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Fulltext Philanthotoxin-343 attenuates retinal and optic nerve injury, and protects visual function in rats with N-methyl-D-aspartate-induced excitotoxicity

Fazel MF, Abu IF, Mohamad MHN, Agarwal R, Iezhitsa I, Bakar NS, et al.

PLoS One, 2020;15(7):e0236450.
PMID: 32706792 DOI: 10.1371/journal.pone.0236450

Retinal ganglion cell (RGC) loss and optic neuropathy, both hallmarks of glaucoma, have been shown to involve N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity. This study investigated the neuroprotective effects of Philanthotoxin (PhTX)-343 in NMDA-induced retinal injury to alleviate ensuing visual impairments. Sprague-Dawley rats were divided into three; Group I was intravitreally injected with phosphate buffer saline as the control, Group II was injected with NMDA (160 nM) to induce retinal excitotoxic injury, while Group III was injected with PhTX-343 (160 nM) 24 h prior to excitotoxicity induction with NMDA. Rats were subjected to visual behaviour tests seven days post-treatment and subsequently euthanized. Rat retinas and optic nerves were subjected to H&E and toluidine blue staining, respectively. Histological assessments showed that NMDA exposure resulted in significant loss of retinal cell nuclei and thinning of ganglion cell layer (GCL). PhTX-343 pre-treatment prevented NMDA-induced changes where the RGC layer morphology is similar to the control. The numbers of nuclei in the NMDA group were markedly lower compared to the control (p<0.05). PhTX-343 group had significantly higher numbers of nuclei within 100 μm length and 100 μm2 area of GCL (2.9- and 1.7-fold, respectively) compared to NMDA group (p<0.05). PhTX-343 group also displayed lesser optic nerve fibres degeneration compared to NMDA group which showed vacuolation in all sections. In the visual behaviour test, the NMDA group recorded higher total distance travelled, and lower total immobile time and episodes compared to the control and PhTX-343 groups (p<0.05). Object recognition tests showed that the rats in PhTX-343 group could recognize objects better, whereas the same objects were identified as novel by NMDA rats despite multiple exposures (p<0.05). Visual performances in the PhTX-343 group were all comparable with the control (p>0.05). These findings suggested that PhTX-343 inhibit retinal cell loss, optic nerve damage, and visual impairments in NMDA-induced rats.

Matched MeSH terms: Optic Nerve Injuries/chemically induced; Optic Nerve Injuries/drug therapy*
Protective effect of magnesium acetyltaurate against endothelin-induced retinal and optic nerve injury

Arfuzir NN, Lambuk L, Jafri AJ, Agarwal R, Iezhitsa I, Sidek S, et al.

Neuroscience, 2016 06 14;325:153-64.
PMID: 27012609 DOI: 10.1016/j.neuroscience.2016.03.041

Vascular dysregulation has long been recognized as an important pathophysiological factor underlying the development of glaucomatous neuropathy. Endothelin-1 (ET1) has been shown to be a key player due to its potent vasoconstrictive properties that result in retinal ischemia and oxidative stress leading to retinal ganglion cell (RGC) apoptosis and optic nerve (ON) damage. In this study we investigated the protective effects of magnesium acetyltaurate (MgAT) against retinal cell apoptosis and ON damage. MgAT was administered intravitreally prior to, along with or after administration of ET1. Seven days post-injection, animals were euthanized and retinae were subjected to morphometric analysis, TUNEL and caspase-3 staining. ON sections were stained with toluidine blue and were graded for neurodegenerative effects. Oxidative stress was also estimated in isolated retinae. Pre-treatment with MgAT significantly lowered ET1-induced retinal cell apoptosis as measured by retinal morphometry and TUNEL staining. This group of animals also showed significantly lesser caspase-3 activation and significantly reduced retinal oxidative stress compared to the animals that received intravitreal injection of only ET1. Additionally, the axonal degeneration in ON was markedly reduced in MgAT pretreated animals. The animals that received MgAT co- or post-treatment with ET1 also showed improvement in all parameters; however, the effects were not as significant as observed in MgAT pretreated animals. The current study showed that the intravitreal pre-treatment with MgAT reduces caspase-3 activation and prevents retinal cell apoptosis and axon loss in ON induced by ET1. This protective effect of ET1 was associated with reduced retinal oxidative stress.

Matched MeSH terms: Optic Nerve Injuries/chemically induced; Optic Nerve Injuries/metabolism; Optic Nerve Injuries/pathology*
Fulltext Case series of children with steroid-Induced glaucoma

Lam, C.S., Umi Kalthum, M.N., Norshamsiah, M.D., Bastion, M.L.C.

