition of the apoptosis executor, caspase-3. In the retina, a part of this complex neuroprotective mechanism has been confirmed in an in vivo model, the monosodium-glutamate induced degeneration. PACAP has been shown to upregulate the antiapoptotic pathways, such as PKA, cAMP response element binding (CREB) and extracellular signal-regulated kinase (ERK) phosphorylation, and the PKA/Bad/14-3-3 protein cascade resulting in increased expression of the protective Bcl-xL and Bcl-2 [119–121]. At the same time, PACAP treatment downregulates the proapoptotic signaling, such c-Jun N-terminal kinase (JNK), apoptosis inducing factor (AIF), caspase-3, and the release of mitochondrial cytochrome c into the cytosol [119–121].
Recently, we have provided evidence that PACAP also reduces ischemic damage of the retina, protecting all inner retinal layers (Figures 1E and 2) [117,122]. This correlates with previous results showing the distribution of PAC1 receptor in the retina [105]. Strongest expression of the receptor is found in the GCL and INL, while weaker expressions are found in the ONL and OPL. This pattern of receptor expression provides basis for the sites of action by intraocular PACAP administration in our studies. Also, the PACAP antagonist PACAP6-38 could counteract the protective effects of PACAP mostly in the INL and GCL, where the strongest receptor expression has been described.

6. PARP Inhibition

The multifunctional nuclear enzyme, poly(ADP-ribose) polymerase (PARP) is implicated as a major regulator of the cell death process induced by a variety of environmental stimuli [123]. It is well established that overproduction of reactive oxygen species in response to the environmental stimuli cause DNA damage that leads to PARP activation [124]. Excessive PARP activation results in depletion of its substrate, NAD+ leading to ATP depletion and necrotic cell death as a consequence of energy loss. PARP activation facilitates other components of the cell death machinery too, namely; destabilization of the mitochondrial membrane systems [125,126], nuclear translocation of AIF [127] and activation of cell death promoting kinases such as JNK [128]. In addition, PARP activation suppresses the cytoprotective phosphatidyl-inositol-3 kinase-Akt pathway [129]. In the retina, increased activation of PARP contributes to retinal ganglion cell death in response to optic nerve transection [130], is involved in photoreceptor degeneration in the retinal degeneration-1 transgenic mouse model [131] and oxidative stress-induced apoptosis of ganglion cells [132]. PARP inhibition, on the other hand, has been demonstrated to decrease retinal damage in NMDA-induced cell death in the retina [133] and N-methyl-N-nitrosourea-induced photoreceptor cell apoptosis [134].
Although involvement of PARP activation in various ischemia models has been thoroughly studied [135–137], only circumstantial evidences are available for the role of PARP activation in chronic hypoperfusion induced neurodegenerative processes [138]. We have recently provided evidence that a novel PARP inhibitor HO3089 suppresses the morphological and biochemical changes induced by chronic hypoperfusion [20]. Upon PARP inhibitor treatment, the normal morphological structure of the retina was preserved and the thickness of the retinal layers was increased compared to the control ischemic eyes (Figures 1F and 2). Western blot analysis revealed activation of poly-ADP-ribose (PAR) synthesis, which was inhibited by the PARP inhibitor indicating that PARP activation was a causative factor behind the hypoperfusion-induced retinal degeneration. Inhibition of PARP also led to increased activation of one of the most important cytoprotective pathways, the phosphatidyl-inositol-3 kinase-Akt system and its downstream target, GSK-3beta. The signal transduction pathways involving MAP kinases play key roles in cellular survival and adaptation in the retina. BCCAO induced phosphorylation of JNK and p38 MAPK. HO3089 decreased the phosphorylation of these proapoptotic MAPKs. In addition, HO3089 treatment induced phosphorylation that is activation, of the protective ERK signaling pathways [20].

7. Conclusions

In the present review we have summarized recent findings describing novel neuroprotective strategies in ischemic retinal lesions induced by chronic BCCAO. The described strategies encompass four substances acting on different protective pathways, such as endogenous neurotrophism (PACAP and Ucn 2), mitochondrial integrity (DIAZ) and PARP inhibition. The vast amount of retinoprotective agents proven to be effective in animal models provides a divergent array of possible therapeutic strategies in ischemic retinal injury. Further studies are necessary to determine the most effective combination of putative therapeutic treatments in human retinal diseases. The perspective we illustrate by histological studies may also yield novel perspectives on other hypoxic-ischemic retinal disorders, including diabetic retinopathy and age-related macular degeneration, diseases, which are characterized by both vascular and neural abnormalities of the retina.

Acknowledgments

This work was supported by Hungarian National Scientific Grants OTKA T061766, K72592, F67830, CNK 78480, ETT278-04/2009, Richter Gedeon Centenary Foundation, Bolyai Scholarship, University of Pecs Medical School Research Grant 2009.

