Sustained neuroprotection from a single intravitreal injection of PGJ₂ in a nonhuman primate model of nonarteritic anterior ischemic optic neuropathy.

Abstract

PURPOSE:

Prostaglandin J₂ (PGJ₂) is neuroprotective in a murine model of nonarteritic anterior ischemic optic neuropathy (NAION). After assessing for potential toxicity, we evaluated the efficacy of a single intravitreal (IVT) injection of PGJ₂ in a nonhuman primate model of NAION (pNAION).

METHODS:

We assessed PGJ₂ toxicity by administering it as a single high-dose intravenous (IV) injection, consecutive daily high-dose IV injections, or a single IVT injection in one eye of five adult rhesus monkeys. To assess efficacy, we induced pNAION in one eye of five adult male rhesus monkeys using a laser-activated rose bengal induction method. We then injected the eye with either PGJ₂ or phosphate-buffered saline (PBS) intravitreally immediately or 5 hours post induction. We performed a clinical assessment, optical coherence tomography, electrophysiological testing, fundus photography, and fluorescein angiography in all animals prior to induction and at 1 day, 1 week, 2 weeks, and 4 weeks after induction. Following analysis of the first eye, we induced pNAION in the contralateral eye and then injected either PGJ₂ or PBS. We euthanized all animals 5 weeks after final assessment of the fellow eye and performed both immunohistochemical and light and electron microscopic analyses of the retina and optic nerves.

RESULTS:

TOXICITY:

PGJ₂ caused no permanent systemic toxicity regardless of the amount injected or route of delivery, and there was no evidence of any ocular toxicity with the dose of PGJ₂ used in efficacy studies. Transient reduction in the amplitudes of the visual evoked potentials and the N95 component of the pattern electroretinogram (PERG) occurred after both IV and IVT administration of high doses of PGJ₂; however, the amplitudes returned to normal in all animals within 1 week.

EFFICACY:

In all eyes, a single IVT dose of PGJ₂ administered immediately or shortly after induction of pNAION resulted in a significant reduction of clinical, electrophysiological, and histological damage compared with vehicle-injected eyes (P = 0.03 for both VEP and PERG; P = 0.05 for axon counts).

CONCLUSIONS:

In nonhuman primates, PGJ₂ administered either intravenously or intravitreally produces no permanent toxicity at even four times the dose given for neuroprotection. Additionally, a single IVT dose of PGJ₂ is neuroprotective when administered up to 5 hours after induction of pNAION.

• Authors: Neil R Miller, Mary A Johnson, Theresa Nolan, Yan Guo, Alexander M Bernstein, Steven L Bernstein
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 55 Issue 11 Pg. 7047-56 (Oct 08 2014) ISSN: 1552-5783 [Electronic] United States
• PMID: 25298416 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Chemical References

• Antineoplastic Agents
• Delayed-Action Preparations
• Prostaglandins, Synthetic
• 9-deoxy-delta-9-prostaglandin D2
• Prostaglandin D2

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• Delayed-Action Preparations
• Disease Models, Animal
• Evoked Potentials, Visual (drug effects)
• Fluorescein Angiography
• Follow-Up Studies
• Fundus Oculi
• Intravitreal Injections
• Male
• Optic Nerve (drug effects, pathology, physiopathology)
• Optic Neuropathy, Ischemic (drug therapy, pathology, physiopathology)
• Prostaglandin D2 (administration & dosage, analogs & derivatives)
• Prostaglandins, Synthetic
• Rats
• Rats, Long-Evans
• Retinal Ganglion Cells (drug effects, pathology)
• Tomography, Optical Coherence