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Exploring the current use of animal models in glaucoma drug discovery: where are we in 2023?

Agarwal R, Agarwal P, Iezhitsa I

Expert Opin Drug Discov, 2023;18(11):1287-1300.
PMID: 37608634 DOI: 10.1080/17460441.2023.2246892

INTRODUCTION: Animal models are widely used in glaucoma-related research. Since the elevated intraocular pressure (IOP) is a major risk factor underlying the disease pathogenesis, animal models with high IOP are commonly used. However, models are also used to represent the clinical context of glaucomatous changes developing despite a normal IOP.
AREAS COVERED: Herein, the authors discuss the various factors that contribute to the quality of studies using animal models based on the evaluation of studies published in 2022. The factors affecting the quality of studies using animal models, such as the animal species, age, and sex, are discussed, along with various methods and outcomes of studies involving different animal models of glaucoma.
EXPERT OPINION: Translating animal research data to clinical applications remains challenging. Our observations in this review clearly indicate that many studies lack scientific robustness not only in their experiment conduct but also in data analysis, interpretation, and presentation. In this context, ensuring the internal validity of animal studies is the first step in quality assurance. External validity, however, is more challenging, and steps should be taken to satisfy external validity at least to some extent.

Matched MeSH terms: Optic Nerve/pathology
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/pathology
Fulltext Bilateral atypical optic neuritis associated with tuberculosis in an immunocompromised patient

Jaafar J, Hitam WH, Noor RA

Asian Pac J Trop Biomed, 2012 Jul;2(7):586-8.
PMID: 23569976 DOI: 10.1016/S2221-1691(12)60102-6

A 27 year-old lady, presented with sudden loss of vision in the right eye for a week. It was followed by poor vision in the left eye after 3 days. It involved the whole entire visual field and was associated with pain on eye movement. She was diagnosed to have miliary tuberculosis and retroviral disease 4 months ago. She was started on anti-TB since then but defaulted highly active anti-retroviral therapy (HAART). On examination, her visual acuity was no perception of light in the right eye and 6/120 (pinhole 3/60) in the left eye. Anterior segment in both eyes was unremarkable. Funduscopy showed bilateral optic disc swelling with presence of multiple foci of choroiditis in the peripheral retina. The vitreous and retinal vessels were normal. Chest radiography was normal. CT scan of orbit and brain revealed bilateral enhancement of the optic nerve sheath that suggest the diagnosis of bilateral atypical optic neuritis. This patient was managed with infectious disease team. She was started on HAART and anti-TB treatment was continued. She completed anti-TB treatment after 9 months without any serious side effects. During follow up the visual acuity in both eyes was not improved. However, funduscopy showed resolving of disc swelling and choroiditis following treatment.

Matched MeSH terms: Optic Nerve/pathology
Fulltext Irreversible visual loss and optic nerve dysfunction associated with central retinal vein occlusion in Waldenstrom Macroglobulinemia

Fadilah SA, Muhaya M, Azlin I

Med J Malaysia, 2007 Oct;62(4):349-51.
PMID: 18551947 MyJurnal

Irreversible optic nerve dysfunction associated with central retinal vein occlusion (CRVO) is an unusual but important complication of Waldenstrom Macroglobulinemia (WM). Acute visual loss in CRVO is mainly due the severe macular oedema. However, ischaemic optic neuropathy needs to be considered in patients with CRVO when, (i) there is a relative afferent papillary defect and central scotoma, (ii) the visual acuity is not consistent with the retinal pathology, and (iii) the visual defects persisted despite resolution of macular oedema following treatment of the hyperviscosity state. The ischaemic type of CRVO is associated with a poor visual prognosis and the presenting visual acuity has a prognostic role. We report the first description of irreversible unilateral optic nerve damage associated with CRVO in a patient with WM.

Matched MeSH terms: Optic Nerve/pathology*
Novel use of 3T MRI in assessment of optic nerve volume in glaucoma

Ramli NM, Sidek S, Rahman FA, Peyman M, Zahari M, Rahmat K, et al.