References

  1. Osborne, NN; Casson, RJ; Wood, JPM; Chidlow, G; Graham, M; Melena, J. Retinal ischemia: Mechanisms of damage and potential therapeutic strategies. Prog. Retin. Eye Res 2004, 23, 91–147. [Google Scholar]
  2. Harris, A; Jonescu-Cuypers, CP; Kagemann, L; Krieglstein, GK. Atlas of Ocular Blood Flow–Vascular Anatomy, Pathophysiology, and Metabolism; Imprint of Butterworth Heinemann: Philadelphia, PA, USA, 2003. [Google Scholar]
  3. Feigl, B. Age-related maculopathy-linking aetiology and pathophysiologycal changes to the ischaemia hypothesis. Prog. Retin. Eye Res 2009, 28, 63–86. [Google Scholar]
  4. Kaur, C; Foulds, WS; Ling, EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog. Retin. Eye Res 2008, 27, 622–647. [Google Scholar]
  5. Pournaras, CJ; Rungger-Brandle, E; Riva, CE; Hardarson, SH; Stefansson, E. Regulation of retinal blood flow in health and disease. Prog. Retin. Eye Res 2008, 27, 284–330. [Google Scholar]
  6. Chen, CS; Miller, NR. Ocular ischemic syndrome: review of clinical presentations, etiology, investigation, and management. Compr. Ophthalmol 2007, 8, 17–28. [Google Scholar]
  7. Osborne, NN; Ugarte, M; Chao, M; Chidlow, G; Bae, JH; Wood, JP; Nash, MS. Neuroprotection in relation to retinal ischemia and relevance to glaucoma. Surv. Ophthalmol 1999, 1, 102–128. [Google Scholar]
  8. Bek, T. Inner retinal ischemia: current understanding and needs for further investigations. Acta Ophthalmol 2009, 87, 362–367. [Google Scholar]
  9. Roth, S. Endogenous neuroprotection in the retina. Brain Res. Bull 2004, 62, 461–466. [Google Scholar]
  10. Fulton, AB; Akula, JD; Mocko, JA; Hansen, RM; Benador, IY; Beck, SC; Fahl, E; Seeliger, MW; Moskowitz, A; Harris, ME. Retinal degenerative and hypoxic ischemic disease. Doc. Ophthalmol 2009, 118, 55–61. [Google Scholar]
  11. Kalesnykas, G; Tuulos, T; Uusitalo, H; Jolkkonen, J. Neurogenereration and cellular stress in the retina and optic nerve in rat cerebral ischemia and hypoperfusion models. Neuroscience 2008, 55, 937–947. [Google Scholar]
  12. Farkas, E; Luiten, PG; Bari, F. Permanent, bilateral common carotid artery occlusion in the rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res. Rev 2007, 54, 162–180. [Google Scholar]
  13. Slakter, JS; Spertus, AD; Weissman, SS; Henkind, P. An experimental model of carotid artery occlusive disease. Am. J. Ophtalmol 1984, 97, 168–172. [Google Scholar]
  14. Spertus, AD; Slakter, JS; Weissman, SS; Henkind, P. Experimental carotid occlusion: funduscopic and fluorescein angiographic findings. Br. J. Ophtalmol 1984, 68, 47–57. [Google Scholar]
  15. Block, F; Schwarz, M; Sontag, KH. Retinal ischemia induced by occlusion of both common carotid arteries in rats as demonstrated by electroretinography. Neurosci. Lett 1992, 144, 124–126. [Google Scholar]
  16. Osborne, NN; Safa, R; Nash, MS. Photoreceptors are preferentially affected in the rat retina following permanent occlusion of the carotid arteries. Vision Res 1999, 39, 3995–4002. [Google Scholar]
  17. Stevens, WD; Fortin, T; Pappas, BA. Retinal and optic nerve degeneration after chronic carotid ligation. Stroke 2002, 33, 1107–1112. [Google Scholar]
  18. Yamamoto, H; Schmidt-Kasner, R; Hamasaki, DI; Yamamoto, H; Parel, JM. Complex neurodegeneration in retina following moderate ischemia induced by bilateral common carotid artery occlusion in Wistar rats. Exp. Eye Res 2006, 82, 767–779. [Google Scholar]
  19. Lavinsky, D; Arterni, NS; Achaval, M; Netto, CA. Chronic bilateral common carotid artery occlusion: a model for ocular ischemic syndrome in the rat. Graefe’s Arch. Clin. Exp. Ophthalmol 2006, 244, 199–204. [Google Scholar]
  20. Mester, L; Szabo, A; Atlasz, T; Szabadfi, K; Reglodi, D; Kiss, P; Racz, B; Tamas, A; Gallyas, F; Sumegi, B; Hocsak, E; Gabriel, R; Kovacs, K. Protection against chronic hypoperfusion-induced retinal neurodegeneration by PARP inhibition via activation of PI3-kinase Akt pathway and suppression of JNK and p38 MAP kinases. Neurotox. Res 2009, 18, 68–76. [Google Scholar]
  21. Atlasz, T; Babai, N; Kiss, P; Reglodi, D; Tamas, A; Szabadfi, K; Toth, G; Hegyi, O; Lubics, A; Gabriel, R. Pituitary adenylate cyclase activating polypeptide is protective in bilateral carotid occlusion-induced retinal lesion in rats. Gen. Comp. Endocrinol 2007, 153, 108–114. [Google Scholar]
  22. Vidal-Sanz, M; Lafuente, M; Sobrado-Calvo, P; Selles-Navarro, I; Rodriguez, E; Mayor-Torroglosa, S; Villegas-Perez, MP. Death and neuroprotection of retinal ganglion cells after different types of injury. Neurotox. Res 2000, 2, 215–227. [Google Scholar]
  23. Dilsiz, N; Sahaboglu, A; Yildiz, MZ; Reichenbach, A. Protective effects of various antioxidants during ischemia-reperfusion in the rat retina. Graefe’s Arch. Clin. Exp. Ophthalmol 2006, 244, 627–633. [Google Scholar]
  24. Li, SY; Fu, ZJ; Ma, H; Jang, WC; So, KF; Wong, D; Lo, AC. Effect of lutein on retinal neurons and oxidative stress in a model of acute retinal ischemia/reperfusion. Invest. Ophthalmol. Vis. Sci 2009, 50, 836–843. [Google Scholar]
  25. Maher, P; Hanneken, A. Flavonoids protect retinal ganglion cells from ischemia in vitro. Exp. Eye Res 2008, 86, 366–374. [Google Scholar]
  26. Roth, S; Li, B; Rosenbaum, PS; Gupta, H; Goldstein, IM; Maxwell, KM; Gidday, JM. Preconditioning provides complete protection against retinal ischemic injury in rats. Invest. Ophthalmol. Vis. Sci 1998, 39, 777–785. [Google Scholar]
  27. Obolensky, A; Berenshtein, E; Konijn, AM; Banin, E; Chevion, M. Ischemic preconditioning of the rat retina: protective role of ferritin. Free Radic. Biol. Med 2008, 44, 1286–1294. [Google Scholar]
  28. Sakamoto, K; Yonoki, Y; Kuwagata, M; Saito, M; Nakahara, T; Ishii, K. Histological protection against ischemia-reperfusion injury by early ischemic preconditioning in rat retina. Brain Res 2004, 1015, 154–160. [Google Scholar]
  29. Chollangi, S; Wang, J; Martin, A; Quinn, J; Ash, JD. Preconditioning-induced protection from oxidative injury is mediated by leukemia inhibitory factor receptor (LIFR) and its ligands in the retina. Neurobiol. Dis 2009, 34, 535–544. [Google Scholar]
