Pentoxifylline suppression of TNF-alpha mediated axonal degeneration in the rabbit optic nerve.
In AIDS patients, axonal degeneration in the optic nerve occurs as a histopathological manifestation of the optic neuropathy. Direct infection of neurons by HIV is unlikely, and the axonal injury may be an indirect effect mediated by cytotoxic factors such as tumor necrosis factor-alpha (TNF-alpha) which we have previously demonstrated to cause axonal degeneration in the rabbit optic nerve. To test the suppressive effects of pentoxifylline in preventing TNF-alpha-mediated axonal degeneration, we applied pentoxifylline to an established rabbit model that demonstrates an AIDS-like optic neuropathy using intravitreal TNF-alpha injections. Degenerated axonal profiles were numerous in control rabbit optic nerve (mean 1879) and reduced in rabbits receiving the medium dose of pentoxifylline (300 mg PO BID, mean 439, p < 0.001) and the highest dose of pentoxifylline (600 mg PO BID, mean 120, p < 0.007). High dose pentoxifylline reduced TNF-alpha-induced axonal losses to less than 10% that seen without pentoxifylline pretreatment. Lower doses of pentoxifylline had a lesser but significant protective effect. Our results suggest that TNF-alpha-mediated axonal degeneration can be suppressed by high doses of pentoxifylline. Pentoxifylline may therefore be useful in AIDS patients demonstrating neurological or neuro-ophthalmological symptoms.
Petrovich
M S
MS
Department of Ophthalmology and Neurosurgery, Doheny Eye Institute, USC School of Medicine, Los Angeles 90033, USA.
Hsu
H Y
HY
Gu
X
X
Dugal
P
P
Heller
K B
KB
Sadun
A A
AA
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D007267:Injections; D009410:Nerve Degeneration / Q000517:prevention & control*; D009900:Optic Nerve / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D010431:Pentoxifylline / Q000494:pharmacology*; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014822:Vitreous Body
D014409:Tumor Necrosis Factor-alpha; D010431:Pentoxifylline