Mouse study suggests role of tumor necrosis factor in glaucoma damage

A study in mice implicates the cytokine tumor necrosis factor-alpha, or TNF-alpha, in the sequence of events that lead to glaucomatous nerve damage.

Elevated IOP may induce a cascade of cellular events, beginning with upregulation of TNF-alpha, that eventually leads to retinal ganglion cell death, according to the study by Toru Nakazawa, MD, PhD, and colleagues at the Massachusetts Eye and Ear Infirmary and Children's Hospital Boston.

The finding suggests that future glaucoma therapies may target TNF-alpha, the study authors said. TNF-alpha-inhibiting drugs are already in use to treat inflammatory diseases such as rheumatoid arthritis, according to a press release from the institutions where the research was done.

"These drugs have potent systemic effects, so we'd want to develop a very safe long-term and local treatment. Theoretically, it might be possible to put slow-release TNF-alpha inhibitors just outside the eye, so you wouldn't have to have frequent injections," said study author Joan Miller, MD, in the release.

Dr. Nakazawa and colleagues examined the relationship between TNF-alpha and retinal ganglion cell death using a mouse model of laser-induced ocular hypertension. The researchers found that ocular hypertension led to a rapid upregulation of TNF-alpha. Mice with elevated IOP had almost a fivefold increase in TNF-alpha compared to control mice.

The high levels of TNF-alpha in turn activated microglial cells. The researchers also observed a threefold increase in microglial cells after injecting TNF-alpha into normal mice.

The researchers postulated that activated microglial cells go on to kill oligodendrocytes in the optic nerve, which produce and maintain myelin. Finally, oligodendrocyte death led to retinal ganglion cell death, according to the study authors.

Mice who were genetically altered to prevent microglial activation showed no detectable loss of oligodendrocytes despite elevated IOP, while wild-type control mice showed an approximate 50% loss in such cells.

Dr. Nakazawa and colleagues also demonstrated that administering a TNF-alpha antibody prevented retinal ganglion cell death despite elevated IOP. This suggests that TNF-alpha inhibition may be a possible new avenue for glaucoma treatment, they said.

The study is published online on the Journal of Neuroscience Web site.