  30. Li, Y; Roth, S; Laser, M; Ma, JX; Crosson, CE. Retinal preconditioning and the induction of heat-shock protein 27. Invest. Ophthalmol. Vis. Sci 2003, 44, 1299–1304. [Google Scholar]
  31. Fernandez, DC; Chianelli, MS; Rosenstein, RE. Involvement of glutamate in retinal protection against ischemia/reperfusion damage induced by post-conditioning. J. Neurochem 2009, 111, 488–498. [Google Scholar]
  32. Macaluso, C; Frishman, LJ; Frueh, B; Kaelin-Lang, A; Onoe, S; Niemeyer, G. Multiple effects of adenosine in the arterially perfused mammalian eye. Possible mechanisms for the neuroprotective function of adenosine in the retina. Doc. Ophthalmol 2003, 106, 51–59. [Google Scholar]
  33. Tomita, H; Ishiguro, S; Abe, T; Tamai, M. Administration of nerve growth factor, brain-derived neurotrophic factor and insulin-like growth factor-II protects phosphate-activated glutaminase in the ischemic and reperfused rat retinas. Tohoku J. Exp. Med 1999, 187, 227–236. [Google Scholar]
  34. Nishijima, K; Ng, Y-S; Zhong, L; Bradley, J; Schubert, W; Jo, N; Akita, J; Samuelsson, SJ; Robinson, GS; Adamis, AP; Shima, DT. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am. J. Pathol 2007, 171, 53–67. [Google Scholar]
  35. Sivilia, S; Giuliani, A; Fernández, M; Turba, ME; Forni, M; Massella, A; de Sordi, N; Giardino, L; Calzà, L. Intravitreal NGF administration counteracts retina degeneration after permanent carotid artery occlusion in rat. BMC Neurosci 2009, 10, 52. [Google Scholar]
  36. Junk, AK; Mammis, A; Savitz, SI; Singh, M; Roth, S; Malhotra, S; Rosenbaum, PS; Cerami, A; Brines, M; Rosenbaum, DM. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc. Natl. Acad. Sci. USA 2002, 99, 10659–10664. [Google Scholar]
  37. Dreixler, JC; Hagevik, S; Hemmert, JW; Shaikh, AR; Rosenbaum, DM; Roth, S. Involvement of erythropoietin in retinal ischemic preconditioning. Anesthesiology 2009, 110, 774–780. [Google Scholar]
  38. Jehle, T; Meschede, W; Dersch, R; Feltgen, N; Bach, M; Lagreze, WA. Erythropoietin protects retinal ganglion cells and visual function after ocular ischemia and optic nerve compression. Ophthalmologe 2009, in press. [Google Scholar]
  39. Schmeer, C; Gamez, A; Tausch, S; Witte, OW; Isenmann, S. Statins modulate heat shock protein expression and enhance retinal ganglion cell survival after transient retinal ischemia/reperfusion in vivo. Invest. Ophthalmol. Vis. Sci 2008, 49, 4971–4981. [Google Scholar]
  40. Russo, R; Cavaliere, F; Watanabe, C; Nucci, C; Bagetta, G; Corasaniti, MT; Sakurada, S; Morrone, LA. 17Beta-estradiol prevents retinal ganglion cell loss induced by acute rise of intraocular pressure in rat. Prog. Brain Res 2008, 173, 583–590. [Google Scholar]
  41. El-Remessy, AB; Khalil, IE; Matragoon, S; Abou-Mohamed, G; Tsai, NJ; Roon, P; Caldwell, RB; Caldwell, RW; Green, K; Liou, GI. Neuroprotective effect of (−)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am. J. Pathol 2003, 163, 1997–2008. [Google Scholar]
  42. Riazi-Esfahani, M; Kiumehr, S; Asadi-Amoli, F; Lashay, AR; Dehpour, AR. Morphine pretreatment provides histologic protection against ischemia-reperfusion injury in rabbit retina. Retina 2008, 28, 511–517. [Google Scholar]
  43. Riazi-Esfahani, M; Kiumehr, S; Asadi-Amoli, F; Dehpour, AR. Effects of intravitreal morphine administered at different time points after reperfusion in a rabbit model of ischemic retinopathy. Retina 2009, 29, 262–268. [Google Scholar]
  44. Kocer, I; Kulacoglu, D; Altuntas, I; Gundogdu, C; Gullulu, G. Protection of the retina from ischemia-reperfusion injury by L-carnitine in guinea pigs. Eur. J. Ophthalmol 2003, 13, 80–85. [Google Scholar]
  45. Lombardi, G; Moroni, F. Glutamate receptor antagonists protect against ischemia-induced retinal damage. Eur. J. Pharmacol 1994, 271, 489–495. [Google Scholar]
  46. Wood, JP; Schmidt, KG; Melena, J; Chidlow, G; Allmeier, H; Osborne, NN. The beta-adrenoceptor antagonists metipranolol and timolol are retinal neuroprotectants: comparison with betaxolol. Exp. Eye Res 2003, 76, 505–516. [Google Scholar]
  47. Donello, JE; Padillo, EU; Webster, ML; Wheeler, LA; Gil, DW. Alpha(2)-Adrenoceptor agonists inhibit vitreal glutamate and aspartate accumulation and preserve retinal function after transient ischemia. J. Pharmacol. Exp. Ther 2001, 296, 216–223. [Google Scholar]
  48. Ettaiche, M; Heurteaux, C; Blondeau, N; Borsotto, M; Tinel, N; Lazdunski, M. ATP-sensitive potassium channels [K(ATP)] in retina: a key role for delayed ischemic tolerance. Brain Res 2001, 890, 118–129. [Google Scholar]
  49. Sakamoto, K; Kawakami, T; Shimada, M; Yamaguchi, A; Kuwagata, M; Saito, M; Nakahara, T; Ishii, K. Histological protection by cilnidipine, a dual L/N-type Ca(2+) channel blocker, against neurotoxicity induced by ischemia-reperfusion in rat retina. Exp. Eye Res 2009, 88, 974–982. [Google Scholar]
  50. Traustason, S; Eysteinsson, T; Agnarsson, BA; Stefánsson, E. GABA agonists fail to protect the retina from ischemia-reperfusion injury. Exp. Eye Res 2009, 88, 361–366. [Google Scholar]
  51. Holman, MC; Chidlow, G; Wood, JP; Casson, RJ. Hyperglycemia rescues retinal neurons from hypoperfusion-induced injury. Invest Ophthalmol Vis Sci 2009, in press. [Google Scholar]
  52. Fekete, ÉM; Zorrilla, EP. Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: Ancient CRF paralogs. Front. Neuroendocrinol 2007, 28, 1–27. [Google Scholar]
  53. Chen, A; Perrin, M; Brar, B; Li, C; Jamieson, P; Digruccio, M; Lewis, K; Vale, W. Mouse corticotropin-releasing factor receptor type 2alpha gene: isolation, distribution, pharmacological characterization and regulation by stress and glucocorticoids. Mol. Endocrinol 2005, 19, 441–458. [Google Scholar]
  54. Latchman, DS. Molecules in focus urocortin. Biochem. Cell Biol 2002, 34, 907–910. [Google Scholar]
  55. Pan, W; Kastin, AJ. Urocortin and the brain. Prog. Neurobiol 2008, 84, 148–156. [Google Scholar]
