Effect of Chondroitin Sulfate on Intraocular Pressure in Rats

Nicolás Belforte, Pablo Sande, Nuria de Zavalía, Paul A. Knepper, Ruth E. Rosenstein
2010 Investigative Ophthalmology and Visual Science  
PURPOSE. To study the effect of intracameral injections of chondroitin sulfate (CS) on intraocular pressure (IOP), retinal function, and histology in rats. METHODS. Acute or chronic injections of CS were performed unilaterally in the rat anterior chamber, whereas the contralateral eye was injected with vehicle. IOP was daily or weekly assessed by a tonometer. Retinal function was assessed by scotopic electroretinography (ERG) and the visual pathway by flash visual evoked potentials (VEPs),
more » ... ntials (VEPs), whereas the retinal and optic nerve head structure were examined by histologic analysis. RESULTS. A single injection of 8 mg (but not 2 or 4 mg) CS induced a significant increase of IOP. The increase of IOP induced by a single injection of 8 mg CS lasted for 7 days, whereas chronic (weekly) administration during 10 weeks induced a significant and sustained increase in IOP compared with eyes injected with vehicle. A significant decrease of scotopic ERG a-and b-wave amplitude was observed after 6 and 10 weeks of CS administration. Moreover, a significant decrease in scotopic flash VEP N2-P2 component amplitude was observed in eyes treated with CS for 6 and 10 weeks. A significant loss of ganglion cell layer cells and optic nerve axons was observed in eyes receiving CS for 10 weeks. CONCLUSIONS. These results suggest that exogenous CS simulates the accumulation of CS in primary open-angle glaucoma and that increased amounts of CS could play a key role in the IOP dysregulation characteristic of glaucoma. (Invest Ophthalmol Vis Sci. 2010;51:5768 -5775) G laucoma, a leading cause of irreversible visual loss, is characterized by loss of retinal ganglion cells (RGCs) and their axons. Intraocular pressure (IOP) is the most critical risk factor for primary open-angle glaucoma (POAG). In fact, nearly all glaucoma therapy relies on lowering the IOP level. 1,2 Elevated IOP often results from alterations in aqueous humor dynamics because of changes in the trabecular meshwork (TM), leading to impaired drainage of aqueous humor. 3 The TM is a specialized tissue forming a biological filter for aqueous humor at the chamber angle and is the major site for regulation of the normal bulk flow of aqueous humor. 4 The normal TM functions as a self-cleaning, unidirectional, pressure-sensitive, and low-flow (2.75 L/min) filter. 5 The TM is divided into the uveal meshwork, corneoscleral meshwork, and juxtacanalicular (JCT) regions. In the uveal and corneoscleral meshwork, sheets of trabecular beams that contain lamellae made of connective tissue or extracellular matrix (ECM) materials are lined by TM cells. In the JCT region, the cells are embedded in a loose ECM, and aqueous outflow resistance is believed to locate largely in the JCT/Schlemm's canal area. 6, 7 It is likely that the pressure gradient and the resistance to aqueous outflow are altered in POAG. The ECM is a major component of the TM for maintaining aqueous humor outflow. Glycosaminoglycans (GAGs), key components of TM ECM, are long linear sugar chains composed of repeating disaccharide units. 8, 9 There are five main types of GAGs-chondroitin sulfate (CS), dermatan sulfate (DS), heparin/heparan sulfate (HS), keratan sulfate (KS), and hyaluronic acid (HA)-that vary depending on the identity of their disaccharide units. All GAGs, except HA, are sulfated in various positions and to various degrees. For instance, CS chains are commonly sulfated at the 4-and/or 6-hydroxyl positions, DS chains undergo 4-and 2-O-sulfation, whereas HS chains can be N-, 2-O-, 6-O-, and/or 3-O-sulfated. 10, 11 With the exception of HA, all GAG chains are covalently attached to and synthesized on core proteins to form proteoglycans as they move through the endoplasmic reticulum and Golgi apparatus. 12,13 These are then integrated into the ECM, where they perform many functions, including cell matrix interactions, growth factor binding, and sequestration and maintenance of tissue structural integrity. 9, 13 The GAG concentration of the TM and of the JCT has been determined by biochemical methods 14 -18 using sequential enzymatic degradation and by histologic staining. 19 -22 GAGs of the TM and of the JCT are considered significant contributors to aqueous outflow resistance in the normal or the POAG TM. Microscale analysis of single human TMs, using GAG-degrading enzymes, both biochemical 18 and computer-aided microscopy studies, 22 localized and quantitated the various types of GAGs in the JCT. HA and CS are the predominant types of GAGs in the normal human TM. In the POAG TM and JCT, HA is decreased and CS is increased, whereas the total concentration of GAGs is similar in normal and in POAG TM. Since 1954, based on the results of the infusion of testicular hyaluronidase (a GAG enzyme that degrades HA and CS) in bovine eyes, GAGs were considered to be a factor in aqueous outflow resistance 23,24 ; however, infusion of testicular hyaluronidase in the human eye does not decrease aqueous outflow resistance. 25, 26 In the rabbit, 27 dog, 28 and bovine 24 eye, but not in the primate eye, 29 removal of HA correlates with a decrease in aqueous outflow resistance. Thus, the evidence to date suggests that in nonprimate species, there is a GAG barrier to aqueous outflow that is sensitive to testicular hyaluronidase infusion. In primate From the
doi:10.1167/iovs.10-5660 pmid:20574017 fatcat:5ai7q3lo5neava22kryu4nqag4