**6. Alpha adrenergic receptor agonist**

α2 adrenergic agonists are a known group of anti glaucoma drugs that inhibit adenylate cyclase, reducing cAMP, thereby decreasing aqueous production. They also act by increasing uveoscleral outflow. α2A receptors can be found in non pigmented ciliary epithelium, α2B receptors on neuronal dendrites and α2C receptors on photoreceptors cell bodies and inner segments [41]. α<sup>2</sup> agonists have been shown to have secondary neuropro‐ tective effects [42,43,44].

### **6.1. Brimonidine**

**Figure 2.** Multiple mechanisms for neurodegeneration which may be aggravated by vascular dysregulation, hypoxia

nNO and iNO are expressed in reactive astrocytes. Increased NO reacts with a superoxide anion which can be toxic to the axons of the retinal ganglion cell. Motallebipour et al, showed a genetic association between iNO and primary open angle glaucoma (POAG) using genetic analysis and nuclear factor [35]. iNO is located in the astrocytes and microglial in the optic nerve head and expresses more activity with exposure to increased intraocular pressure and cytokines. This results in increased in NO production and the induction of the apoptotic cascade [36]. The NO oxide has its effect in both the astrocytes of the optic nerve head and the

The endothelial NO synthase (eNOS) is expressed in the trabecular membrane and schlem's canal cells. eNOS produces nitric oxide which regulates the vascular tone causing smooth muscle relaxation and relaxation of the trabecular meshwork which improves aqueous humour outflow [37]. Elevation of the IOP increases the shear stress which activates eNOS

which results in increase in the pressure dependent outflow.

and elevated IOP

208 Glaucoma - Basic and Clinical Aspects

pericytes of the vasculature [32].

*5.3.2. Vascular modulation*

α2 adrenergic receptors can modulate the release of neurotransmitters such as glutamate [45]. NMDA receptors when stimulated results in an increase in intracellular Ca2+ and an inward current in the RGC. Brimonidine, an α2 agonist, can block the NMDA receptors which results in controlling the intracellular calcium, hereby allowing neuroprotection [23,46]. Brimonidine is also thought to up regulate brain derived neurotrophic factor (BDNF), activating anti apoptotic genes and the cell survival signaling pathway. It is also thought to modulate the N methyl-D-aspartate receptors [43,46-48].

Brimonidine is also known to upregulate not only BDNF, but prosurvival factors, such as anti apoptotic factors B-cell lymphoma -2 (Bcl-2) and B-cell lymphoma extra large (bcl-xl), basic fibroblastic growth factor (bFGF) and extracellular signal regulated kinases (ERKs). These actions assist in the prevention of neuronal death and promotes cell survival [49].
