Topical flunarizine reduces IOP and protects the retina against ischemia-excitotoxicity.
OBJECTIVE
To determine whether topical application of flunarizine reduces intraocular pressure (IOP) and acts as a retinal neuroprotectant and to compare the effectiveness of flunarizine with betaxolol and nifedipine at reducing the influx of calcium and sodium.


METHODS
Ischemia was delivered to the rabbit retina by raising the IOP. After 3 days, a flash electroretinogram (ERG) was recorded, and the retina processed for the localization of certain antigens. In the rat, N-methyl-D-aspartate (NMDA) was injected intravitreally, and 8 days later, the retinas were analyzed for the localization of Thy-1 or the relative amounts of mRNAs for antigens located to ganglion cells or photoreceptors. Rats and rabbits received topical flunarizine or vehicle before and after ischemia or NMDA. IOP was measured in rabbits after a single topical application of 2% flunarizine. Studies were conducted on isolated rat retinas, cortical cultures, and brain synaptosomes to compare the effectiveness of flunarizine with nifedipine and betaxolol at reducing the influx of calcium or sodium.


RESULTS
Changes in rabbit retinal choline acetyltransferase and parvalbumin immunoreactivities and the b-wave of the ERG caused by ischemia-reperfusion were blunted by topical treatment with flunarizine. Similarly, NMDA induced reductions in Thy-1 immunoreactivity and mRNA for rat ganglion cell antigens (Thy-1 and neurofilament light form) were counteracted by topical application of flunarizine. Topical application of 2% flunarizine significantly lowered the IOP in rabbits over a period of 5 hours. Flunarizine was more effective than betaxolol and much stronger than nifedipine at attenuating veratridine-induced influx of sodium into synaptosomes. Nifedipine, flunarizine, and betaxolol all reduced the NMDA-induced influx of calcium into the isolated retina or cortical neurons, but betaxolol was the least effective.


CONCLUSIONS
Topically applied flunarizine reduces IOP and attenuates injury to the whole of the retina, including the ganglion cells. The neuroprotective action of flunarizine is to reduce the influx of calcium and sodium into stressed neurons. The potent effect of flunarizine on sodium influx would be particularly protective to axons.
Osborne
Neville N
NN
Nuffield Laboratory of Ophthalmology, University of Oxford, Walton Street, Oxford GB-OX2 6AW, United Kingdom. neville.osborne@eye.ox.ac.uk
Wood
John P M
JP
Cupido
Alexander
A
Melena
José
J
Chidlow
Glyn
G
D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015784:Betaxolol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004596:Electroretinography / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005444:Flunarizine; D007429:Intraocular Pressure / Q000187:drug effects*; D016202:N-Methylaspartate / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010320:Parvalbumins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D010320:Parvalbumins; D012333:RNA, Messenger; D018800:Thy-1 Antigens; D014665:Vasodilator Agents; D016202:N-Methylaspartate; D012964:Sodium; D002795:Choline O-Acetyltransferase; D009543:Nifedipine; D015784:Betaxolol; D005444:Flunarizine; D002118:Calcium