The long-range objective of this competing continuation research project is improved therapy for incomplete cerebral ischemia based on a better understanding of the role of ornithine decarboxylase (ODC) and its polyantines products in the pathophysiology of cerebral ischemia. Polyamines have both harmful and beneficial possible effects after ischemia. This balance of effects is dependent on ODC, the rate limiting enzyme of polyamine metabolism, and s-adenosyl methionine decarboxylase (SAMDC), an enzyme important in the synthesis of polyamines as well as in the relative distribution of the three major polyamines. Questions to be evaluated in the focal ischemia model include: 1) If changes in SAMDC activity contribute to disturbances in polyamine levels, 2) If administration of s-adenosyl methionine results in improvement in physiologic outcome, 3) If extracellular release of polyamines contribute to ischemic damage through the n-methyl-d-aspartate (NMDA) receptor, and 4) If combined blockade of extra and intracellular polyamines provides improvement. Questions to be evaluated in the transient ischemia model include: 1) If changes in SAMDC gene expression correlate with changes in enzyme and polyamine activity, 2) If metabolic recovery of high energy phosphates is a prerequisite for the enzyme system changes, 3) If polyamines have extracellular activity at NMDA receptors, and 4) If combined extra and intracellular blockade of polyamines decreases calcium dependent formation of other metabolites. MR spectroscopy, brain microdialysis, enzyme activity, molecular biological probes and electron microscopy will be used to assess ODC and SAMDC's role in the pathophysiologic events following cerebral ischemia. Completion of these studies will increase our understanding of the potentially harmful and beneficial metabolic events after incomplete cerebral ischemia leading to improved therapies to limit infarction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028000-05
Application #
2266714
Study Section
Neurology A Study Section (NEUA)
Project Start
1990-07-01
Project End
1996-09-29
Budget Start
1994-09-30
Budget End
1995-09-29
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Surgery
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Dempsey, Robert J; Raghavendra Rao, Vemuganti L (2003) Cytidinediphosphocholine treatment to decrease traumatic brain injury-induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. J Neurosurg 98:867-73
Babu, G Nagesh; Sailor, Kurt A; Beck, Joseph et al. (2003) Ornithine decarboxylase activity in in vivo and in vitro models of cerebral ischemia. Neurochem Res 28:1851-7
Raghavendra Rao, Vemuganti L; Bowen, Kellie K; Dhodda, Vinay K et al. (2002) Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia. J Neurochem 83:1072-86
Adibhatla, Rao Muralikrishna; Hatcher, James F; Sailor, Kurt et al. (2002) Polyamines and central nervous system injury: spermine and spermidine decrease following transient focal cerebral ischemia in spontaneously hypertensive rats. Brain Res 938:81-6
Song, G; Cechvala, C; Resnick, D K et al. (2001) GeneChip analysis after acute spinal cord injury in rat. J Neurochem 79:804-15
Rao, V L; Dogan, A; Bowen, K K et al. (2001) Antisense knockdown of the glial glutamate transporter GLT-1 exacerbates hippocampal neuronal damage following traumatic injury to rat brain. Eur J Neurosci 13:119-28
Rao, V L; Bowen, K K; Rao, A M et al. (2001) Up-regulation of the peripheral-type benzodiazepine receptor expression and [(3)H]PK11195 binding in gerbil hippocampus after transient forebrain ischemia. J Neurosci Res 64:493-500
Nagesh Babu, G; Sailor, K A; Sun, D et al. (2001) Spermidine/spermine N1-acetyl transferase activity in rat brain following transient focal cerebral ischemia and reperfusion. Neurosci Lett 300:17-20
Rao, V L; Dogan, A; Todd, K G et al. (2001) Neuroprotection by memantine, a non-competitive NMDA receptor antagonist after traumatic brain injury in rats. Brain Res 911:96-100
Raghavendra Rao, V L; Dogan, A; Bowen, K K et al. (2001) Ornithine decarboxylase knockdown exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain. J Cereb Blood Flow Metab 21:945-54

Showing the most recent 10 out of 27 publications