  56. Skelton, KH; Owens, MJ; Nemeroff, CB. The neurobiology of urocortin. Regul. Pept 2000, 93, 85–92. [Google Scholar]
  57. Tsatsanis, C; Androulidaki, A; Dermitzaki, E; Charalampopoulos, I; Spiess, J; Gravanis, A; Margioris, AN. Urocortin 1 and Urocortin 2 induce macrophage apoptosis via CRFR2. FEBS Lett 2005, 579, 4259–4264. [Google Scholar]
  58. Uchida, M; Suzuki, M; Shimizu, K. Effects of urocortin, corticotropin-releasing factor (CRF) receptor agonist, and astressin, CRF receptor antagonist, on the sleep-wake pattern: analysis by radiotelemetry in conscious rats. Biol. Pharm. Bull 2007, 10, 1895–1897. [Google Scholar]
  59. Brar, BK; Jonassen, AK; Egorina, EM; Chen, A; Negro, A; Perrin, MH; Mjøs, OD; Latchman, DS; Lee, KF; Vale, W. Urocortin-II and urocortin-III are cardioprotective against ischemia reperfusion injury: an essential endogenous cardioprotective role for corticotropin releasing factor receptor type 2 in the murine heart. Endocrinology 2004, 145, 24–35. [Google Scholar]
  60. Liu, CN; Yang, C; Liu, XY; Li, S. In vivo protective effects of urocortin on ischemiareperfusion injury in rat heart via free radical mechanisms. Can. J. Physiol. Pharmacol 2005, 83, 459–465. [Google Scholar]
  61. Rademaker, MT. Urocortin: cardiovascular actions and therapeutic implications. Lett. Drug Des. Discov 2004, 1, 168–172. [Google Scholar]
  62. Tao, J; Li, S. Effects of UCN via ion mechanisms or CRF receptors? Biochem. Biophys. Res. Commun 2005, 336, 731–736. [Google Scholar]
  63. Facci, L; Stevens, DA; Pangallo, M; Franceschini, D; Skaper, SD; Strijbos, PJLM. Corticotropin-releasing factor (CRF) and related peptides confer neuroprotection via type 1 CRF receptors. Neuropharmacol 2003, 45, 623–636. [Google Scholar]
  64. Pedersen, WA; Wan, R; Zhang, P; Mattson, MP. Urocortin, but not urocortin II, protects cultured hippocampal neurons from oxidative and excitotoxic cell death via corticotropin-releasing hormone receptor type I. J. Neurosci 2002, 22, 404–412. [Google Scholar]
  65. Dautzenberg, FM; Huber, G; Higelin, J; Py-Lang, G; Kilpatrick, GJ. Evidence for the abundant expression of arginine 185 containing human CRF2 receptors and the role of position 185 for receptor-ligand selectivity. Neuropharmacol 2000, 39, 1368–1376. [Google Scholar]
  66. Zmijewski, MA; Sharma, RK; Slominski, AT. Expression of molecular equivalent of hypothalamic-pituitary-adrenal axis in adult retinal pigment epithelium. J. Endocrinol 2007, 193, 157–169. [Google Scholar]
  67. Skofitsch, G; Jacobowitz, DM. Corticotropin releasing factor-like immunoreactive neurons in the rat retina. Brain Res. Bull 1984, 12, 539–542. [Google Scholar]
  68. Williamson, DE; Eldred, WD. Synaptic organization of two types of amacrine cells with CRF-like immunoreactivity in the turtle retina. Vis. Neurosci 1991, 6, 257–269. [Google Scholar]
  69. Williamson, DE; Eldred, WD. Amacrine and ganglion cells with corticotropinreleasing-factor-like immunoreactivity in the turtle retina. J. Comp. Neurol 1989, 280, 424–435. [Google Scholar]
  70. Zhang, DR; Gallagher, M; Sladek, CD; Yeh, HH. Postnatal development of corticotrophin releasing factor-like immunoreactive amacrine cells in the rat retina. Brain Res. Dev. Brain Res 1990, 51, 185–194. [Google Scholar]
  71. Zhang, DR; Yeh, HH. Corticotropin releasing factor-like immunoreactivity (CRFLI) in horizontal cells of the developing rat retina. Vis. Neurosci 1991, 6, 383–391. [Google Scholar]
  72. Zhang, DR; Yeh, HH. Histogenesis of corticotropin releasing factor-like immunoreactive amacrine cells in the rat retina. Brain Res. Dev. Brain Res 1990, 53, 194–199. [Google Scholar]
  73. Szabadfi, K; Atlasz, T; Reglodi, D; Kiss, P; Danyáadi, B; Fekete, ÉM; Zorrilla, EP; Tamas, A; Szabo, K; Gabriel, R. Urocortin 2 protects against retinal degeneration following bilateral common carotid artery occlusion in the rat. Neurosci. Lett 2009, 455, 42–45. [Google Scholar]
  74. Busija, DW; Lacza, Z; Rajapakse, N; Shimizu, K; Kis, B; Bari, F; Domoki, F; Horiguchi, T. Targeting mitochondrial ATP-sensitive potassium channels - a novel approach to neuroprotection. Brain Res. Rev 2004, 46, 282–294. [Google Scholar]
  75. Yamauchi, T; Kashii, S; Yasuyoshi, H; Zhang, S; Honda, Y; Akaike, A. Mitochondrial ATP-sensitive potassium channel: a novel site for neuroprotection. Invest. Ophthalmol. Vis. Sci 2003, 44, 2750–2756. [Google Scholar]
  76. Domoki, F; Perciaccante, JV; Veltkamp, R; Bari, F; Busija, DW. Mitochondrial potassium channel opener diazoxide preserves neuronal-vascular function after cerebral ischemia in newborn pigs. Stroke 1999, 30, 2713–2718. [Google Scholar]
  77. Liu, D; Lu, C; Wan, R; Auyeung, WW; Mattson, MP. Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome c release. J. Cereb. Blood Flow Metab 2002, 22, 431–443. [Google Scholar]
  78. Minners, J; McLeod, CJ; Sack, MN. Mitochondrial plasticity in classical ischemic preconditioning-moving beyond the mitochondrial KATP channel. Cardiovasc. Res 2003, 59, 1–6. [Google Scholar]
  79. Shake, JG; Peck, EA; Marban, E; Gott, VL; Johnston, MV; Troncoso, JC; Redmond, JM; Baumgartner, WA. Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection. Ann. Thorac. Surg 2001, 72, 1849–1854. [Google Scholar]
  80. Nagy, K; Kis, B; Rajapakse, NC; Bari, F; Busija, DW. Diazoxide preconditioning protects against neuronal cell death by attenuation of oxidative stress upon glutamate stimulation. J. Neurosci. Res 2004, 76, 697–704. [Google Scholar]
  81. Teshima, Y; Akao, M; Li, RA; Chong, TH; Baumgartner, WA; Johnston, MV; Marban, E. Mitochondrial ATP-sensitive potassium channel activation protects cerebellar granule neurons from apoptosis induced by oxidative stress. Stroke 2003, 34, 1796–1802. [Google Scholar]
  82. Rajapakse, N; Kis, B; Horiguchi, T; Snipes, J; Busija, DW. Diazoxide pretreatment induces delayed preconditioning in astrocytes against oxygen glucose deprivation and hydrogen peroxide-induced toxicity. J. Neurosci. Res 2003, 73, 206–214. [Google Scholar]
