Abstract
Excitotoxicity leads to the activation of a cytotoxic cascade that causes neuronal death. In the retina, retinal ganglion cells (RGCs) die after an excitotoxic insult. Multiple pathways have been proposed to contribute to RGC death after an excitotoxic insult, including TNF signaling, JNK activation, and ER stress. To test the importance of these pathways in RGC death after excitotoxic injury, the excitotoxin N-methyl-D-aspartate (NMDA) was intravitreally injected into mice deficient in components of these pathways. Absence of Tnf or its canonical downstream mediator, Bid, did not confer short- or long-term protection to RGCs. Despite known activation in RGCs and a prominent role in mediating RGC death after other insults, attenuating JNK signaling did not prevent RGC death after excitotoxic insult. Additionally, deficiency of the ER stress protein DDIT3 (CHOP), which has been shown to be involved in RGC death, did not lessen NMDA induced RGC death. Furthermore, absence of both Jun (JNK’s canonical target) and Ddit3, which together provide robust, long-term protection to RGC somas after axonal insult, did not lessen RGC death. Collectively, these results indicate that the drivers of excitotoxic injury remain to be identified and/or multiple cell death pathways are activated in response to injury.
Highlights
Excessive stimulation of glutamate receptors has been shown to disrupt the intracellular environment and lead to activation of cytotoxic cascades culminating in neuronal death[1]
In order to establish a relevant concentration of NMDA to study NMDA-induced retinal ganglion cells (RGCs) death, the effect on RGC survival of different concentrations of NMDA was examined. 2 μl of three concentrations of NMDA (2 mM, 20 mM, or 80 mM) were intravitreally injected into C57BL/6 J mice
We tested whether combined deficiency in Jun and Ddit[3] provided additive protection to RGCs after excitotoxic insult
Summary
Excessive stimulation of glutamate receptors has been shown to disrupt the intracellular environment and lead to activation of cytotoxic cascades culminating in neuronal death[1]. Multiple intrinsic and extrinsic cell death signaling pathways have been implicated in neuronal death after excitotoxic injury. If BID is important for NMDA induced RGC death, it is not acting through BAX activation, since Bax deficiency does not prevent RGC death after excitotoxic insult[8,12]. The JNK (c-Jun N-terminal kinases) pathway has been proposed as a regulator of neuronal death after excitotoxic insult. JNK and JUN activation in RGCs is present after induced ischemia, axonal injury, increased intraocular pressure, and excitotoxicity[14,15,16,17,18,19]. Pan inhibitors against JNK, as well as Jun antisense oligodeoxynucleotides, provided some protection to inner retinal neurons after an excitotoxic insult[20,21,22]. The importance of these pathways in excitotoxic RGC death is critically tested using mice deficient in critical molecular components of these pathways
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