The Role of Peroxisome Proliferator-Activated Receptor and Effects of Its Agonist, Pioglitazone, on a Rat Model of Optic Nerve Crush: PPARγ in Retinal Neuroprotection
It has been shown that peroxisome proliferators-activated receptor gamma (PPARγ) is beneficial for central nervous system injury. However its role on optic nerve injury remains unknown. In the present study, we examined the change of PPARγ expression in rat retina following optic nerve injury and investigated the effect of pioglitazone (Pio), a PPARγ agonist, on retinal ganglion cells (RGCs) neuroprotection using a rat optic nerve crush (ONC) model. Our results showed that PPARγ mRNA and protein levels were increased after ONC, and most of PPARγ-immunoreactive cells colocalized with Müller cells. Pio treatment significantly enhanced the number of surviving RGCs and inhibited RGCs apoptosis induced by ONC. However, when PPARγ antagonist GW9662 was used, these neuroprotective effects were abolished. In addition, pio attenuated Müller cell activation after ONC. These results indicate that PPARγ appears to protect RGCs from ONC possibly via the reduction of Müller glial activation. It provides evidence that activation of PPARγ may be a potential alternative treatment for RGCs neuroprotection.
References
[1]
Schmidt KG, Bergert H, Funk RH (2008) Neurodegenerative diseases of the retina and potential for protection and recovery. Curr Neuropharmacol 6: 164–178.
[2]
Kisiswa L, Dervan AG, Albon J, Morgan JE, Wride MA (2010) Retinal ganglion cell death postponed: giving apoptosis a break? Ophthalmic Res 43: 61–78.
[3]
Quigley HA, McKinnon SJ, Zack DJ, Pease ME, Kerrigan-Baumrind LA, et al. (2000) Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci 41: 3460–3466.
[4]
Sucher NJ, Lipton SA, Dreyer EB (1997) Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res 37: 3483–3493.
[5]
Tezel G (2006) Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog Retin Eye Res 25: 490–513.
[6]
Neufeld AH, Liu B (2003) Glaucomatous optic neuropathy: when glia misbehave. Neuroscientist 9: 485–495.
[7]
Leung CK, Lindsey JD, Crowston JG, Lijia C, Chiang S, et al. (2008) Longitudinal profile of retinal ganglion cell damage after optic nerve crush with blue-light confocal scanning laser ophthalmoscopy. Invest Ophthalmol Vis Sci 49: 4898–4902.
Fu QL, Li X, Yip HK, Shao Z, Wu W, et al. (2009) Combined effect of brain-derived neurotrophic factor and LINGO-1 fusion protein on long-term survival of retinal ganglion cells in chronic glaucoma. Neuroscience 162: 375–382.
[10]
Vidal-Sanz M, Lafuente M, Sobrado-Calvo P, Selles-Navarro I, Rodriguez E, et al. (2000) Death and neuroprotection of retinal ganglion cells after different types of injury. Neurotox Res 2: 215–227.
[11]
Kusari J, Zhou S, Padillo E, Clarke KG, Gil DW (2007) Effect of memantine on neuroretinal function and retinal vascular changes of streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci 48: 5152–5159.
[12]
Wilhelm B, Ludtke H, Wilhelm H (2006) Efficacy and tolerability of 0.2% brimonidine tartrate for the treatment of acute non-arteritic anterior ischemic optic neuropathy (NAION): a 3-month, double-masked, randomised, placebo-controlled trial. Graefes Arch Clin Exp Ophthalmol 244: 551–558.
[13]
Escher P, Wahli W (2000) Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res 448: 121–138.
[14]
Rosen ED, Spiegelman BM (2001) PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276: 37731–37734.
[15]
Lehrke M, Lazar MA (2005) The many faces of PPARgamma. Cell 123: 993–999.
[16]
Escribano L, Simon AM, Perez-Mediavilla A, Salazar-Colocho P, Del Rio J, et al. (2009) Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer’s disease mouse model. Biochem Biophys Res Commun 379: 406–410.
[17]
Carta AR, Frau L, Pisanu A, Wardas J, Spiga S, et al. (2011) Rosiglitazone decreases peroxisome proliferator receptor-gamma levels in microglia and inhibits TNF-alpha production: new evidences on neuroprotection in a progressive Parkinson’s disease model. Neuroscience 194: 250–261.