  83. Domoki, F; Bari, F; Nagy, K; Busija, DW; Siklós, L. Diazoxide prevents mitochondrial swelling and Ca2+ accumulation in CA1 pyramidal cells after cerebral ischemia in newborn pigs. Brain Res 2004, 1019, 97–104. [Google Scholar]
  84. Kis, B; Rajapakse, NC; Snipes, JA; Nagy, K; Horiguchi, T; Busija, DW. Diazoxide induces delayed pre-conditioning in cultured rat cortical neurons. J. Neurochem 2003, 87, 969–980. [Google Scholar]
  85. Liu, Y; Sato, T; Seharaseyon, J; Szewczyk, A; O’Rourke, B; Marban, E. Mitochondrial ATP-dependent potassium channels. Viable candidate effectors of ischemic preconditioning. Ann. NY Acad. Sci 1999, 874, 27–37. [Google Scholar]
  86. Shimizu, K; Lacza, Z; Rajapakse, N; Horiguchi, T; Snipes, J; Busija, DW. MitoK(ATP) opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat. Am. J. Physiol. Heart Circ. Physiol 2002, 283, 1005–1011. [Google Scholar]
  87. Busija, DW; Katakam, P; Rajapakse, NC; Kis, B; Grover, G; Domoki, F; Bari, F. Effects of ATP-sensitive potassium channel activators diazoxide and BMS-191095 on membrane potential and reactive oxygen species production in isolated piglet mitochondria. Brain Res. Bull 2005, 66, 85–90. [Google Scholar]
  88. Farkas, E; Annahazi, A; Institoris, A; Mihaly, A; Luiten, PG; Bari, F. Diazoxide and dimethyl sulphoxide alleviate experimental cerebral hypoperfusion-induced white matter injury in the rat brain. Neurosci. Lett 2005, 373, 195–199. [Google Scholar]
  89. Farkas, E; Timmer, NM; Domoki, F; Mihaly, A; Luiten, PG; Bari, F. Post-ischemic administration of diazoxide attenuates long-term microglial activation in the rat brain after permanent carotid artery occlusion. Neurosci. Lett 2005, 387, 168–172. [Google Scholar]
  90. Lenzser, G; Kis, B; Bari, F; Busija, DW. Diazoxide preconditioning attenuates global cerebral ischemia-induced blood-brain barrier permeability. Brain Res 2005, 1051, 72–80. [Google Scholar]
  91. Farkas, E; Institoris, A; Domoki, F; Mihaly, A; Luiten, PG; Bari, F. Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res 2004, 1008, 252–260. [Google Scholar]
  92. Farkas, E; Institoris, A; Domoki, F; Mihaly, A; Bari, F. The effect of pre- and posttreatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat. Brain Res 2006, 1087, 168–174. [Google Scholar]
  93. Sheu, SJ; Wu, SN. Mechanism of inhibitory actions of oxidizing agents on calcium-activated potassium current in cultured pigment epithelial cells of the human retina. Invest. Ophthalmol. Vis. Sci 2003, 44, 1237–1244. [Google Scholar]
  94. Pielen, A; Kirsch, M; Hofmann, HD; Feuerstein, TJ; Lagreze, WA. Retinal ganglion cell survival is enhanced by gabapentin-lactam in vitro: evidence for involvement of mitochondrial KATP channels. Graefe’s Arch. Clin. Exp. Ophthalmol 2004, 242, 240–244. [Google Scholar]
  95. Hankins, MW; Ikeda, H. Consequences of transient retinal hypoxia on rod input to horizontal cells in the rat retina. Vision Res 1993, 33, 429–436. [Google Scholar]
  96. Roth, S; Dreixler, JC; Shaikh, AR; Lee, KH; Bindokas, V. Mitochondrial potassium ATP channels and retinal ischemic preconditioning. Invest. Ophthalmol. Vis. Sci 2006, 47, 2114–2124. [Google Scholar]
  97. Jehle, T; Lagreze, WA; Blauth, E; Knorle, R; Schnierle, P; Lucking, CH; Feuerstein, TJ. Gabapentin-lactam (8-aza-spiro[5,4]decan-9-on; GBP-L) inhibits oxygen glucose deprivation-induced [3H]glutamate release and is a neuroprotective agent in a model of acute retinal ischemia. Naunyn Schmiedebergs Arch. Pharmacol 2000, 362, 74–81. [Google Scholar]
  98. Atlasz, T; Babai, N; Reglodi, D; Kiss, P; Tamas, A; Bari, F; Domoki, F; Gabriel, R. Diazoxide is protective in the rat retina against ischemic injury induced by bilateral carotid occlusion and glutamate-induced degeneration. Neurotox. Res 2007, 12, 105–111. [Google Scholar]
  99. Unoki, K; La Vail, MM. Protection of the rat retina from ischemic injury by brain-derived neurotrophic factor, ciliary neurotrophic factor, and basic fibroblast growth factor. Invest. Ophtalmol. Vis. Sci 1994, 35, 907–915. [Google Scholar]
  100. Ogata, N; Wang, L; Jo, N; Tombran-Tink, J; Takahashi, K; Mrazek, D; Matsumura, M. Pigment epithelium derived factor as a neuroprotective agent against ischemic retinal injury. Curr. Eye Res 2001, 22, 245–252. [Google Scholar]
  101. Shibuki, H; Katai, N; Kuroiwa, S; Kurokawa, T; Arai, J; Matsumoto, K; Nakamura, T; Yoshimura, N. Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemia-reperfusion injury. Invest. Ophthalmol. Vis. Sci 2002, 43, 528–536. [Google Scholar]
  102. Vaudry, D; Falluel-Morel, A; Bourgault, S; Basille, M; Burel, D; Wurtz, O; Fournier, A; Chow, BK; Hashimoto, H; Galas, L; Vaudry, H. Pituitary adenylate cyclase activating polypeptide and its receptors: 20 years after the discovery. Pharmacol. Rev 2009, 61, 283–357. [Google Scholar]
  103. Ohtaki, H; Nakamachi, T; Dohi, K; Shioda, S. Role of PACAP in ischemic neural death. J. Mol. Neurosci 2008, 36, 16–25. [Google Scholar]
  104. Somogyvari-Vigh, A; Reglodi, D. Pituitary adenylate cyclase activating polypeptide: a potential neuroprotective peptide-review. Curr. Pharm. Des 2004, 10, 2861–2889. [Google Scholar]
  105. Seki, T; Izumi, S; Shioda, S; Zhou, CJ; Arimura, A; Koide, R. Gene expression for PACAP receptor mRNA in the rat retina by in situ hybridization and in situ RT-PCR. Ann. N. Y. Acad. Sci 2000, 921, 366–369. [Google Scholar]
  106. Seki, T; Shioda, S; Ogino, D; Nakai, Y; Arimura, A; Koide, R. Distribution and ultrastructural localization of a receptor for pituitary adenylate cyclase activating polypeptide and its mRNA in the rat retina. Neurosci. Lett 1997, 238, 127–130. [Google Scholar]
  107. Waschek, JA. Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration. Dev. Neurosci 2002, 24, 14–23. [Google Scholar]
  108. Bagnoli, P; Dal Monte, M; Casini, G. Expression of neuropeptides and their receptors in the developing retina of mammals. Histol. Histopathol 2003, 18, 1219–1242. [Google Scholar]
