Of three isozymes of cyclooxygenases (COX) that have been identified, COX-2 is the focus of growing attention not only because it is inducible in inflammation, but also because it is implicated in certain neurologic disorders such as epilepsy, and pathogeneses of neurodegenerative diseases (multiple sclerosis, Parkinson's and Alzheimer's diseases), and the contribution to the traumatic brain injury- and ischemia- induced neuronal damage. It has been long thought that COX-2-mediated neuronal injury/degeneration is due to the increased production of arachidonic acid-derived prostaglandins. Recent evidence indicates that endocannabinoids (ECs) are substrates for COX-2, and COX-2 is capable of degrading ECs to form new types of prostanoids, meaning that the functional significance of COX-2 is far beyond what was initially revealed. ECs are an endogenous protection system. It is likely that the excessive activation of COX-2 that degrades ECs is an important mechanism that causes neurotoxicity. The proposed project is to test our hypothesis that the COX-2 oxidative metabolism of endocannabinoids alters hippocampal synaptic signaling and produces neurotoxicity. We will employ several approaches including electrophysiological recordings, molecular biology, lipidomic and cytotoxicity analyses to test this hypothesis by accomplishing the following three specific aims: 1) To test the hypothesis that the elevation of COX-2 facilitates degrading endocannabinoids and producing novel prostaglandins;2) To test the hypothesis that the COX-2 oxidative metabolism of endocannabinoids alters hippocampal synaptic signaling;and 3) To test the hypothesis that COX-2 oxidative metabolites of endocannabinoids induce neurotoxicity. The proposed project will be of great significance in elucidating roles of COX-2-mediated EC signaling in synaptic transmission and neuronal survival that have not been revealed before. We expect to gain a better understanding of cellular and molecular mechanisms underlying cognitive impairments and brain disorders (such as stroke, epilepsy and Alzheimer's disease) involving alterations in EC signaling resulting from abnormally excessive activation of COX-2. The outcome from the proposed project will also provide new targets for designing drugs aimed at treating or alleviating COX-2-mediated degenerative diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Whittemore, Vicky R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Louisiana State Univ Hsc New Orleans
Schools of Medicine
New Orleans
United States
Zip Code
Xu, Jian-Yi; Chen, Chu (2015) Endocannabinoids in synaptic plasticity and neuroprotection. Neuroscientist 21:152-68
Chen, Rongqing; Zhang, Jian; Fan, Ni et al. (2013) ?9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling. Cell 155:1154-1165
Xu, Jian-Yi; Zhang, Jian; Chen, Chu (2012) Long-lasting potentiation of hippocampal synaptic transmission by direct cortical input is mediated via endocannabinoids. J Physiol 590:2305-15
Chen, Rongqing; Zhang, Jian; Wu, Yan et al. (2012) Monoacylglycerol lipase is a therapeutic target for Alzheimer's disease. Cell Rep 2:1329-39
Chen, X; Zhang, J; Chen, C (2011) Endocannabinoid 2-arachidonoylglycerol protects neurons against ?-amyloid insults. Neuroscience 178:159-68
Du, Huizhi; Chen, Xiaolei; Zhang, Jian et al. (2011) Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-?. Br J Pharmacol 163:1533-49
Sang, Nan; Zhang, Jian; Chen, Chu (2010) Anandamide potentiation of miniature spontaneous excitatory synaptic transmission is mediated via IP3 pathway. Neurochem Int 56:590-6
Xu, Jian-Yi; Chen, Rongqing; Zhang, Jian et al. (2010) Endocannabinoids differentially modulate synaptic plasticity in rat hippocampal CA1 pyramidal neurons. PLoS One 5:e10306
Fan, Ni; Yang, Hongwei; Zhang, Jian et al. (2010) Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Delta9-THC exposure-impaired hippocampal synaptic plasticity. J Neurochem 112:691-702
Yang, Hongwei; Zhang, Jian; Breyer, Richard M et al. (2009) Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor. J Neurochem 108:295-304

Showing the most recent 10 out of 15 publications