Cutamesine (SA4503) Protects Retinal Ganglion Cells in an Ocular Hypertension Model of Glaucoma Determined Using Detection of Apoptosing Retinal Cells Technology and RBPMS Cell Marker
Restricted accessResearch articleFirst published online April, 2026
Cutamesine (SA4503) Protects Retinal Ganglion Cells in an Ocular Hypertension Model of Glaucoma Determined Using Detection of Apoptosing Retinal Cells Technology and RBPMS Cell Marker
This study aimed to evaluate the neuroprotective effects of cutamesine (SA4503), a potent sigma-1-receptor agonist (S1R-agonist), in rat models of retinal degeneration induced by elevated intraocular pressure (IOP) using the Detection of Apoptosing Retinal Cells (DARC) technology. A secondary aim was to test its effect in a rat retinal oxidative stress model.
Methods:
Ocular hypertension (OHT) model was induced in Dark Agouti rats via episcleral vein injection of hypertonic saline, while a retinal oxidative stress was induced in Sprague-Dawley rats by intravitreal rotenone injection. In the OHT model, cutamesine (10 nmol) and recombinant human nerve growth factor [rh-NGF (positive control); 0.09 nmol] were intravitreally administered. Their effects were evaluated using DARC technology and RNA-binding protein with multiple splicing (RBPMS) immunohistochemistry. In the oxidative stress model, cutamesine (10 and 300 nmol) was coadministered with rotenone, and neurofilament light chain (Nfl) gene expression was measured by RT-PCR.
Results:
OHT induced a significant elevation of IOP over 3 weeks, peaked at day 1 (P < 0.001), and gradually decreased by day 21. Cutamesine significantly reduced the number of DARC spots (P < 0.05) and preserved retinal ganglion cells labeled with RBPMS (P < 0.01), similar to rh-NGF (P < 0.01). In the oxidative stress model, cutamesine preserved retinal Nfl expression levels in a dose-dependent manner.
Conclusions:
Cutamesine demonstrated significant neuroprotective activity in rat models of OHT and oxidative stress using DARC and RBPMS labeling techniques. These findings provide further evidence that S1R-agonists possess substantial neuroprotective potential and may be beneficial for patients with OHT/glaucoma.
JonasJB, AungT, BourneRR, et al.Glaucoma. Lancet, 2017; 390(10108):2183–2193; doi: 10.1016/S0140-6736(17)31469-1
2.
CordeiroMF, NormandoEM, CardosoMJ, et al.Real-time imaging of single neuronal cell apoptosis in patients with glaucoma. Brain, 2017; 140(6):1757–1767; doi: 10.1093/brain/awx088
3.
WeinrebRN, AungT, MedeirosFA. The pathophysiology and treatment of glaucoma. JAMA, 2014; 311(18):1901–1911; doi: 10.1001/jama.2014.3192
4.
Anonymous. European glaucoma society terminology and guidelines for glaucoma, 5th edition. Br J Ophthalmol, 2021; 105(Suppl 1):1–169; doi: 10.1136/bjophthalmol-2021-egsguidelines
5.
ThamY-CC, LiX, WongTY, et al.Global prevalence of glaucoma and projections of glaucoma burden through 2040. Ophthalmology, 2014; 121(11):2081–2090; doi: 10.1016/j.ophtha.2014.05.013
6.
SharifNA. Glaucomatous optic neuropathy treatment options: The promise of novel therapeutics, techniques and tools to help preserve vision. Neural Regen Res, 2018; 13(7):1145–1150; doi: 10.4103/1673-5374.235017
7.
GuoL, MossSE, AlexanderRA, et al.Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-Induced effects on extracellular matrix. Invest Ophthalmol Vis Sci, 2005; 46(1):175–182; doi: 10.1167/iovs.04-0832
8.
LeskeMC, HeijlA, HymanL, et al.Factors for progression and glaucoma treatment: The early manifest glaucoma trial. Curr Opin Ophthalmol, 2004; 15(2):102–106; doi: 10.1097/00055735-200404000-00008
9.
LeskeMC, HeijlA, HymanL, et al.; EMGT Group. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology, 2007; 114(11):1965–1972; doi: 10.1016/j.ophtha.2007.03.016
10.
CalkinsDJ, HornerPJ. The cell and molecular biology of glaucoma: Axonopathy and the brain. Invest Ophthalmol Vis Sci, 2012; 53(5):2482–2484; doi: 10.1167/iovs.12-9483i
11.
HowellGR, MacNicollKH, BraineCE, et al.Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma. Neurobiol Dis, 2014; 71:44–52; doi: 10.1016/j.nbd.2014.07.016
12.
