The aim of this study was to investigate the neuroprotective effect of olanzapine (OLA), an atypical antipsychotic drug, on N-methyl-d-aspartate (NMDA)-induced retinal injury.
Methods:
Retinal neuronal ischemia was induced by NMDA in Wistar rats. OLA was administered intraperitoneally in 2 different dosages: 2 and 12 mg/kg. At the end of 2 weeks of OLA treatment, 1 eye of each animal was enucleated for histopathologic examination. We also measured malondialdehyde (MDA) levels in retinal homogenates as a marker of ischemic injury.
Results:
The retinal ganglion cell (RGC) count was significantly higher in cases where we used OLA 2 mg/kg or OLA 12 mg/kg compared to the control group (P=0.0032 and P=0.0005, respectively). We also found that MDA was significantly reduced by OLA 2 mg/kg or OLA 12 mg/kg compared to the control group (P=0.0001 and P=0.0001, respectively). There was no statistically significant difference between OLA 2 mg/kg or OLA 12 mg/kg groups in terms of RGC count and MDA levels (P>0.05 for all).
Conclusion:
Our data showed that OLA preserved RGCs from NMDA-induced retinal injury; thus, it may have potential neuroprotective effects.
Get full access to this article
View all access options for this article.
References
1.
NealM.J., CunninghamJ.R., HutsonP.H., HoggJ.Effects of ischaemia on neurotransmitter release from the isolated retina. J. Neurochem., 62:1025–1033. 1994.
2.
KowluruR.A., EngermanR.L., CaseG.L., KernT.S.Retinal glutamate in diabetes and effect of antioxidants. Neurochem. Int., 38:385–390. 2001.
3.
KimT.W., KangK.B., ChoungH.K., ParkK.H., KimD.M.Elevated glutamate levels in the vitreous body of an in vivo model of optic nerve ischemia. Arch. Ophthalmol., 118:533–536. 2000.
AdachiK., KashiiS., MasaiH.et al.Mechanism of the pathogenesis of glutamate neurotoxicity in retinal ischemia. Graefes Arch. Clin. Exp. Ophthalmol., 236:766–774. 1998.
6.
ZhangS., KashiiS, YasuyoshiH.et al.Involvement of NMDA-receptor in kainate-induced neurotoxicity in cultured fetal retinal neurons. Graefes Arch. Clin. Exp. Ophthalmol., 238:243–248. 2000.
7.
KuribayashiK., KitaokaY., KumaiT.et al.Neuroprotective effect of atrial natriuretic peptide against NMDA-induced neurotoxicity in the rat retina. Brain Res., 1071:34–41. 2006.
8.
DkhissiO., ChanutE., WasowiczM.et al.Retinal TUNEL-positive cells and high glutamate levels in vitreous humor of mutant quail with a glaucoma-like disorder. Invest. Ophthalmol. Vis. Sci., 40:990–995. 1999.
9.
HensonM.A., RobertsA.C., Pérez-OtañoI., PhilpotB.D.Influence of the NR3A subunit on NMDA receptor functions. Prog. Neurobiol., 91:23–37. 2010.
10.
KitaokaY., KumaiT., IsenoumiK.et al.Neuroprotective effect of nitric oxide against NMDA-induced neurotoxicity in the rat retina is associated with tyrosine hydroxylase expression. Brain Res., 977:46–54. 2003.
11.
GrossR.L., HensleyS.H., GaoF., WuS.M.Retinal ganglion cell dysfunction induced by hypoxia and glutamate: potential neuroprotective effects of beta-blockers. Surv. Ophthalmol., 43,Suppl 1:162–170. 1999.
12.
KashiiS., TakahashiM., MandaiM.et al.Protective action of dopamine against glutamate neurotoxicity in the retina. Invest. Ophthalmol. Vis. Sci., 35:685–695. 1994.
13.
YulugB., YildizA., HüdaogluO., KilicE., CamE., SchäbitzW.R.Olanzapine attenuates brain damage after focal cerebral ischemia in vivo. Brain Res. Bull., 71:296–300. 2006.
14.
HeJ., XuH., YangY., ZhangX., LiX.M.Neuroprotective effects of olanzapine on methamphetamine-induced neurotoxicity are associated with an inhibition of hyperthermia and prevention of Bcl-2 decrease in rats. Brain Res., 1018:186–192. 2004.
15.
WeiZ., BaiO., RichardsonJ.S., MousseauD.D., LiX.M.Olanzapine protects PC12 cells from oxidative stress induced by hydrogen peroxide. J. Neurosci. Res., 73:364–368. 2003.
16.
LiX.M., Chlan-FourneyJ., JuorioA.V.et al.Differential effects of olanzapine on the gene expression of superoxide dismutase and the low affinity nerve growth factor receptor. J. Neurosci. Res., 56:72–75. 1999.
17.
GessaG.L., DevotoP., DianaM., FloreG., MelisM., PistisM.Dissociation of haloperidol, clozapine, and olanzapine effects on electrical activity of mesocortical dopamine neurons and dopamine release in the prefrontal cortex. Neuropsychopharmacology, 22:642–649. 2000.
LowryO.H., RosebroughN.J., FarrA.L., RandallR.J.Protein measurement with the Folin phenol reagent. J. Biol. Chem., 193:265–275. 1951.
20.
WuS.M., MapleB.R.Amino acid neurotransmitters in the retina: a functional overview. Vision Res., 38:1371–1384. 1998.
21.
CastroN.G., de MelloM.C., de MelloF.G., AracavaY.Direct inhibition of the N-methyl-D-aspartate receptor channel by dopamine and (+)-SKF38393. Br. J. Pharmacol., 126:1847–1855. 1999.
22.
LucasD.R., NewhouseJ.P.The toxic effect of sodium L-glutamate on the inner layers of the retina. Arch. Ophthalmol., 58:193–201. 1957.
23.
SucherN.J., LiptonS.A., DreyerE.B.Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res., 37:3483–3493. 1997.
24.
CsernanskyJ.G., MartinM.V., CzeislerB., MeltzerM.A., AliZ., DongH.Neuroprotective effects of olanzapine in a rat model of neurodevelopmental injury. Pharmacol. Biochem. Behav., 83:208–213. 2006.
25.
BymasterF.P., NelsonD.L., DeLappN.W.et al.Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro. Schizophr. Res., 37:107–122. 1999.
26.
ChidaM., SuzukiK., Nakanishi-UedaT.et al.In vitro testing of antioxidants and biochemical end-points in bovine retinal tissue. Ophthalmic Res., 31:407–415. 1999.
27.
HareW.A., WoldeMussieE., WeinrebR.N.et al.Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, II: structural measures. Invest. Ophthalmol. Vis. Sci., 45:2640–2651. 2004.