Graefes Arch Clin Exp Ophthalmol, 2014 Jun;252(6):995-1000.
PMID: 24770532 DOI: 10.1007/s00417-014-2622-6

PURPOSE: To measure optic nerve (ON) volume using 3 T magnetic resonance imaging (MRI), to correlate ON volume with retinal nerve fiber layer (RNFL) thickness, and to determine the viability of MRI as an objective tool in distinguishing glaucoma severity.
METHODS: In this cross-sectional study, 30 severe glaucoma patients, 30 mild glaucoma patients and 30 age-matched controls were recruited. All subjects underwent standard automated perimetry, RNFL analysis and 3 T MRI examinations. Glaucoma patients were classified according to the Hodapp-Anderson-Parish classification. Pearson's correlation coefficient was used to correlate ON volume with RNFL, and receiver operating curve (ROC) analysis was performed to determine the sensitivity and specificity of ON volume in detecting glaucoma severity.
RESULTS: Optic nerve volume was significantly lower in both the left and right eyes of the severe glaucoma group (168.70 ± 46.28 mm(3); 167.40 ± 45.36 mm(3)) than in the mild glaucoma group (264.03 ± 78.53 mm(3); 264.76 ± 78.88 mm(3)) and the control group (297.80 ± 71.45 mm(3); 296.56 ± 71.02 mm(3)). Moderate correlation was observed between: RNFL thickness and ON volume (r = 0.51, p <0.001), and in mean deviation of visual field and optic nerve volume (r = 0.60, p optic nerve volume is a reliable method of assessing glaucomatous damage beyond the optic nerve head. A value of 236 mm(3) and below can be used to define severe glaucoma.

Matched MeSH terms: Optic Nerve/pathology*
Neuroprotective Effect of Magnesium Acetyltaurate Against NMDA-Induced Excitotoxicity in Rat Retina

Lambuk L, Jafri AJ, Arfuzir NN, Iezhitsa I, Agarwal R, Rozali KN, et al.

Neurotox Res, 2017 01;31(1):31-45.
PMID: 27568334 DOI: 10.1007/s12640-016-9658-9

Glutamate excitotoxicity plays a major role in the loss of retinal ganglion cells (RGCs) in glaucoma. The toxic effects of glutamate on RGCs are mediated by the overstimulation of N-methyl-D-aspartate (NMDA) receptors. Accordingly, NMDA receptor antagonists have been suggested to inhibit excitotoxicity in RGCs and delay the progression and visual loss in glaucoma patients. The purpose of the present study was to examine the potential neuroprotective effect of Mg acetyltaurate (MgAT) on RGC death induced by NMDA. MgAT was proposed mainly due to the combination of magnesium (Mg) and taurine which may provide neuroprotection by dual mechanisms of action, i.e., inhibition of NMDA receptors and antioxidant effects. Rats were divided into 5 groups and were given intravitreal injections. Group 1 (PBS group) was injected with vehicle; group 2 (NMDA group) was injected with NMDA while groups 3 (pre-), 4 (co-), and 5 (post-) treatments were injected with MgAT, 24 h before, in combination or 24 h after NMDA injection respectively. NMDA and MgAT were injected in PBS at doses 160 and 320 nmol, respectively. Seven days after intravitreal injection, the histological changes in the retina were evaluated using hematoxylin & eosin (H&E) staining. Optic nerves were dissected and stained in Toluidine blue for grading on morphological neurodegenerative changes. The extent of apoptosis in retinal tissue was assessed by TUNEL assay and caspase-3 immunohistochemistry staining. The estimation of neurotrophic factor, oxidative stress, pro/anti-apoptotic factors and caspase-3 activity in retina was done using enzyme-linked immunosorbent assay (ELISA) technique. The retinal morphometry showed reduced thickness of ganglion cell layer (GCL) and reduction in the number of retinal cells in GCL in NMDA group compared to the MgAT-treated groups. TUNEL and caspase-3 staining showed increased number of apoptotic cells in inner retina. The results were further corroborated by the estimation of neurotrophic factor, oxidative stress, pro/anti-apoptotic factors, and caspase-3 activity in retina. In conclusion, current study revealed that intravitreal MgAT prevents retinal and optic nerve damage induced by NMDA. Overall, our data demonstrated that the pretreatment with MgAT was more effective than co- and posttreatment. This protective effect of MgAT against NMDA-induced retinal cell apoptosis could be attributed to the reduction of retinal oxidative stress and activation of BDNF-related neuroprotective mechanisms.

Matched MeSH terms: Optic Nerve/pathology