Abstract

Glaucoma is one of the leading causes of blindness worldwide. Elevated intraocular pressure (IOP) is the primary risk factor for optic nerve damage in glaucoma. Many studies conducted on human subjects and animal models have shown that marijuana and its active components cannabinoids lower IOP. This project is focused on understanding the mechanisms by which cannabinoids, potential therapeutic agents for glaucoma, lower intraocular pressure (IOP). In the previous funding period, we have established that CB1 and CB2 cannabinoid receptors are expressed on the trabecular meshwork (TM) cells, and cannabinoid agonists enhance aqueous humor outflow through both CB1 and CB2 receptors. For the competitive renewal application of this project, we hypothesize that non-CB1/CB2 cannabinoid derivatives may cause an enhancement of aqueous humor outflow through a novel, non-CB1/CB2 cannabinoid receptor, and the novel cannabinoid receptor may mediates the IOP-lowering effects of the non-CB1/CB2 cannabinoid agonists through metalloprotease (MMP)-mediated mechanisms.
Two specific aims are designed to test the above three hypotheses.
Specific Aim 1 : To study the effects of non-CB1/CB2 cannabinoid agonists, and the role of GPR55, a novel, non- CB1/CB2 cannabinoid receptor on aqueous humor outflow.
Specific Aim 2 : To study the mechanisms of actions for the aqueous humor outflow-enhancing effects of non-CB1/CB2 cannabinoid agonists. Completing this project should provide mechanistic insight regarding cannabinoid-induced enhancement of aqueous humor outflow facility. These studies should also contribute to our understanding of the homeostasis of aqueous humor outflow and may lead to the development of better therapeutic agents for lowering IOP.

Public Health Relevance

Cannabinoids are potential novel anti-glaucoma agents. This proposal aims to study the mechanisms underlying the aqueous humor outflow-enhancing effects of synthetic and endogenous cannabinoids. These studies should provide mechanistic insight regarding the IOP-lowering effects of cannabinoids. These studies should also contribute to our understanding of the homeostasis of aqueous humor outflow and may lead to the development of better therapeutic agents for lowering IOP.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013632-06
Application #
7895529
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
Project Start
2001-07-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
6
Fiscal Year
2010
Total Cost
$370,000
Indirect Cost

  Institution

Name
University of Louisville
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292

  Publications

Brown, Kevin J; Laun, Alyssa S; Song, Zhao-Hui (2017) Cannabidiol, a novel inverse agonist for GPR12. Biochem Biophys Res Commun 493:451-454
Kumar, Pritesh; Carrasquer, Carl A; Carter, Arren et al. (2014) A categorical structure-activity relationship analysis of GPR119 ligands. SAR QSAR Environ Res 25:891-903
Kumar, Pritesh; Song, Zhao-Hui (2014) CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene. Biochem Biophys Res Commun 443:144-9
Kumar, Pritesh; Kumar, Akhilesh; Song, Zhao-Hui (2014) Structure-activity relationships of fatty acid amide ligands in activating and desensitizing G protein-coupled receptor 119. Eur J Pharmacol 723:465-72
Kumar, Pritesh; Song, Zhao-Hui (2013) Identification of raloxifene as a novel CB2 inverse agonist. Biochem Biophys Res Commun 435:76-81
Qiao, Zhuanhong; Kumar, Akhilesh; Kumar, Pritesh et al. (2012) Involvement of a non-CB1/CB2 cannabinoid receptor in the aqueous humor outflow-enhancing effects of abnormal-cannabidiol. Exp Eye Res 100:59-64
Kumar, Akhilesh; Qiao, Zhuanhong; Kumar, Pritesh et al. (2012) Effects of palmitoylethanolamide on aqueous humor outflow. Invest Ophthalmol Vis Sci 53:4416-25
He, Fang; Kumar, Akhilesh; Song, Zhao-Hui (2012) Heat shock protein 90 is an essential molecular chaperone for CB2 cannabinoid receptor-mediated signaling in trabecular meshwork cells. Mol Vis 18:2839-46
Carrasquer, Alex; Nebane, Nstang M; Williams, Walter M et al. (2010) Functional consequences of nonsynonymous single nucleotide polymorphisms in the CB2 cannabinoid receptor. Pharmacogenet Genomics 20:157-66
Nebane, Ntsang M; Hurst, Dow P; Carrasquer, Carl A et al. (2008) Residues accessible in the binding-site crevice of transmembrane helix 6 of the CB2 cannabinoid receptor. Biochemistry 47:13811-21

Showing the most recent 10 out of 21 publications