While severe acidosis exacerbates brain injury due to global cerebral ischemia, moderate acidosis appears to promote recovery during reperfusion. This application proposes to test 3 mechanistic hypotheses related to the effects of ischemic and postischemic tissue acidosis and alkalosis on animal survival and neural cell death in a rat model of cardiac arrest and resuscitation. The first hypothesis is that the primary cause of death within the first 6 hr of reperfusion is metabolic and vascular failure as a result of cytotoxic edema initiated by activation of the Na exchanger in the brainstem nuclei that control cardiovascular and respiratory function. The second hypothesis is that death within a few days after resuscitation is metabolic and a result of vascular failure in the brainstem due to vasogenic edema caused by blood-brain barrier leakiness through factors such as VEGF induced by oxidative stress. The third hypothesis is that delayed neuronal death in selectively vulnerable areas such as the hippocampal CA1 region is promoted by acidosis during and immediately following cardiac arrest. The general experimental approach to testing these hypotheses will be to define the regional intracellular pH changes in the brainstem and hippocampus of rats in response to cardiac arrest and resuscitation and to correlate these changes to structural and functional indicators of metabolic stress and energy balance. The project will utilize animals that are either normoglycemic and normocapnic, hyperglycemic and normocapnic, or normoglycemic and hypercapnic. Some animals will also be treated with Na+/H+ transport inhibitors to provide further support that this transporter promotes postischemic intracellular alkalosis and worsens neurological outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037111-03
Application #
6126362
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Jacobs, Tom P
Project Start
1997-12-15
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
3
Fiscal Year
2000
Total Cost
$216,374
Indirect Cost
Name
Case Western Reserve University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Pichiule, Paola; Chavez, Juan C; LaManna, Joseph C (2004) Hypoxic regulation of angiopoietin-2 expression in endothelial cells. J Biol Chem 279:12171-80
Pichiule, Paolo; Agani, Faton; Chavez, Juan C et al. (2003) HIF-1 alpha and VEGF expression after transient global cerebral ischemia. Adv Exp Med Biol 530:611-7
Pichiule, Paola; LaManna, Joseph C (2003) Expression of angiopoietin-1 and -2 in the rat brain during chronic hypoxia and de-adaptation. Adv Exp Med Biol 510:331-5
Chavez, Juan C; LaManna, Joseph C (2003) Hypoxia-inducible factor-1alpha accumulation in the rat brain in response to hypoxia and ischemia is attenuated during aging. Adv Exp Med Biol 510:337-41
Aliev, Gjumrakch; Smith, Mark A; Seyidov, Dilara et al. (2002) The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer's disease. Brain Pathol 12:21-35
Agani, Faton H; Pichiule, Paola; Carlos Chavez, Juan et al. (2002) Inhibitors of mitochondrial complex I attenuate the accumulation of hypoxia-inducible factor-1 during hypoxia in Hep3B cells. Comp Biochem Physiol A Mol Integr Physiol 132:107-9
Chavez, Juan C; LaManna, Joseph C (2002) Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growth factor-1. J Neurosci 22:8922-31
Aliev, G; Smith, M A; Seyidova, D et al. (2002) Increased expression of NOS and ET-1 immunoreactivity in human colorectal metastatic liver tumours is associated with selective depression of constitutive NOS immunoreactivity in vessel endothelium. J Submicrosc Cytol Pathol 34:37-50
Agani, Faton H; Puchowicz, Michelle; Chavez, Juan Carlos et al. (2002) Role of nitric oxide in the regulation of HIF-1alpha expression during hypoxia. Am J Physiol Cell Physiol 283:C178-86
Aliev, Gjumrakch; Seyidova, Dilara; Neal, Maxwell L et al. (2002) Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann N Y Acad Sci 977:45-64

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