  109. Borba, JC; Henze, IP; Silveira, MS; Kubrusly, RC; Gardino, PF; de Mello, MC; Hokoc, JN; de Mello, FG. Pituitary adenylate cyclase activating polypeptide (PACAP) can act as determinant of the tyrosine hydoxylase phenotype of dopaminergic cells during retina development. Dev. Brain Res 2005, 156, 193–201. [Google Scholar]
  110. Shoge, K; Mishima, HK; Saitoh, T; Ishihara, K; Tamura, Y; Shiomi, H; Sasa, M. Attenuation by PACAP of glutamate-induced neurotoxicity in cultured retinal neurons. Brain Res 1999, 839, 66–73. [Google Scholar]
  111. Silveira, MS; Costa, MR; Bozza, M; Linden, R. Pituitary adenylate cyclase activating polypeptide prevents induced cell death in retinal tissue through activation of cyclic AMP-dependent protein kinase. J. Biol. Chem 2002, 277, 16075–16080. [Google Scholar]
  112. Rabl, K; Reglodi, D; Banvolgyi, T; Somogyvari-Vigh, A; Lengvari, I; Gabriel, R; Arimura, A. PACAP inhibits anoxia-induced changes in physiological responses in horizontal cells in the turtle retina. Regul. Pept 2002, 109, 71–74. [Google Scholar]
  113. Seki, T; Itoh, H; Nakamachi, T; Shioda, S. Suppression of ganglion cell death by PACAP following optic nerve transection in the rat. J. Mol. Neurosci 2008, 36, 57–60. [Google Scholar]
  114. Babai, N; Atlasz, T; Tamas, A; Reglodi, D; Toth, G; Kiss, P; Gabriel, R. Search for the optimal monosodium glutamate treatment schedule to study the neuroprotective effects of PACAP in the retina. Ann. N.Y. Acad. Sci 2006, 1070, 149–155. [Google Scholar]
  115. Babai, N; Atlasz, T; Tamas, A; Reglodi, D; Toth, G; Kiss, P; Gabriel, R. Degree of damage compensation by various PACAP treatments in monosodium glutamate-induced retinal degeneration. Neurotox. Res 2005, 8, 227–233. [Google Scholar]
  116. Tamas, A; Gabriel, R; Racz, B; Denes, V; Kiss, P; Lubics, A; Lengvari, I; Reglodi, D. Effects of pituitary adenylate cyclase activating polypeptide in retinal degeneration induced by monosodium-glutamate. Neurosci. Lett 2004, 372, 110–113. [Google Scholar]
  117. Atlasz, T; Szabadfi, K; Reglodi, D; Kiss, P; Tamas, A; Toth, G; Molnar, A; Szabo, K; Gabriel, R. Effects of pituitary adenylate cyclase activating polypeptide (PACAP1-38) and its fragments on retinal degeneration induced by neonatal MSG treatment. Ann. NY Acad. Sci 2009, 1163, 348–352. [Google Scholar]
  118. Seki, T; Nakatani, M; Taki, C; Shinonara, Y; Ozawa, M; Nishimura, S; Shioda, S. Neuroprotective effect of PACAP against kainic acid (KA)-induced neurotoxicity in rat retina. Ann. NY Acad. Sci 2006, 1070, 531–534. [Google Scholar]
  119. Racz, B; Tamas, A; Kiss, P; Toth, G; Gasz, B; Borsiczky, B; Ferencz, A; Gallyas, F, Jr; Roth, E; Reglodi, D. Involvement of ERK and CREB signalling pathways in the protective effect of PACAP on monosodium glutamate-induced retinal lesion. Ann. NY Acad. Sci 2006, 1070, 507–511. [Google Scholar]
  120. Racz, B; Gallyas, F, Jr; Kiss, P; Toth, G; Hegyi, O; Gasz, B; Borsiczky, B; Ferencz, A; Roth, E; Tamas, A; Lengvari, I; Lubics, A; Reglodi, D. The neuroprotective effects of PACAP in monosodium glutamate-induced retinal lesion involves inhibition of proapoptotic signaling pathways. Regul. Pept 2006, 137, 20–26. [Google Scholar]
  121. Racz, B; Gallyas, F, Jr; Kiss, P; Tamas, A; Lubics, A; Lengvari, I; Roth, E; Toth, G; Hegyi, O; Verzar, Zs; Fabricsek, Cs; Reglodi, D. Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the PKA-Bad-14-3-3 signaling pathway in glutamate-induced retinal injury in neonatal rats. Neurotox. Res 2007, 12, 95–104. [Google Scholar]
  122. Atlasz, T; Szabadfi, K; Kiss, P; Tamas, A; Toth, G; Reglodi, D; Gabriel, R. Evaluation of the protective effects of PACAP with cell-specific markers in ischemia-induced retinal degeneration. Brain Res Bull 2009, in press. [Google Scholar]
  123. Virag, L; Szabo, C. The therapeutic potential of poly(ADPribose) polymerase inhibitors. Pharmacol. Rev 2002, 54, 375–429. [Google Scholar]
  124. Pacher, P; Szabo, C. Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. Am. J. Pathol 2008, 173, 2–13. [Google Scholar]
  125. Halmosi, R; Berente, Z; Osz, E; Toth, K; Literati-Nagy, P; Sumegi, B. Effect of poly(ADP-ribose) polymerase inhibitors on the ischemia-reperfusion-induced oxidative cell damage and mitochondrial metabolism in Langendorff heart perfusion system. Mol. Pharmacol 2001, 59, 1497–1505. [Google Scholar]
  126. Hong, SJ; Dawson, TM; Dawson, VL. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol. Sci 2004, 25, 259–264. [Google Scholar]
  127. Yu, SW; Wang, H; Poitras, MF; Coombs, C; Bowers, WJ; Federoff, HJ; Poirier, GG; Dawson, TM; Dawson, VL. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 2002, 297, 259–263. [Google Scholar]
  128. Xu, Y; Huang, S; Liu, ZG; Han, J. Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J. Biol. Chem 2006, 281, 8788–8795. [Google Scholar]
  129. Veres, B; Gallyas, F, Jr; Varbiro, G; Berente, Z; Osz, E; Szekeres, G; Szabo, C; Sumegi, B. Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock. Biochem. Pharmacol 2003, 65, 1373–1382. [Google Scholar]
  130. Weise, J; Isenmann, S; Bahr, M. Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection. Cell Death Differ 2001, 8, 801–807. [Google Scholar]
  131. Paquet-Durand, F; Silva, J; Talukdar, T; Johnson, LE; Azadi, S; van Veen, T; Ueffing, M; Hauck, SM; Ekstrom, PA. Excessive activation of poly-(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse. Neurobiol. Dis 2007, 27, 10311–10319. [Google Scholar]
  132. Li, GY; Osborne, NN. Oxidative-induced apoptosis to an immortalized ganglion cell line is caspase independent but involves the activation of poly (ADP-ribose) polymerase and apoptosis-inducing factor. Brain Res 2008, 1188, 35–43. [Google Scholar]
  133. Goebel, DJ; Winkler, BS. Blockade of PARP activity attenuates poly(ADP-ribosyl)ation but offers only partial neuroprotection against NMDA-induced cell death in the rat retina. J. Neurochem 2006, 98, 1732–1745. [Google Scholar]
