*3.1.2 Glaucoma induced by modifying the trabecular meshwork*

Topical application or injection of steroids as IOP modulators has also been studied in a variety of animals as a mechanism to elevate IOP and mimic POAG [20]. Its mechanism of action is not fully delineated but is believed to function by stabilization of the lysosomal membrane and the accumulation of glycosaminoglycans polymerized in the trabecular meshwork, which creates resistance to outflow of aqueous humor. Outflow resistance is further increased by elevated expression of fibronectin, elastin, and laminin, which also hinder outflow [15]. Glaucoma induced via this mechanism has been studied in a New Zealand rabbit breed [54], which demonstrated that the angle of the anterior chamber is an important regulatory mechanism of outflow of aqueous humor. It has been used to further understand the composition of the trabecular meshwork, as well as identifying its components such as glycosaminoglycans, hyaluronic acid, keratan sulfate, heparan sulfate, and sulfate-chondroitin [55, 56].

Based on the increased presence of hyaluronic acid in the trabecular meshwork induced by steroids, it was demonstrated that a single application of 1% hyaluronic acid in rat models induced an elevation of IOP for up to 8 days, proving a useful acute model [15]. Though not well understood, this injection causes an accumulation of glycosaminoglycans in the trabecular meshwork, which obstructs outflow. This model is noteworthy for its low cost, ease of execution, and sustainability as it induces a more chronic hypertensive state and could be used for pharmacological studies [15, 57, 58]. As a candidate for animal models, rats have similar benefits to mice. There is a comparable elevation of IOP and corresponding optic nerve changes as seen in humans [11]. As such, a second steroidal approach involves topical dexamethasone used in rats to elevate IOP and study the regulation of myocilin, previously identified as a causative gene of POAG in humans. Though the model demonstrated IOP elevation, mRNA levels of myocilin in the trabecular meshwork and in proximity to Schlemm's canal were not different from the control [59].

#### *3.1.3 Reperfusion ischemia*

An additional model to mimic open angle glaucoma is via induction of reperfusion ischemia by paracentesis in the anterior chamber. In this method, the cannulation of the anterior chamber with a microneedle allows precise control of the IOP and suppression of blood flow through the retinal and uveal vasculature. This causes IOP-induced damage to the RGCs [15, 47].

## **3.2 PACG models**

Microspheres have been injected to block the trabecular meshwork and emulate PACG. The microspheres do not block the pupil, which allows observation of the fundus, which makes this a suitable model. However, fluctuations in IOP can limit the efficacy as well as location of the microspheres. Yet, elevation of nitric oxide in the aqueous humor was detected in neovascular and angle closure subtypes, thought to be due to the inflammatory mechanism [15, 60]. Bouhenni *et al*. also writes that there are various rat, mice, and rabbit models of PACG to study the effects of elevated IOP on RGCs and the optic nerve. These models have been created with techniques such as hypertonic saline injection into the episcleral veins, cauterization or ligation of the episcleral veins, or laser photocoagulation as discussed prior [11].
