Oxygen-Induced Retinopathy in the Newborn Rat: Morphological and Immunohistological Findings in Animals Treated with Topical Timolol Maleate

Abstract

Oxygen-induced retinopathy (OIR) similar to that seen in premature infants can be produced in newborn rats by exposure to 80% oxygen for the first 5 days of life, with subsequent recovery for 7 days in a room air environment. Previous studies have shown that the latter phase is associated with degeneration of retinal astrocytes. In the absence of astrocytes, the vascular endothelial growth factor (VEGF) is produced by the neurons of the inner retina. In this study, immunohistochemical methods were used to assess retinal expression of VEGF protein in ratlings exposed to the above protocol, with and without simultaneous treatment with topical timolol maleate. Intraocular pressure (IOP) and arterial pressure were measured. The severity of OIR was also evaluated in retinal flat mounts after India ink perfusion. The mean IOP was 8.25 ± 0.32 mm Hg in untreated ratlings and 5.15 ± 0.24 mm Hg in timolol-treated animals. OIR in retinas from the timolol group was less severe than that seen in untreated ratlings. VEGF protein expression was almost completely absent in the latter group. Retinas from timolol-treated animals expressed VEGF protein, though the level was inferior to that found in controls raised under room air conditions. In conclusion, these data seem to indicate that experimental OIR can be attenuated by a reduction of the IOP during and after oxygen supplementation. It is possible that these effects are due to improved ocular perfusion pressure, which would mitigate the hypoxic insult to the retina during the room air recovery period.

Attenuation of Choroidal Neovascularization by β2-Adrenoreceptor Antagonism

“…In the rat, topical timolol (a β-adrenergic receptor antagonist with highest affinity for the β2-adrenoreceptor 36 ) diminishes retinal neovascularization during OIR 37 . More recently, the Bagnoli group showed that propranolol 32 and a selective β2-adrenoreceptor blocker 33 can both attenuate retinal neovascularization during OIR in mice by decreasing VEGF production.…”

Systemic Beta-Blockers May Reduce the Need for Repeated Intravitreal Injections in Patients With Wet Age-Related Macular Degeneration Treated by Bevacizumab

“…The authors attributed this effect to a decreased intraocular pressure induced by topical timolol as occurs in glaucoma patients, thus improving ocular perfusion pressure. 20 Systemic BABA are frequently used in the clinical practice to treat cardiac arrhythmia, hypertension, migraine, and hyperthyroidism among other conditions. Propanolol has been used to treat neovascular conditions such as infantile capillary hemangiomas [21][22][23][24][25][26][27][28][29][30][31] and retinopathy of prematurity 32 ; clinical trials are underway to elucidate the effect of these therapies.…”

The pathophysiology of retinopathy of prematurity: an update of previous and recent knowledge

“…Propranolol does not affect the VEGF retinal levels in rats with DR (Zheng et al 2007). In contrast, a decrease in VEGF has been observed in the retinas of neonatal OIR rats, in which a reduction in intraocular pressure induced by the b-AR antagonist timolol diminishes the severity of OIR (Ricci et al 1991(Ricci et al , 1995(Ricci et al , 2000. This discrepancy might be explained by either the different drug administration routes or different dosages or the possibility that the control of angiogenesis by b-ARs can be regulated by distinct mechanisms in OIR and DR.…”

“…2007). In contrast, a decrease in VEGF has been observed in the retinas of neonatal OIR rats, in which a reduction in intraocular pressure induced by the β‐AR antagonist timolol diminishes the severity of OIR (Ricci et al. 1991, 1995, 2000).…”