  134. Uehara, N; Miki, K; Tsukamoto, R; Matsuoka, Y; Tsubura, A. Nicotinamide blocks N-methyl-N-nitrosourea-induced photoreceptor cell apoptosis in rats through poly (ADP-ribose) polymerase activity and Jun N-terminal kinase/activator protein-1 pathway inhibition. Exp. Eye Res 2006, 82, 488–495. [Google Scholar]
  135. Ferrer, I; Planas, AM. Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J. Neuropathol. Exp. Neurol 2003, 62, 329–339. [Google Scholar]
  136. Meli, E; Pangallo, M; Baronti, R; Chiarugi, A; Cozzi, A; Pellegrini-Giampietro, DE; Moroni, F. Poly(ADP-ribose) polymerase as a key player in excitotoxicity and post-ischemic brain damage. Toxicol. Lett 2003, 139, 153–162. [Google Scholar]
  137. Ikeda, Y; Hokamura, K; Kawai, T; Ishiyama, J; Ishikawa, K; Anraku, T; Uno, T; Umemura, K. Neuroprotective effects of KCL-440, a new poly(ADP-ribose) polymerase inhibitor, in the rat middle cerebral artery occlusion model. Brain Res 2005, 1060, 73–80. [Google Scholar]
  138. Cozzi, A; Cipriani, G; Fossati, S; Faraco, G; Formentini, L; Min, W; Cortes, U; Wang, ZQ; Moroni, F; Chiarugi, A. Poly(ADPribose) accumulation and enhancement of postischemic brain damage in 110-kDa poly(ADP-ribose) glycohydrolase null mice. J. Cereb. Blood Flow Metab 2006, 26, 684–695. [Google Scholar]
Ijms 11 00544f1 1024
Figure 1. Microphotographs of different retinal sections. (A) Histological sections of control animals; (B) effects of bilateral common carotid artery occlusion (BCCAO). Extreme swelling of neuronal cell bodies and the fusion of the INL, IPL and GCL layers were observed. BCCAO caused severe overall retinal degeneration ameliorated by intravitreal injection of (C) urocortin 2, (D) diazoxide, (E) pituitary adenylate cyclase activating polypeptide and (F) the poly(ADP-ribose) polymerase inhibitor HO3089. Scale bar: 20 μm. Abbreviations: PL: photoreceptor layer; ONL: outer nuclear layer; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: inner plexiform layer; GCL: ganglion cell layer.
Figure 1. Microphotographs of different retinal sections. (A) Histological sections of control animals; (B) effects of bilateral common carotid artery occlusion (BCCAO). Extreme swelling of neuronal cell bodies and the fusion of the INL, IPL and GCL layers were observed. BCCAO caused severe overall retinal degeneration ameliorated by intravitreal injection of (C) urocortin 2, (D) diazoxide, (E) pituitary adenylate cyclase activating polypeptide and (F) the poly(ADP-ribose) polymerase inhibitor HO3089. Scale bar: 20 μm. Abbreviations: PL: photoreceptor layer; ONL: outer nuclear layer; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: inner plexiform layer; GCL: ganglion cell layer.
Ijms 11 00544f1
Ijms 11 00544f2 1024
Figure 2. Quantification of the whole retina thickness (OLM-ILM), distinct retinal layers (A) and the cell number of GCL/100 μm in different conditions (B) by morphometrical analysis. Significant decreases were observed in BCCAO-induced retinal degeneration. The neuroprotective effects of urocortin 2; diazoxide; pituitary adenylate cyclase activating polypeptide and HO3089 treatments were quantified by the thickness of different retinal layers and also the cell number of GCL/100 μm. *p < 0.05 between untreated and BCCAO; #p < 0.05 BCCAO vs. BCCAO+different treatments. Results are presented as mean ± S.E.M. Statistical comparisons were made using the ANOVA test followed by Tukey-B`s post hoc analysis. Abbreviations: OLM: outer limiting membrane; ONL: outer nuclear layer; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: inner plexiform layer; GCL: ganglion cell layer; ILM: inner limiting membrane.
Figure 2. Quantification of the whole retina thickness (OLM-ILM), distinct retinal layers (A) and the cell number of GCL/100 μm in different conditions (B) by morphometrical analysis. Significant decreases were observed in BCCAO-induced retinal degeneration. The neuroprotective effects of urocortin 2; diazoxide; pituitary adenylate cyclase activating polypeptide and HO3089 treatments were quantified by the thickness of different retinal layers and also the cell number of GCL/100 μm. *p < 0.05 between untreated and BCCAO; #p < 0.05 BCCAO vs. BCCAO+different treatments. Results are presented as mean ± S.E.M. Statistical comparisons were made using the ANOVA test followed by Tukey-B`s post hoc analysis. Abbreviations: OLM: outer limiting membrane; ONL: outer nuclear layer; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: inner plexiform layer; GCL: ganglion cell layer; ILM: inner limiting membrane.
Ijms 11 00544f2
Table
Table 1. Brief overview of potential retinoprotective strategies proven in animal models of retinal ischemia.
Table 1. Brief overview of potential retinoprotective strategies proven in animal models of retinal ischemia.
SubstanceMain effectsReferences
Antioxidants (e.g., Vitamin E, lutein, flavonoids)↓ oxidative damage
↓ caspase3
↑ glutathione
↓ nitrotyrosine
↓ nuclear PAR
↓ loss of ATP		[23]
[24]
[25]
Ischemic preconditioningprotein kinase C activation
ATP-sensitive K+ channel opening
↑ ferritin level
adenosine A1 receptor stimulation
STAT-3 activation
↑ HSP27		[26]
[27]
[28]
[29]
[30]
Ischemic postconditioning↓ glutamate[31]
Adenosinevasodilation
↓ neuronal activity
↑ glycogenolysis		[32]
Growth factors (IGFII, NGF, BDNF, VEGF)↑ phosphate activated glutaminase (PAG)
↓ ammonia
↑ blood flow to the retina
↑ Bcl-2
↓ Bax		[33]
[34]
[35]
Erythropoietin↓ apoptosis
↑ ischemic preconditioning		[36]
[37]
[38]
Statins↓ HSP27[39]
Estradiol↓ glutamate[40]
Cannabinoids↓ peroxynitrite[41]
Morphine↑ ischemic preconditioning[42,43]
L-carnitine↓ oxidative stress[44]
Glutamate receptor antagonists↓ glutamate excitotoxicity[45]
Adrenergic receptor blockers↓ influx of sodium and calcium[46]
Alpha2 adrenergic agonist (brimonidine)↓ glutamate and aspartate[47]
Ca2+, K+, Na+ channel blockers↓ influx of sodium and calcium
↑ ischemic preconditioning
↓ c-jun, p-JNK		[48,49]
Hypothermia↓ energy demand[50]
Hyperglycaemia↑ HSP-27[51]

