Stroke is the third leading cause of death in the United States and the leading cause of disability. Diseases of neurodegeneration and brain damage from non-missile head trauma account for nearly 500,000 hospital admissions in the U.S. annually. Although the etiology may differ, the same anatomic and physiologic substrates are involved in these conditions, including ischemia and hypoxic injury and the release of excitatory amino acids, especially glutamate from diseased or damaged cells. We have been using in vitro and in vivo models of experimental ischemia and cellular models of glutamate toxicity to examine these mechanisms of neuronal injury, and to target early intervention treatment strategies for neurodegeneration. One promising strategy that has not been explored is the use of low doses of chemicals to enhance cell tolerance and recovery. High doses of toxic chemicals will inhibit and kill biological systems, while low doses frequently stimulate those systems. Stimulation of cell function by exposure to low doses of chemicals can often mitigate the adverse effects produced by high doses. This phenomenon has been extensively studied in the area of toxicology called """"""""hormesis"""""""" and is the theoretical basis for the observed effects in some types of homeopathy (specifically isopathy). While paradoxical dose effects have been demonstrated across multiple cell types and phyla they have not yet been examined in neurodegeneration. In preliminary research we have demonstrated that protective effects occur in neuronal cells exposed to low and ultra-low doses of glutamate and NMDA and that certain doses of glutamate/potassium combinations protect against stroke in vivo. The objective of this project is to use neuronal culture systems to identify the optimal protective doses and of four neurotoxins that work by different mechanisms - a glutamate/potassium preparation, NMDA, cycloheximide, MPPepsilon, a combination of these. We will also begin preliminary examination of selected mechanisms of the optimal protective combination and dose. This project will, for the first time, have produced a systematic approach for use of protective hormesis and will lay the foundation for the scientific development of homeopathic and isopathic drugs in neurodegeneration and brain injury.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AT000350-02
Application #
6621275
Study Section
Special Emphasis Panel (ZAT1-C (12))
Program Officer
Hopp, Craig
Project Start
2002-02-15
Project End
2005-04-30
Budget Start
2003-06-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$185,875
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Rockville
State
MD
Country
United States
Zip Code
20817
Arun, Peethambaran; Moffett, John R; Ives, John A et al. (2005) Rapid sodium cyanide depletion in cell culture media: outgassing of hydrogen cyanide at physiological pH. Anal Biochem 339:282-9
Szeto, A L; Rollwagen, F; Jonas, W B (2004) Rapid induction of protective tolerance to potential terrorist agents: a systematic review of low- and ultra-low dose research. Homeopathy 93:173-8
Marotta, Diane; Marini, Ann; Banaudha, Krishna et al. (2003) Nonlinear effects of glutamate and KCl on glutamate toxicity in cultured rat cerebellar neurons. Int J Neurosci 113:491-502