AUTHOR=Mohamad Mohamad Haiqal Nizar , Abu Izuddin Fahmy , Fazel Muhammad Fattah , Agarwal Renu , Iezhitsa Igor , Juliana Norsham , Mellor Ian R. , Franzyk Henrik 

TITLE=Neuroprotection Against NMDA-Induced Retinal Damage by Philanthotoxin-343 Involves Reduced Nitrosative Stress

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.798794

DOI=10.3389/fphar.2021.798794

ISSN=1663-9812

ABSTRACT=N-methyl-D-aspartate receptor (NMDAR) overstimulation is known to mediate neurodegeneration, hence represent a relevant therapeutic target for neurodegenerative disorders including glaucoma. This study examined the neuroprotective effects of philanthotoxin (PhTX)-343 against NMDA-induced retinal injury in rats. Male Sprague Dawley rats were divided into three groups; group 1 received phosphate buffer saline (PBS) as the negative control, group 2 was injected with NMDA (160 nM) to induce retinal excitotoxic injury, and group 3 was pre-treated with PhTX-343 (160 nM) 24 hours before NMDA exposure. All treatments were given intravitreally and bilaterally. Seven days post-treatment, rats were subjected to visual behaviour assessments using open field and colour recognition tests. Rats were then euthanized, and the retina were harvested and subjected to haematoxylin and eosin (H&E) staining for morphometric analysis and 3-nitrotyrosine (3-NT) ELISA protocol as the nitrosative stress biomarker. PhTX-343 pre-treatment prior to NMDA exposure improved the ability of rats to recognize visual cues and preserved visual functions (i.e. recognition of objects with different colours). Morphological examination on retinal tissues showed that the fractional ganglion cell layer (GCL) thickness within the inner retina (IR) in PhTX-343 group was greater by 1.28-fold compared to NMDA-treated rats (p<0.05) and comparable to control rats (p>0.05). Additionally, the number of retinal cell nuclei/100 μm2 in IR for PhTX-343-treated group was greater by 1.82-fold compared to NMDA-treated rats (p<0.05) and comparable to control group (p>0.05). PhTX-343 also reduced the retinal 3-NT levels by 1.74-fold compared to NMDA-treated rats (p<0.05). PhTX-343 pre-treatment protects against NMDA-induced retinal morphological changes and visual impairments by suppressing nitrosative stress as reflected by the reduced retinal 3-NT level.