Share and Cite

MDPI and ACS Style

Szabadfi, K.; Mester, L.; Reglodi, D.; Kiss, P.; Babai, N.; Racz, B.; Kovacs, K.; Szabo, A.; Tamas, A.; Gabriel, R.; et al. Novel Neuroprotective Strategies in Ischemic Retinal Lesions. Int. J. Mol. Sci. 2010, 11, 544-561. https://doi.org/10.3390/ijms11020544

AMA Style

Szabadfi K, Mester L, Reglodi D, Kiss P, Babai N, Racz B, Kovacs K, Szabo A, Tamas A, Gabriel R, et al. Novel Neuroprotective Strategies in Ischemic Retinal Lesions. International Journal of Molecular Sciences. 2010; 11(2):544-561. https://doi.org/10.3390/ijms11020544

Chicago/Turabian Style

Szabadfi, Krisztina, Laszlo Mester, Dora Reglodi, Peter Kiss, Norbert Babai, Boglarka Racz, Krisztina Kovacs, Aliz Szabo, Andrea Tamas, Robert Gabriel, and et al. 2010. "Novel Neuroprotective Strategies in Ischemic Retinal Lesions" International Journal of Molecular Sciences 11, no. 2: 544-561. https://doi.org/10.3390/ijms11020544

Article Metrics

Back to TopTop