LevinLA, PatrickC, ChoudryNB, et al.Neuroprotection in neurodegenerations of the brain and eye: Lessons from the past and directions for the future. Front Neurol, 2022; 13:964197; doi: 10.3389/fneur.2022.964197
13.
BucoloC, PlataniaCBM, DragoF, et al.Novel therapeutics in glaucoma management. Curr Neuropharmacol, 2018; 16(7):978–992; doi: 10.2174/1570159X15666170915142727
14.
HeS, StankowskaDL, EllisDZ, et al.Targets of neuroprotection in glaucoma. J Ocul Pharmacol Ther, 2018; 34(1–2):85–106; doi: 10.1089/jop.2017.0041
15.
HillD, CompagnoniC, CordeiroMF. Investigational neuroprotective compounds in clinical trials for retinal disease. Expert Opin Investig Drugs, 2021; 30(5):571–577; doi: 10.1080/13543784.2021.1896701
16.
SharifNA. Therapeutic drugs and devices for tackling ocular hypertension and glaucoma, and need for neuroprotection and cytoprotective therapies. Front Pharmacol, 2021; 12:729249; doi: 10.3389/fphar.2021.729249
17.
CordeiroMF, GuoL, LuongV, et al.Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Proc Natl Acad Sci U S A, 2004; 101(36):13352–13356; doi: 10.1073/pnas.0405479101
18.
DavisBM, TianK, PahlitzschM, et al.Topical coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension. Mitochondrion, 2017; 36:114–123; doi: 10.1016/j.mito.2017.05.010
19.
GuoL, CordeiroMF. Assessment of neuroprotection in the retina with DARC. Prog Brain Res, 2008; 173:437–450; doi: 10.1016/S0079-6123(08)01130-8
20.
NizariS, GuoL, DavisBM, et al.Non-amyloidogenic effects of α2 adrenergic agonists: Implications for brimonidine-mediated neuroprotection. Cell Death Dis, 2016; 7(12):e2514–e2514; doi: 10.1038/cddis.2016.397
21.
NormandoEM, YapTE, MaddisonJ, et al.A CNN-aided method to predict glaucoma progression using DARC (Detection of Apoptosing Retinal Cells). Expert Rev Mol Diagn, 2020; 20(7):737–748; doi: 10.1080/14737159.2020.1758067
22.
GalvaoJ, ElvasF, MartinsT, et al.Adenosine A3 receptor activation is neuroprotective against retinal neurodegeneration. Exp Eye Res, 2015; 140:65–74; doi: 10.1016/j.exer.2015.08.009
23.
SasaokaM, OtaT, KageyamaM. Rotenone-induced inner retinal degeneration via presynaptic activation of voltage-dependent sodium and L-type calcium channels in rats. Sci Rep, 2020; 10(1):969; doi: 10.1038/s41598-020-57638-y
24.
DavisBM, PahlitzschM, GuoL, et al.Topical curcumin nanocarriers are neuroprotective in eye disease. Sci Rep, 2018; 8(1):11066; doi: 10.1038/s41598-018-29393-8
25.
GuoL, DavisBM, RavindranN, et al.Topical recombinant human Nerve Growth Factor (rh-NGF) is neuroprotective to retinal ganglion cells by targeting secondary degeneration. Sci Rep, 2020; 10(1):3375; doi: 10.1038/s41598-020-60427-2
26.
UrferR, MoebiusHJ, SkoloudikD, Cutamesine Stroke Recovery Study Group. et al.; Phase II trial of the sigma-1 receptor agonist cutamesine (SA4503) for recovery enhancement after acute ischemic stroke. Stroke, 2014; 45(11):3304–3310; doi: 10.1161/STROKEAHA.114.005835
27.
MorrisonJC, MooreCG, DeppmeierLMH, et al.A rat model of chronic pressure-induced optic nerve damage. Exp Eye Res, 1997; 64(1):85–96; doi: 10.1006/exer.1996.0184
28.
HusainS, AhmadA, SinghS, et al.PI3K/Akt pathway: A role in δ-Opioid receptor–mediated RGC neuroprotection. Invest Ophthalmol Vis Sci, 2017; 58(14):6489–6499; doi: 10.1167/iovs.16-20673
29.
TezelG, YangX, CaiJ. Proteomic identification of oxidatively modified retinal proteins in a chronic pressure-induced rat model of glaucoma. Invest Ophthalmol Vis Sci, 2005; 46(9):3177–3187; doi: 10.1167/iovs.05-0208
30.
