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Glaucoma is a neurodegenerative disease characterized by the loss of retinal ganglion cells (RGCs), with intraocular pressure (IOP) being its primary risk factor. Despite controlling IOP, the neurodegenerative process often continues. Therefore, substances with neuroprotective, antioxidant, and anti-inflammatory properties could protect against RGC death. This study investigated the neuroprotective effects on RGCs and visual pathway neurons of a compound consisting of citicoline and coenzyme Q10 (CoQ10) in a mouse model of unilateral, laser-induced ocular hypertension (OHT). Four groups of mice were used: vehicle group (n = 6), citicoline + CoQ10 group (n = 6), laser–vehicle group (n = 6), and laser–citicoline + CoQ10 group (n = 6). The citicoline + CoQ10 was administered orally once a day starting 15 days before laser treatment, continuing until sacrifice (7 days post-laser). Retinas, the dorsolateral geniculate nucleus (dLGN), the superior colliculus (SC), and the visual cortex (V1) were analyzed. The citicoline + CoQ10 compound used in the laser–citicoline + CoQ10 group demonstrated (1) an ocular hypotensive effect only at 24 h post-laser; (2) prevention of Brn3a+ RGC death in OHT eyes; and (3) no changes in NeuN+ neurons in the dLGN. This study demonstrates that the oral administration of the citicoline + CoQ10 combination may exert a neuroprotective effect against RGC death in an established rodent model of OHT. Full article

Glaucoma is a multifactorial disease leading to irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form and is associated with the elevation of intraocular pressure (IOP). Reduced aqueous humor (AH) outflow due to trabecular meshwork (TM) dysfunction is responsible for IOP elevation in POAG. Extracellular matrix (ECM) accumulation, actin cytoskeletal reorganization, and stiffening of the TM are associated with increased outflow resistance. Transforming growth factor (TGF) β2, a profibrotic cytokine, is known to play an important role in the development of ocular hypertension (OHT) in POAG. An appropriate mouse model is critical in understanding the underlying molecular mechanism of TGFβ2-induced OHT. To achieve this, TM can be targeted with recombinant viral vectors to express a gene of interest. Lentiviruses (LV) are known for their tropism towards TM with stable transgene expression and low immunogenicity. We, therefore, developed a novel mouse model of IOP elevation using LV gene transfer of active human TGFβ2 in the TM. We developed an LV vector-encoding active hTGFβ2^C226,228S under the control of a cytomegalovirus (CMV) promoter. Adult C57BL/6J mice were injected intravitreally with LV expressing null or hTGFβ2^C226,228S. We observed a significant increase in IOP 3 weeks post-injection compared to control eyes with an average delta change of 3.3 mmHg. IOP stayed elevated up to 7 weeks post-injection, which correlated with a significant drop in the AH outflow facility (40.36%). Increased expression of active TGFβ2 was observed in both AH and anterior segment samples of injected mice. The morphological assessment of the mouse TM region via hematoxylin and eosin (H&E) staining and direct ophthalmoscopy examination revealed no visible signs of inflammation or other ocular abnormalities in the injected eyes. Furthermore, transduction of primary human TM cells with LV_hTGFβ2^C226,228S exhibited alterations in actin cytoskeleton structures, including the formation of F-actin stress fibers and crossed-linked actin networks (CLANs), which are signature arrangements of actin cytoskeleton observed in the stiffer fibrotic-like TM. Our study demonstrated a mouse model of sustained IOP elevation via lentiviral gene delivery of active hTGFβ2^C226,228S that induces TM dysfunction and outflow resistance. Full article