The objectives of this research proposal are to examine the pathophysiologic and metabolic consequences of bacterial meningitis in a rabbit model. Principal areas of study are changes in cerebral blood flow and cerebrovascular autoregulation, alteration in metabolic processes in the brain including glucose utilization and lactic acid production, and the factors relating to development of intracranial hypertension. These abnormalities are seen in children and adults with bacterial meningitis and are likely to contribute to neurologic sequelae which commonly occur. We will attempt to define the interrelationships between these variables and the etiologic factors responsible for them. The role of microbiologic factors and the host inflammatory response will be valuated to assess their independent contribution to the derangements which accompany meningitis. Studies will be developed in this laboratory, of a well established model of meningitis the rabbit with which we can make simultaneous and repeated measurement of a number of physiologic and biochemical parameters. We will perform sequential determinations of cerebral blood flow, cerebral metabolic rate for oxygen and glucose, cerebral lactic acid production, intracranial pressure, and cerebrospinal fluid white blood cell counts, bacterial titers and concentration of glucose and lactate. Selective manipulation of intracranial pressure, lactic acid, bacterial titers and concentration of bacterial cell wall components, and white blood cell response will allow us to assess their relative contribution to alterations in cerebral perfusion. The proposed studies will define the evolution of pathophysiologic and biochemical changes in bacterial meningitis and the etiologic factors responsible for these changes, and establish the interrelationships between circulatory and metabolic alterations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027310-03
Application #
3413549
Study Section
Neurology A Study Section (NEUA)
Project Start
1989-04-01
Project End
1992-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Tureen, J (1995) Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide. J Clin Invest 95:1086-91
Tauber, M G; Sande, E; Fournier, M A et al. (1993) Fluid administration, brain edema, and cerebrospinal fluid lactate and glucose concentrations in experimental Escherichia coli meningitis. J Infect Dis 168:473-6
Guerra-Romero, L; Tureen, J H; Fournier, M A et al. (1993) Amino acids in cerebrospinal and brain interstitial fluid in experimental pneumococcal meningitis. Pediatr Res 33:510-3
Tauber, M G; Kennedy, S L; Tureen, J H et al. (1992) Experimental pneumococcal meningitis causes central nervous system pathology without inducing the 72-kd heat shock protein. Am J Pathol 141:53-60
Tureen, J H; Tauber, M G; Sande, M A (1992) Effect of hydration status on cerebral blood flow and cerebrospinal fluid lactic acidosis in rabbits with experimental meningitis. J Clin Invest 89:947-53
Guerra-Romero, L; Tauber, M G; Fournier, M A et al. (1992) Lactate and glucose concentrations in brain interstitial fluid, cerebrospinal fluid, and serum during experimental pneumococcal meningitis. J Infect Dis 166:546-50
Tureen, J H; Tauber, M G; Sande, M A (1991) Effect of indomethacin on the pathophysiology of experimental meningitis in rabbits. J Infect Dis 163:647-9
Tureen, J H; Dworkin, R J; Kennedy, S L et al. (1990) Loss of cerebrovascular autoregulation in experimental meningitis in rabbits. J Clin Invest 85:577-81
Heyman, J S; Jiang, Q; Rothman, R B et al. (1989) Modulation of mu-mediated antinociception by delta agonists: characterization with antagonists. Eur J Pharmacol 169:43-52
Heyman, J S; Vaught, J L; Mosberg, H I et al. (1989) Modulation of mu-mediated antinociception by delta agonists in the mouse: selective potentiation of morphine and normorphine by [D-Pen2,D-Pen5]enkephalin. Eur J Pharmacol 165:1-10