[18]
Kiaei M, Kipiani K, Chen J, Calingasan NY, Beal MF (2005) Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol 191: 331–336.
[19]
Esposito E, Cuzzocrea S (2011) Targeting the peroxisome proliferator-activated receptors (PPARs) in spinal cord injury. Expert Opin Ther Targets 15: 943–959.
[20]
Qi L, Jacob A, Wang P, Wu R (2010) Peroxisome proliferator activated receptor-gamma and traumatic brain injury. Int J Clin Exp Med 3: 283–292.
[21]
Lee CH, Park OK, Yoo KY, Byun K, Lee B, et al. (2011) The role of peroxisome proliferator-activated receptor gamma, and effects of its agonist, rosiglitazone, on transient cerebral ischemic damage. J Neurol Sci 300: 120–129.
[22]
Vigneswara V, Berry M, Logan A, Ahmed Z (2012) Pharmacological inhibition of caspase-2 protects axotomised retinal ganglion cells from apoptosis in adult rats. PLoS One 7: e53473.
[23]
Mabuchi F, Aihara M, Mackey MR, Lindsey JD, Weinreb RN (2004) Regional optic nerve damage in experimental mouse glaucoma. Invest Ophthalmol Vis Sci 45: 4352–4358.
[24]
Mackenzie P, Cioffi G (2008) How does lowering of intraocular pressure protect the optic nerve? Surv Ophthalmol 53 Suppl1: S39–43.
[25]
Schwartz M (2004) Optic nerve crush: protection and regeneration. Brain Res Bull 62: 467–471.
[26]
Goldblum D, Mittag T (2002) Prospects for relevant glaucoma models with retinal ganglion cell damage in the rodent eye. Vision Res 42: 471–478.
[27]
Michalik L, Desvergne B, Dreyer C, Gavillet M, Laurini RN, et al. (2002) PPAR expression and function during vertebrate development. Int J Dev Biol 46: 105–114.
[28]
Pershadsingh HA, Moore DM (2008) PPARgamma Agonists: Potential as Therapeutics for Neovascular Retinopathies. PPAR Res 2008: 164273.
[29]
Herzlich AA, Ding X, Shen D, Ross RJ, Tuo J, et al. (2009) Peroxisome Proliferator-Activated Receptor Expression in Murine Models and Humans with Age-related Macular Degeneration. Open Biol J 2: 141–148.
[30]
Sarayba MA, Li L, Tungsiripat T, Liu NH, Sweet PM, et al. (2005) Inhibition of corneal neovascularization by a peroxisome proliferator-activated receptor-gamma ligand. Exp Eye Res 80: 435–442.
[31]
Zhao Y, Patzer A, Herdegen T, Gohlke P, Culman J (2006) Activation of cerebral peroxisome proliferator-activated receptors gamma promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats. FASEB J 20: 1162–1175.
[32]
Yi JH, Park SW, Brooks N, Lang BT, Vemuganti R (2008) PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. Brain Res 1244: 164–172.
[33]
Bernardo A, Levi G, Minghetti L (2000) Role of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and its natural ligand 15-deoxy-Delta12, 14-prostaglandin J2 in the regulation of microglial functions. Eur J Neurosci 12: 2215–2223.
[34]
Aoun P, Simpkins JW, Agarwal N (2003) Role of PPAR-gamma ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells. Invest Ophthalmol Vis Sci 44: 2999–3004.
[35]
Victor NA, Wanderi EW, Gamboa J, Zhao X, Aronowski J, et al. (2006) Altered PPARgamma expression and activation after transient focal ischemia in rats. Eur J Neurosci 24: 1653–1663.
[36]
Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, et al. (2006) Muller cells in the healthy and diseased retina. Prog Retin Eye Res 25: 397–424.
[37]
Nakazawa T, Matsubara A, Noda K, Hisatomi T, She H, et al. (2006) Characterization of cytokine responses to retinal detachment in rats. Mol Vis 12: 867–878.
[38]
Tura A, Schuettauf F, Monnier PP, Bartz-Schmidt KU, Henke-Fahle S (2009) Efficacy of Rho-kinase inhibition in promoting cell survival and reducing reactive gliosis in the rodent retina. Invest Ophthalmol Vis Sci 50: 452–461.
[39]
Bringmann A, Wiedemann P (2012) Muller glial cells in retinal disease. Ophthalmologica 227: 1–19.
