Acute ischemic stroke is a major cause of disability especially among the elderly and is the third leading cause of death. Reactive nitrogen species (NO and ONOO') are being increasingly implicated in the pathophysiology of cerebral ischemia-reperfusion injury. Since inducible nitric oxide synthase (iNOS) is a high output enzyme and it is active for days when induced, we hypothesized that NO produced by iNOS is an important factor in the pathophysiology of cerebral ischemia-reperfusion injury. We have identified a number of compounds (N-acetylcysteine, lovastatin, mevastatin and sodium phenylacetic acid) which will inhibit the induction of iNOS and proinflammatory cytokines in brain cells in culture. The proposed studies will test the therapeutic potential of these drugs against cerebral ischemia-reperfusion injury. The first and second specific aims are designed to investigate whether N-acetylcysteine, alpha-lipoic acid and/or lovastatin will block/down regulated the induction of proinflammatory cytokines and iNOS in brain exposed to ischemia/reperfusion injury. The third specific aims is designed to investigate whether N-acetylcysteine or lipoic acid and/or lovastatin will block/down regulate the induction of delayed cell loss by apoptosis in brain exposed to ischemia/reperfusion injury. From these studies we will seek to answer the following questions: 1) Does treatment with the drugs prevent the neuronal injury given prior to the onset of ischemia? 2) Does treatment with the drugs prevent the neuronal injury by altering the course of the disease when given after the ischemic insult. These are relatively nontoxic compounds and are presently being prescribed for human consumption in other diseases. Therefore, demonstration of beneficial effects of these drugs in an animal model of cerebral ischemia-reperfusion injury will help identify the ideal candidates for subsequent use in clinical trials involving cerebral ischemia and stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS040144-01
Application #
6128294
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (03))
Program Officer
Behar, Toby
Project Start
2000-04-15
Project End
2004-03-31
Budget Start
2000-04-15
Budget End
2001-03-31
Support Year
1
Fiscal Year
2000
Total Cost
$324,829
Indirect Cost
Name
Arizona Institute for Bio-Medical Research
Department
Type
DUNS #
City
Scottsdale
State
AZ
Country
United States
Zip Code
85260
Paintlia, Ajaib S; Paintlia, Manjeet K; Singh, Inderjit et al. (2009) Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis. Glia 57:182-93
Paintlia, Ajaib S; Paintlia, Manjeet K; Singh, Inderjit et al. (2008) Combined medication of lovastatin with rolipram suppresses severity of experimental autoimmune encephalomyelitis. Exp Neurol 214:168-80
Lee, Jin-Koo; Won, Je-Seong; Singh, Avtar K et al. (2008) Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death. Neurosci Lett 440:260-4
Khan, Mushfiquddin; Elango, Chinnasamy; Ansari, Mubeen A et al. (2007) Caffeic acid phenethyl ester reduces neurovascular inflammation and protects rat brain following transient focal cerebral ischemia. J Neurochem 102:365-77
Prasad, Ratna; Giri, Shailendra; Nath, Narender et al. (2007) GSNO attenuates EAE disease by S-nitrosylation-mediated modulation of endothelial-monocyte interactions. Glia 55:65-77
Paintlia, Ajaib S; Paintlia, Manjeet K; Singh, Inderjit et al. (2006) Immunomodulatory effect of combination therapy with lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside alleviates neurodegeneration in experimental autoimmune encephalomyelitis. Am J Pathol 169:1012-25
Prasad, Ratna; Giri, Shailendra; Nath, Narender et al. (2006) 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside attenuates experimental autoimmune encephalomyelitis via modulation of endothelial-monocyte interaction. J Neurosci Res 84:614-25
Nath, Narender; Prasad, Ratna; Giri, Shailendra et al. (2006) T-bet is essential for the progression of experimental autoimmune encephalomyelitis. Immunology 118:384-91
Jatana, Manu; Singh, Inderjit; Singh, Avtar K et al. (2006) Combination of systemic hypothermia and N-acetylcysteine attenuates hypoxic-ischemic brain injury in neonatal rats. Pediatr Res 59:684-9
Rattan, R; Giri, S; Singh, A K et al. (2006) Rho/ROCK pathway as a target of tumor therapy. J Neurosci Res 83:243-55

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