GRANT=6673599;P20RR Decreased hippocampal volume and reduced glial cell number in the cortex have been documented in major depression. Based largely on animal studies, stress-induced hypercortisolemia, leading to neurotoxicity and/or Active Cell Death (apoptosis) is the probable cause of the hippocampal volume loss in depression. Active Cell Death is known to involve NMDA glutamate receptor (NMDA-R) activation and nitric oxide overproduction. Agmatine, an endogenous polyamine derived from decarboxylation of arginine and mainly stored in synaptic vesicles of neurons, has been found to antagonize both NMDA-R and Nitric Oxide synthase, and thereby to possess natural neuroprotective properties (i.e., shown against hypoxic ischemia). Hippocampal volume loss has been well-established to occur in animal models of chronic stress. Agmatine is normally abundant in the hippocampus where it may normally be co-released with glutamate to protect from excito-neurotoxicity through a polyamine site in the NMDA-R of normal rats. We hypothesize that in subjects suffering from major depression, agmatine becomes depleted as a consequence of long term release under prolonged stress, and therefore the hippocampal neurons become exposed to neuronal damage. The goal of my proposal is to examine the neuroprotective properties of agmatine against neurotoxicity induced by excitotoxins or higher concentrations of glucocorticoids as have been detected in patients with major depression. To address this goal, the neuroprotective effects of agmatine will be measured in 1) cultured fetal rat hippocampal neurons exposed to glutamate as well as related chemicals, or high concentrations of glucocorticoids in vitro which mimic conditions found in depressed patients in vivo, 2) the hippocampi of rats treated with excitotoxins, and 3) the hippocampi of rats after undergoing chronic mild stress. Concentrations of endogenous agmatine in hippocampi will be correlated with the extent of structural injury to neurons and glial cells in the hippocampal primary culture and in the hippocampus in vivo of treated rats and the rat chronic mild stress model. This research is designed to elucidate the functional significance of agmatine as an endogenous neuroprotective agent of relevance to the effects of chronic stress as occurs in depression. Clarification of structural and biochemical changes in the hippocampus of the chronic mild stress animal model will add to evidence of hippocampal neuron loss in depression, and hopefully suggest ways to augment agmatine's natural neuroprotective effects.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Mississippi Medical Center
United States
Zip Code
Stoppelbein, Laura; McRae, Elizabeth; Greening, Leilani (2017) A Longitudinal Study of Hardiness as a Buffer for Posttraumatic Stress Symptoms in Mothers of Children with Cancer. Clin Pract Pediatr Psychol 5:149-160
Ginley, Meredith K; Bagge, Courtney L (2017) Psychiatric heterogeneity of recent suicide attempters: A latent class analysis. Psychiatry Res 251:1-7
Greening, Leilani; Stoppelbein, Laura; Cheek, Kara (2017) Racial/ethnic disparities in the risk of posttraumatic stress disorder symptoms among mothers of children diagnosed with cancer and Type-1 diabetes mellitus. Psychol Trauma 9:325-333
Dalwadi, Dhwanil A; Kim, Seongcheol; Amdani, Shahnawaz M et al. (2016) Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz. Pharmacol Res 110:10-24
Stewart, Courtney; Yu, Yue; Huang, Jun et al. (2016) Effects of high intensity noise on the vestibular system in rats. Hear Res 335:118-127
Duncan, Jeremy W; Zhang, Xiao; Wang, Niping et al. (2016) Binge ethanol exposure increases the Krüppel-like factor 11-monoamine oxidase (MAO) pathway in rats: Examining the use of MAO inhibitors to prevent ethanol-induced brain injury. Neuropharmacology 105:329-340
Fisher, Lauren B; Overholser, James C; Dieter, Lesa (2015) Methods of committing suicide among 2,347 people in Ohio. Death Stud 39:39-43
Duncan, Jeremy; Wang, Niping; Zhang, Xiao et al. (2015) Chronic Social Stress and Ethanol Increase Expression of KLF11, a Cell Death Mediator, in Rat Brain. Neurotox Res 28:18-31
Stoppelbein, Laura; Greening, Leilani (2015) A longitudinal study of the role of cortisol in posttraumatic stress disorder symptom clusters. Anxiety Stress Coping 28:17-30
Johnson, Shakevia; Duncan, Jeremy; Hussain, Syed A et al. (2015) The IFN?-PKR pathway in the prefrontal cortex reactions to chronic excessive alcohol use. Alcohol Clin Exp Res 39:476-84

Showing the most recent 10 out of 142 publications