Malaysian Family Physician, 2018;13(3):32-37.
MyJurnal

Steroid-induced glaucoma is the most serious complication of the injudicious use of steroids,
particularly among children affected by allergic conjunctivitis. This condition is steroid-dependent,
and children are commonly being prescribed topical anti-inflammatories, including topical steroids,
by general practitioners. Furthermore, topical steroids are also available over the counter, and this
availability contributes to overuse without proper monitoring by an ophthalmologist. We present
a series of five cases illustrating the devastating effect of unmonitored, long-term use of steroids
among children for vernal keratoconjunctivitis. The medications were prescribed initially by general
ophthalmologists and were continually bought over the counter by parents. At the presentation to
our center, these patients were already compromised visually, exhibiting glaucomatous optic disc
changes and high intraocular pressure. The series highlights the optic nerve damage resulting in
irreversible visual compromises among children on long-term, topical steroids and the importance
of regular monitoring with a low threshold for ophthalmologist referral.

Matched MeSH terms: Optic Nerve Injuries
Fulltext Taurine protects against retinal and optic nerve damage induced by endothelin-1 in rats via antioxidant effects

Nor Arfuzir NN, Agarwal R, Iezhitsa I, Agarwal P, Sidek S, Ismail NM

Neural Regen Res, 2018 Nov;13(11):2014-2021.
PMID: 30233077 DOI: 10.4103/1673-5374.239450

Endothelin-1 (ET-1), a potent vasoconstrictor, is involved in retinal vascular dysregulation and oxidative stress in glaucomatous eyes. Taurine (TAU), a naturally occurring free amino acid, is known for its neuroprotective and antioxidant properties. Hence, we evaluated its neuroprotective properties against ET-1 induced retinal and optic nerve damage. ET-1 was administered intravitreally to Sprague-Dawley rats and TAU was injected as pre-, co- or post-treatment. Animals were euthanized seven days post TAU injection. Retinae and optic nerve were examined for morphology, and were also processed for caspase-3 immunostaining. Retinal redox status was estimated by measuring retinal superoxide dismutase, catalase, glutathione, and malondialdehyde levels using enzyme-linked immuosorbent assay. Histopathological examination showed significantly improved retinal and optic nerve morphology in TAU-treated groups. Morphometric examination showed that TAU pre-treatment provided marked protection against ET-1 induced damage to retina and optic nerve. In accordance with the morphological observations, immunostaining for caspase showed a significantly lesser number of apoptotic retinal cells in the TAU pre-treatment group. The retinal oxidative stress was reduced in all TAU-treated groups, and particularly in the pre-treatment group. The findings suggest that treatment with TAU, particularly pre-treatment, prevents apoptosis of retinal cells induced by ET-1 and hence prevents the changes in the morphology of retina and optic nerve. The protective effect of TAU against ET-1 induced retinal and optic nerve damage is associated with reduced retinal oxidative stress.

Matched MeSH terms: Optic Nerve Injuries
Time- and dose-related effects of amyloid beta1-40 on retina and optic nerve morphology in rats

Mohd Lazaldin MA, Iezhitsa I, Agarwal R, Bakar NS, Agarwal P, Mohd Ismail N

Int J Neurosci, 2018 Oct;128(10):952-965.
PMID: 29488424 DOI: 10.1080/00207454.2018.1446953

PURPOSE: Amyloid beta (Aβ) is known to contribute to the pathophysiology of retinal neurodegenerative diseases such as glaucoma. Effects of intravitreal Aβ(1-42) on retinal and optic nerve morphology in animal models have widely been studied but not those of Aβ(1-40). Hence, we evaluated the time- and dose-related effects of intravitreal Aβ(1-40) on retinal and optic nerve morphology. Since oxidative stress and brain derived neurotrophic factor (BDNF) are associated with Aβ-induced neuronal damage, we also studied dose and time-related effects of Aβ(1-40) on retinal oxidative stress and BDNF levels.
MATERIALS AND METHODS: Five groups of rats were intravitreally administered with vehicle or Aβ(1-40) in doses of 1.0, 2.5, 5 and 10 nmol. Animals were sacrificed and eyes were enucleated at weeks 1, 2 and 4 post-injection. The retinae were subjected to morphometric analysis and TUNEL staining. Optic nerve sections were stained with toluidine blue and were graded for neurodegenerative effects. The estimation of BDNF and markers of oxidative stress in retina were done using ELISA technique.
RESULTS AND CONCLUSIONS: It was observed that intravitreal Aβ(1-40) causes significant retinal and optic nerve damage up to day 14 post-injection and there was increasing damage with increase in dose. However, on day 30 post-injection both the retinal and optic nerve morphology showed a trend towards normalization. The observations made for retinal cell apoptosis, retinal glutathione, superoxide dismutase activity and BDNF were in accordance with those of morphological changes with deterioration till day 14 and recovery by day 30 post-injection. The findings of this study may provide a guide for selection of appropriate experimental conditions for future studies.

Matched MeSH terms: Optic Nerve Injuries