INFLUENCE OF SEX AND MOUSE LINEAGE ON THE NEUROPROTECTIVE EFFECTS OF CILASTATIN IN GLAUCOMA

Aims: Glaucoma is a neurodegenerative retinal disease that leads to irreversible blindness, in which elevated intraocular pressure (IOP) induces neuroinflammation and retinal ganglion cells (RGCs) loss. We previously demonstrated the efficacy of cilastatin (CIL) in an albino mice experimental glaucoma model. Here, we evaluated CIL in the same model using pigmented mice, analyzing differences between mouse lineages and sexes.
Methods: glaucoma was unilaterally induced in the left eye of male and female C57BL/6 mice by ocular hypertension (OHT) via laser photocoagulation of episcleral and limbal veins. CIL was administered daily (300 mg/kg, i.p.) starting 2 days before surgery and continuing 28 days, until sacrifice. IOP was monitored throughout the study. Retinal sections were immunostained to assess RGCs survival and macroglial and microglial responses using Brn3a, GFAP, and Iba-1 markers.
Results: Laser treatment induced a significant increase in IOP in the left eye of both sexes, which was not prevented by CIL. OHT increased glial activation and reduced retinal Brn3a expression, with more pronounced effects in males than in females. CIL administration significantly attenuated glial activation and RGC loss in both sexes.
Conclusions: OHT-induced retinal damage was greater in albino than pigmented mice, possibly due to the lack of a functional retinal pigment epithelium. Among pigmented mice, females were more resistant to OHT, possibly due to the oestrogens neuroprotective and anti-inflammatory effects. CIL is effective against glaucomatous retinal damage in both mice strains. Future studies will focus on the molecular mechanisms mediating CIL-induced protected effects in both male and female animals.