MorrisonJC, CepurnaWO, JohnsonEC. Modeling glaucoma in rats by sclerosing aqueous outflow pathways to elevate intraocular pressure. Exp Eye Res, 2015; 141:23–32; doi: 10.1016/j.exer.2015.05.012
31.
TaniguchiT, AkaishiT, HataT, et al.Felodipine re-positioned as a neuroprotectant via improved optic nerve head blood circulation in retinal ischemic rabbits and ocular hypertensive rats. Sci Rep, 2025; 15(1):23811; doi: 10.1038/s41598-025-09733-1
32.
GuoL, NormandoEM, NizariS, et al.Tracking longitudinal retinal changes in experimental ocular hypertension using the cSLO and spectral domain-OCT. Invest Ophthalmol Vis Sci, 2010; 51(12):6504–6513; doi: 10.1167/iovs.10-5551
33.
RodriguezAR, de Sevilla MüllerLP, BrechaNC. The RNA binding protein RBPMS is a selective marker of ganglion cells in the mammalian retina. J Comp Neurol, 2014; 522(6):1411–1443; doi: 10.1002/cne.23521
34.
GevaM, Gershoni-EmekN, NaiaL, et al.Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma. Sci Rep, 2021; 11(1):21975; doi: 10.1038/s41598-021-01077-w
35.
TischlerA, RisebergJ, HardenbrookM, et al.Nerve growth factor is a potent inducer of proliferation and neuronal differentiation for adult rat chromaffin cells in vitro. J Neurosci, 1993; 13(4):1533–1542; doi: 10.1523/JNEUROSCI.13-04-01533.1993
36.
HaY, DunY, ThangarajuM, et al.Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons. Invest Ophthalmol Vis Sci, 2011; 52(1):527–540; doi: 10.1167/iovs.10-5731
37.
LiL, HeS, LiuY, et al.Sigma-1R protects retinal ganglion cells in optic nerve crush model for glaucoma. Invest Ophthalmol Vis Sci, 2021; 62(10):17; doi: 10.1167/iovs.62.10.17
38.
MuellerBH, ParkY, DaudtDR, et al.Sigma-1 receptor stimulation attenuates calcium influx through activated L-type voltage gated calcium channels in purified retinal ganglion cells. Exp Eye Res, 2013; 107:21–31; doi: 10.1016/j.exer.2012.11.002
39.
SmithSB, DuplantierJ, DunY, et al.In vivo protection against retinal neurodegeneration by sigma receptor 1 Ligand (+)-Pentazocine. Invest Ophthalmol Vis Sci, 2008; 49(9):4154–4161; doi: 10.1167/iovs.08-1824
40.
SmithSB, WangJ, CuiX, et al.Sigma 1 receptor: A novel therapeutic target in retinal disease. Prog Retin Eye Res, 2018; 67:130–149; doi: 10.1016/j.preteyeres.2018.07.003
41.
TranMN, MedveczkiT, BeszterceiB, et al.Sigma-1 receptor activation is protective against TGFβ2-Induced extracellular matrix changes in human trabecular meshwork cells. Life (Basel), 2023; 13(7):1581; doi: 10.3390/life13071581
42.
MatsunoK, NakazawaM, OkamotoK, et al.Binding properties of SA4503, a novel and selective σ1 receptor agonist. Eur J Pharmacol, 1996; 306(1–3):271–279; doi: 10.1016/0014-2999(96)00201-4
43.
ShimazawaM, SugitaniS, InoueY, et al.Effect of a sigma-1 receptor agonist, cutamesine dihydrochloride (SA4503), on photoreceptor cell death against light-induced damage. Exp Eye Res, 2015; 132:64–72; doi: 10.1016/j.exer.2015.01.017
44.
WangW-F, IshiwataK, KiyosawaM, et al.Visualization of sigma1 receptors in eyes by ex vivo autoradiography and in vivo positron emission tomography. Exp Eye Res, 2002; 75(6):723–730; doi: 10.1006/exer.2002.2048
45.
HayashiT, SuT-P. Sigma-1 receptor chaperones at the ER- Mitochondrion interface regulate Ca2+ signaling and cell survival. Cell, 2007; 131(3):596–610; doi: 10.1016/j.cell.2007.08.036
46.
SrivatsS, BalasuriyaD, PascheM, et al.Sigma1 receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orai1. J Cell Biol, 2016; 213(1):65–79; doi: 10.1083/jcb.201506022
47.
TchedreKT, HuangR-Q, DibasA, et al.Sigma-1 receptor regulation of voltage-gated calcium channels involves a direct interaction. Invest Ophthalmol Vis Sci, 2008; 49(11):4993–5002; doi: 10.1167/iovs.08-1867
48.
