What Is the Present Pathogenetic Concept of Glaucomatous Optic Neuropathy?

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Abstract

Glaucomatous optic neuropathy implies loss of neural tissue, activation of glial cells, tissue remodeling, and change of blood flow. The blood flow reduction is not only secondary but has a primary component. Activation of astrocytes leads to an altered microenvironment. An unstable ocular perfusion, either due to IOP fluctuation or a disturbed autoregulation (due to primary vascular dysregulation syndrome) leads to a mild reperfusion injury. The superoxide (O2) anion produced in the mitochondria of the axons, fuses with the nitric oxide (NO) diffusing from the astrocytes, leading to the damaging peroxynitrite (ONOO). It is possible that the diffusion of endothelin and metalloproteinases to the surrounding of the optic nerve head leads to a local vasoconstriction and thereby increases the risk for venous occlusion and weakens the blood–brain barrier, which in extreme situations results in splinter hemorrhages. Activated retinal astrocytes can be visualized clinically. The involvement of primary vascular dysregulation in the pathogenesis of glaucomatous optic neuropathy may explain why women, as well as Japanese, suffer more often from normal-tension glaucoma.

Section snippets

Glaucomatous Optic Neuropathy

Glaucomatous optic neuropathy (GON) comprises of the following mutually dependant basic components: loss of neural tissue, activation of glial cells, tissue remodeling, change of blood flow.

Risk Factors for Glaucoma

Factors associated with an increase of IOP are not the same as factors associated with the development of GON. Furthermore, factors related to either IOP increase or to damage may not automatically be causal.

Ocular Blood Flow and Glaucomatous Optic Neuropathy

Whether OBF plays a role in the pathogenesis of GON has often been discussed in the past. For decades the literature remained controversial.

The Pathogenetic Concept of GON

Among others, there are two major pathogenetic components: damage to the axons and the activation of the astrocytes (Fig. 4).

Mechanical stress (e.g., by an increase in IOP) activates astrocytes by stimulating the epidermal growth factor receptor (EGFR).71 Astrocytes, however, are also activated by endothelin, which is upregulated as a consequence of cell stress—for example, by RI.

The major insult to the axons is brought about by RI, which is the consequence of an unstable oxygen supply (due to

Method of Literature Search

A systematic search of the Medline database using the PubMed Web site for the years 1966 through January 2007 was conducted using the following key words: POAG, pathogenesis, glaucoma, vasospasm, vascular dysregulation, autoregulation, ischemia, endothelin, glaucomatous optic neuropathy, glial cells, tissue remodeling, ocular blood flow, risk factors, trabecular meshwork, primary vascular dysregulation, nitric oxide synthase, secondary vascular dysregulation, reperfusion damage, oxidative

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