Date of Award

Spring 2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Program/Concentration

Biomedical Sciences

Committee Director

Frank A. Lattanzio

Committee Director

Patricia B. Williams

Committee Member

Peter F. Blackmore

Committee Member

Stephen J. Beebe

Abstract

Synthetic and naturally occurring cannabinoids are known to decrease intraocular pressure (IOP). Glaucomatous damage to the retina and optic nerve progresses even after therapy to maintain normal intraocular pressure (IOP). Topical application of cannabinoids decreases IOP while not affecting blood pressure or heart rate. Based upon their effects on other tissues, we hypothesize that these analogs reduce IOP and may also confer direct neuroprotective effects on the retina, possibly via CB1 and/or CB2 receptors. The purpose of this study is to determine if the newly synthesized CB agonists, lipid soluble O-1812 (CB 1), and water soluble O-2545 (CB 1

The IOP effects were tested in a rat glaucoma model, which was created Sprague-Dawley rats by ligating 3 of 4 episcleral veins. IOP increased by at least 5 mm Hg in the operated eye, measured via Goldmann tonometry under sedation. Retinal damage was induced by injecting NMDA (2 µl of 10 mM) intravitreally in Sprague-Dawley rats. In other groups O-1812 (2 mM) and O-2545 (2mM) were co-injected with NMDA. Electroretinograms (ERG) were recorded at baseline, 1 wk and 2 wk after injection. Contralateral normal eyes served as controls. After 2 wk, retinas were flat mounted and stained with H&E.

While both O-compounds showed significant IOP decrease, lipid soluble O-1812 had the most rapid onset. O-1812 was also effectively restricted a-wave amplitude loss; O-2545 was less effective. Retinal whole mounts of NMDA alone showed areas devoid of cells, while those treated with O-1812 and O-2545 were intact with an even distribution of retinal ganglionic cells. Considering both IOP and neuroprotective effects, lipid soluble O-1812 was deemed to be most effective.

Comments

A Dissertation Submitted to the Faculty of Old Dominion University and Eastern Virginia Medical School in Partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy in Biomedical Sciences.

DOI

10.25777/026v-d196

ISBN

9780549614609

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