MK-801 Reduces Retinal Ganglion Cell Survival but Improves Visual Performance After Controlled Optic Nerve Crush

Abstract

Excitotoxicity is implicated in secondary cell death after ischemic or traumatic brain injury. We therefore evaluated the role of excitotoxicity mediated by the NMDA glutamate receptor subtype on retinal ganglion cell (RGC) survival and visual performance after optic nerve injury in adult rats. To monitor visual deficits after mild optic nerve crush, rats were trained in a two-choice pattern discrimination task. Immediately after the crush and on postoperative day 1, MK-801 (1 nmol), a noncompetitive open channel blocker of the NMDA-receptor, was injected intraocularly. Within the first few days after crush, all rats showed a loss of their discrimination ability that was followed by a significant recovery within a 3-week testing period. Although animals treated with MK-801 had a significantly smaller initial deficit compared with PBS-injected controls, anatomic investigations using retrograde HRP tracing revealed a significant retrograde loss of RGC in lesioned rats that was significantly exacerbated by MK-801. These results confirm our earlier studies suggesting that neuronal damage does not uniformly match behavioral defects in CNS injury paradigms and that near-normal visual performance occurs in rats with only about 10% of RGC being connected to their target. The observation that after traumatic injury MK-801 is neuroprotective functionally while being neurotoxic anatomically is a structural-functional paradox that needs to be explored further.

Reduction of Potassium Currents and Phosphatidylinositol 3-Kinase-Dependent Akt Phosphorylation by Tumor Necrosis Factor-α Rescues Axotomized Retinal Ganglion Cells from Retrograde Cell DeathIn Vivo

“…In our experimental setting, treatment with the NMDA antagonist memantine did not result in significant rescue of axotomized RGCs in vivo, indicating that excitotoxicity does not play a major role in retrograde cell death after axotomy of the optic nerve (Klöcker et al, 1999). This is in good agreement with results demonstrating even adverse effects of the NMDA antagonist MK-801 on the survival of axotomized RGCs (Schmitt and Sabel, 1996). For similar reasons, TNF-␣-induced decrease of NMDA-and AMPA-dependent currents described in hippocampal neurons (Furukawa and Mattson, 1998) appears to be an alternative neuroprotective signaling pathway but should not account for neuronal rescue under our experimental conditions.…”

Electrical brain stimulation induces dendritic stripping but improves survival of silent neurons after optic nerve damage

“…This finding is in line with our results and the hypothesis that in general additive challenges - like axotomy and artificial in vitro conditions in the retinal explant model - may lead to fast dendritic pruning and by this mechanism assure survival of neurons. The current finding is also in agreement with our previous study demonstrating that the NMDA-antagonist MK801 leads to increased cell death after ONC 40 . As we hypothesize that a fast post-lesional dendritic pruning protects cells from further excitotoxic threat, acute MK801 application may prevent lesion-induced pruning but leave the neurons vulnerable to delayed death due to excitotoxicity.…”

“…However, our research and that of others laboratories propose the need for a more refined concept of cell death and survival because a treatment can increase cell death yet improve brain function 40 , post-lesional re-structured networks of surviving neurons can lead to dysfunction 41–43 , a very defined, local lesion can lead to very complex functional deficits 44 and, as shown in our studies, surviving neurons may become “silent” 17, 28 .…”

Rodent Models for Glaucoma Retinopathy and Optic Neuropathy

“…In various studies, different levels of cell loss owing to apoptosis and sometimes necrosis were reported several days to weeks after the surgery. 63,109,182,183,[189][190][191][192][193][194][195][196][197][198] Similarly, optic nerve crush caused a graded reduction of VEP and pattern VEP amplitudes, whose magnitude correlated with the crushing force. 132…”