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Editors Selection IGR 17-4
Basic Science: Neuroprotection
Comment by Adriana DiPolo on:
57402 Neuroprotective effects of C3 exoenzyme in excitotoxic retinopathy, Wang Y; Yang Q et al., Experimental Eye Research, 2014; 125: 128-134
The C3 exoenzyme is a toxin produced by the bacterium Clostridium botulinum that selectively inhibits a subfamily of the Rho GTPases (RhoA, RhoB and RhoC). These Rho proteins regulate multiple processes including actin dynamics and cell motility in response to extracellular signals. Inactivation with C3 was previously shown to stimulate retinal ganglion cell survival and axon regeneration after optic nerve crush.1,2
Wang et al. investigated the effect of intravitreal administration of C3 on N-methyl-Daspartate (NMDA)-induced retinal damage in adult Sprague-Dawley rats. Their data convincingly show that C3 attenuated thinning of the inner plexiform layer and apoptotic cell loss in the ganglion cell layer. However, the neuroprotective effect of C3 was transient and did not reach significant values at 72 hours after administration.
C3 might exert a combination of neuroprotective and pressure lowering effects that might be highly beneficial in the context of glaucoma
The results are interesting and support a beneficial role of C3, however, the findings presented could be extended in a number of ways. First, the quantification of cells in the ganglion cell layer was carried out using cresyl violet, which does not distinguish ganglion cells from displaced amacrine cells. Given that both cell types are susceptible to NMDA damage, the extent of C3-mediated neuroprotection specifically on ganglion cells remains to be determined. Second, the NMDA model is acute and leads to extensive retinal damage. It will be of future interest to evaluate the efficacy of C3 in glaucoma models. Lastly, although the survival effect of C3 is likely to occur via Rho inhibition, its precise mechanism of action is unknown. Future studies are needed to identify effectors downstream of Rho that promote neuronal survival.
Interestingly, it is now recognized that RhoA and its target Rho kinase (ROCK) regulate cytoskeleton dynamics in trabecular meshwork cells hence controlling aqueous humor outflow.3 (Pattabiraman and Rao, 2010). Furthermore, C3 was shown to increase outflow facility in organ cultures of monkey anterior segments (Liu et al., 2005). This raises the intriguing possibility that C3 might exert a combination of neuroprotective and pressure lowering effects that might be highly beneficial in the context of glaucoma.
References
- Bertrand J, Winton MJ, Rodriguez-Hernandez N, Campenot RB, McKerracher L. Application of Rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats. J Neurosci. 2005;25:1113-1121.
- Lehmann M, Fournier A, Selles-Navarro I, Dergham P, Sebok A, Leclerc N, Tigyi G, McKerracher L. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J Neurosci. 1999;19:7537-7547.
- Pattabiraman P, Rao P. Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells. Am J Physiol Cell Physiol. 2010;298:C749-C763.
- Liu X, Hu Y, Filla M, Gabelt B, Peters D, Brandt C, Kaufman P. The effect of C3 transgene expression on actin and cellular adhesions in cultured human trabecular meshwork cells and on outflow facility in organ cultured monkey eyes. Mol Vis. 2005;11:1112-1121.
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