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Editors Selection IGR 11-4

Basic Science: Neuroprotection

Comment by Makoto Araie on:

Many previous studies have reported that pharmacological agents could demonstrate in vivo neuroprotective effects by directly exerting their pharmacological actions onto the retinal ganglion cell (RGC) bodies or their axons. Using a mice experimental glaucoma model, Quigley and his associates reported that systemic administration of a selective angiotensin 1 receptor (AT1R) inhibitor, losartan, demonstrated neuroprotective effects on RGCs not through its direct pharmacological actions on RGCs, but through modification of glaucoma-related changes in peripapillary sclera (PPS).

According to engineering models, PPS behavior is important in determining the effect of intraocular pressure (IOP) on the optic nerve head (ONH), and it has been known that biomechanical characteristics of PPS are substantially altered in human glaucoma eyes and experimental glaucoma eyes.^1-3 Among the drugs tested including enalapril, an ACE inhibitor (ATR1- and ATR2-inhibiting actions), only systemic losartan showed pressure-independent neuroprotective effects in the mice experimental glaucoma model. Results of supplementary experiments suggested that the observed effects of losartan were not attributable to losartan’s direct pharmacological actions on RGCs, whereas morphological and biomechanical studies of PPS indicated that the losartan-pretreated mice with normal IOP had PPS’s features similar to those in non-losartan-treated mice after induction of experimental glaucoma, and showed little further changes after exposure to high IOP. Losartan-treatment altered biomechanical responses of PPS so that it maintained its creep rate in the normal range. A molecular biological finding which might be related to the above mentioned losartan’s effects on PPA was that losartan inhibited TGF-b-mediated activation of pERK and modified extracellular matrix remodeling, leaving signaling through ATR2 little affected.

Glaucomatous damage of RGC axons are at least partly mediated through alteration of PPS including lamina cribrosa (LC). Although the current losartan-induced effects on PPS and RGCs in mice experimental glaucoma model need to be further confirmed in other species, especially non-human primates, the result reported by the authors suggest a possibility of medical treatment of PPS including LC to ameliorate glaucoma-induced damage of RGCs. Several previous studies suggested that topically instilled drugs may reach posterior retina at pharmacologically active concentrations by local diffusion,^4.5 but it should be much easier for a topically administered drug to reach PPS, since it is directly exposed to retrobulbar space.⁶ Further, PPS has no blood-retinal barrier which limits penetration of systemically administered drugs to RGCs. If PPS could be pharmacologically modified so that it is more resistant to further biomechanical changes caused by glaucomatous mechanical stress, beneficial effects on axons which pass through it would be also expected.

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