Abstract
The in vivo neuroprotective effect of PhTx3-4, a spider toxin N-P/Q calcium channel blocker, was studied in a rat model of NMDA-induced injury of the retina. NMDA (N-Methyl-d-Aspartate)-induced retinal injury in rats reduced the b-wave amplitude by 62% ± 3.6%, indicating the severity of the insult. PhTx3-4 treatment increased the amplitude of the b-wave, which was almost equivalent to the control retinas that were not submitted to injury. The PhTx3-4 functional protection of the retinas recorded on the ERG also was observed in the neuroprotection of retinal cells. NMDA-induced injury reduced live cells in the retina layers and the highest reduction, 84%, was in the ganglion cell layer. Notably, PhTx3-4 treatment caused a remarkable reduction of dead cells in the retina layers, and the highest neuroprotective effect was in the ganglion cells layer. NMDA-induced cytotoxicity of the retina increased the release of glutamate, reactive oxygen species (ROS) production and oxidative stress. PhTx3-4 treatment reduced glutamate release, ROS production and oxidative stress measured by malondialdehyde. Thus, we presented for the first time evidence of in vivo neuroprotection from NMDA-induced retinal injury by PhTx3-4 (-ctenitoxin-Pn3a), a spider toxin that blocks N-P/Q calcium channels.
Highlights
N-Methyl-D-Aspartate (NMDA) basically induces excitotoxicity contributing to damage in stroke and neurodegenerative retinopathies, leading to blindness, such as diabetic retinopathy, glaucoma, retinal vascular occlusion, optic nerve neuropathy, and retinopathy of prematurity [1,2].The etiology and pathogenesis of these neurodegenerative diseases are different; at the cellular and molecular level, retinal injury is present in all of them [3]
The effect of the PhTx3-4 treatment, ω-conotoxin MVIIC treatment and no treatment of the retinas on NMDA-induced injury was initially evaluated by the amplitude of the retina b-wave of the ERG, Figure 1A
NMDA-induced injury of the retinas reduced the b-wave amplitude of the retinas by 62% ̆ 3.6%, whereas PhTx3-4 treatment and MVIIC treatment caused a reduction of only 9% ̆ 2% and 12% ̆ 6%, respectively, which was no different from the control retinas that were not submitted to NMDA-induced injury, p > 0.05
Summary
The etiology and pathogenesis of these neurodegenerative diseases are different; at the cellular and molecular level, retinal injury is present in all of them [3]. The b-wave of the ERG is a sensitive index of retinal injury of the retina, and ERG can be used to evaluate the efficacy of therapeutic drugs. Glutamate is the major excitatory retinal neurotransmitter and is released in vivo by photoreceptors, bipolar cells and ganglion cells [5]. Excessive amounts of glutamate are released and lead to neuronal cell toxicity [6]. In adult rats, intravitreal administration of glutamate causes retinal toxicity [7]. Evidences indicates that glutamate initiates neurotoxic cascades by several different mechanisms, most of which depend on [Ca2+ ]i increases
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