VagnerovaK, HurnPD, BhardwajA, et al.Sigma 1 receptor agonists act as neuroprotective drugs through inhibition of inducible nitric oxide synthase. Anesth Analg, 2006; 103(2):430–434, table of contents; doi: 10.1213/01.ane.0000226133.85114.91
49.
DeCosterMA, KletteKL, KnightES, et al.σ receptor-mediated neuroprotection against glutamate toxicity in primary rat neuronal cultures. Brain Res, 1995; 671(1):45–53; doi: 10.1016/0006-8993(94)01294-R
50.
MartinPM, OlaMS, AgarwalN, et al.The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate. Brain Res Mol Brain Res, 2004; 123(1–2):66–75; doi: 10.1016/j.molbrainres.2003.12.019
51.
BogárF, FülöpL, PenkeB. Novel therapeutic target for prevention of neurodegenerative diseases: Modulation of neuroinflammation with Sig-1R Ligands. Biomolecules, 2022; 12(3):363; doi: 10.3390/biom12030363
52.
VoglerS, WintersH, PannickeT, et al.Sigma-1 receptor activation inhibits osmotic swelling of rat retinal glial (Müller) cells by transactivation of glutamatergic and purinergic receptors. Neurosci Lett, 2016; 610:13–18; doi: 10.1016/j.neulet.2015.10.042
53.
BrimsonJM, SafranyST, QassamH, et al.Dipentylammonium binds to the Sigma-1 receptor and protects against glutamate toxicity, attenuates dopamine toxicity and potentiates neurite outgrowth in various cultured cell lines. Neurotox Res, 2018; 34(2):263–272; doi: 10.1007/s12640-018-9883-5
54.
KimuraY, FujitaY, ShibataK, et al.Sigma-1 receptor enhances neurite elongation of cerebellar granule neurons via TrkB signaling. Hetman M. ed. PLoS One, 2013; 8(10):e75760; doi: 10.1371/journal.pone.0075760
55.
RossiD, MarraA, PicconiP, et al.Identification of RC-33 as a potent and selective σ1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells. Part 2: G -Scale synthesis, physicochemical characterization and in vitro metabolic stability. Bioorg Med Chem, 2013; 21(9):2577–2586; doi: 10.1016/j.bmc.2013.02.029
56.
MuellerBH, ParkY, MaH-YY, et al.Sigma-1 receptor stimulation protects retinal ganglion cells from ischemia-like insult through the activation of extracellular-signal-regulated kinases 1/2. Exp Eye Res, 2014; 128:156–169; doi: 10.1016/j.exer.2014.10.007
57.
BarwickSR, SiddiqMS, WangJ, et al.Sigma 1 receptor Co-Localizes with NRF2 in retinal photoreceptor cells. Antioxidants (Basel), 2021; 10(6):981; doi: 10.3390/antiox10060981
58.
WangJ, XiaoH, BarwickSR, et al.Comparison of sigma 1 receptor ligands SA4503 and PRE084 to (+)-Pentazocine in the rd10 mouse model of RP. Invest Ophthalmol Vis Sci, 2020; 61(13):3; doi: 10.1167/iovs.61.13.3
59.
YamashitaD, SunG, Wei CuiY, et al.Neuroprotective effects of cutamesine, a ligand of the sigma-1 receptor chaperone, against noise-induced hearing loss. J Neurosci Res, 2015; 93(5):788–795; doi: 10.1002/jnr.23543
60.
TuerxunT, NumakawaT, AdachiN, et al.SA4503, a sigma-1 receptor agonist, prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression. Neurosci Lett, 2010; 469(3):303–308; doi: 10.1016/j.neulet.2009.12.013
61.
SendaT, MitaS, KanedaK, et al.Effect of SA4503, a novel σ1 receptor agonist, against glutamate neurotoxicity in cultured rat retinal neurons. Eur J Pharmacol, 1998; 342(1):105–111; doi: 10.1016/S0014-2999(97)01450-7
62.
MysonaBA, ZhaoJ, De GreefO, et al.Sigma-1 receptor agonist, (+)-pentazocine, is neuroprotective in a brown Norway rat microbead model of glaucoma. Exp Eye Res, 2023; 226:109308; doi: 10.1016/j.exer.2022.109308
63.
EllisDZ, LiL, ParkY, et al.Sigma-1 receptor regulates mitochondrial function in glucose- and oxygen-deprived retinal ganglion cells. Invest Ophthalmol Vis Sci, 2017; 58(5):2755–2764; doi: 10.1167/iovs.16-19199
64.
FujimotoM, HayashiT, UrferR, et al.Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor. Synapse, 2012; 66(7):630–639; doi: 10.1002/syn.21549
65.
MysonaBA, ZhaoJ, SmithS, et al.Relationship between Sigma-1 receptor and BDNF in the visual system. Exp Eye Res, 2018; 167:25–30; doi: 10.1016/j.exer.2017.10.012
66.
ArenaE, CacciatoreI, CerasaLS, et al.New bifunctional antioxidant/σ1 agonist ligands: Preliminary chemico-physical and biological evaluation. Bioorg Med Chem, 2016; 24(14):3149–3156; doi: 10.1016/j.bmc.2016.05.045
67.
EstradaM, PérezC, SorianoE, et al.New neurogenic lipoic-based hybrids as innovative Alzheimer’S Drugs with σ-1 agonism and β-Secretase inhibition. Future Med Chem, 2016; 8(11):1191–1207; doi: 10.4155/fmc-2016-0036
68.
HashimotoK, LondonED. Interactions of erythro-ifenprodil, threo-ifenprodil, erythro-iodoifenprodil, and eliprodil with subtypes of σ receptors. Eur J Pharmacol, 1995; 273(3):307–310; doi: 10.1016/0014-2999(94)00763-W
69.
SharifNA, XuSX. Pharmacological characterization of [3 H]-Ifenprodil binding to polyamine binding sites on rabbit and rat retinal homogenates: Role in neuroprotection? J Ocul Pharmacol Ther, 1999; 15(3):271–281; doi: 10.1089/jop.1999.15.271
70.
PernetV, BourgeoisP, PoloA, et al.A role for polyamines in retinal ganglion cell excitotoxic death. J Neurochem, 2007; 103(4):1481–1490; doi: 10.1111/j.1471-4159.2007.04843.x
71.
LachanceV, BélangerS-M, HayC, et al.Overview of Sigma-1R subcellular specific biological functions and role in neuroprotection. Int J Mol Sci, 2023; 24(3):1971; doi: 10.3390/ijms24031971
72.
LincianoP, SorbiC, RossinoG, et al.Novel S1R agonists counteracting NMDA excitotoxicity and oxidative stress: A step forward in the discovery of neuroprotective agents. Eur J Med Chem, 2023; 249:115163; doi: 10.1016/j.ejmech.2023.115163
73.
MalarDS, ThitilertdechaP, RuckvongacheepKS, et al.Targeting sigma receptors for the treatment of neurodegenerative and neurodevelopmental disorders. CNS Drugs, 2023; 37(5):399–440; doi: 10.1007/s40263-023-01007-6
74.
SchmidtHR, KruseAC. The molecular function of σ receptors: Past, present, and future. Trends Pharmacol Sci, 2019; 40(9):636–654; doi: 10.1016/j.tips.2019.07.006
75.
SuT-PP, HayashiT, MauriceT, et al.The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci, 2010; 31(12):557–566; doi: 10.1016/j.tips.2010.08.007
76.
Arranz-RomeraA, DavisBMM, Bravo-OsunaI, et al.Simultaneous co-delivery of neuroprotective drugs from multi-loaded PLGA microspheres for the treatment of glaucoma. J Control Release, 2019; 297:26–38; doi: 10.1016/j.jconrel.2019.01.012
77.
BucoloC, CampanaG, Di ToroR, et al.Sigma1 recognition sites in rabbit iris-ciliary body: Topical sigma1-site agonists lower intraocular pressure. J Pharmacol Exp Ther, 1999; 289(3):1362–1369.
78.
CampanaG, BucoloC, MurariG, et al.Ocular hypotensive action of topical flunarizine in the rabbit: Role of ς1 recognition sites. J Pharmacol Exp Ther, 2002; 303(3):1086–1094; doi: 10.1124/jpet.102.040584
79.
WoodJPM, DeSantisL, ChaoH-MM, et al.Topically applied betaxolol attenuates ischaemia-induced effects to the rat retina and stimulates BDNF mRNA. Exp Eye Res, 2001; 72(1):79–86; doi: 10.1006/exer.2000.0929
80.
RebustiniIT, Bernardo-ColónA, NalvarteAI, et al.Delivery systems of retinoprotective proteins in the retina. Int J Mol Sci, 2021; 22(10):5344; doi: 10.3390/ijms22105344
81.
MohantyS, IdigoC, AyyagariA, et al.Optogenetic Approaches to Gene Therapy for Vision Restoration in Retinal Degenerative Diseases. In: Handbook of Basic and Clinical Ocular Pharmacology and Therapeutics. Elsevier; 2022; pp. 581–606; doi: 10.1016/B978-0-12-819291-7.00004-6
