Approximately 15,000 cases of bacterial meningitis occur each year in the United States. Meningitis in newborns has a particularly poor prognosis with mortality rates up to 35% for cases caused by group B streptococci (GBS), a major pathogen of neonatal meningitis. Only 50% of survivors of GBS meningitis are neurologically intact, while 21% have severe neurologic sequelae, including global mental retardation, cerebral palsy, and uncontrolled seizure disorder's. The goal of our research is to identify the mechanisms that lead to brain injury in neonatal meningitis in order to develop new therapies that protect the brain. The hypotheses to be tested in the present grant are (1) meningitis leads to global and focal Cerebral blood flow changes; (2) cerebral blood flow is modulated by the interplay of vasodilative and vasoconstrictive mediators; (3) ischemia resulting from cerebral hypoperfusion is a major factor leading to brain damage; and (4) hallmarks of parenchymal brain damage include the release of excitatory amino acids and activation of glial cells (as evidenced by the expression, of cytokines). These hypotheses will be tested in an infant rat model of neonatal meningitis that closely mimics the human disease and in primary cultures of neurons, astrocytes, and microglia. The project has five specific aims: 1. To analyze cerebral blood flow in a rat model of GBS neonatal meningitis and to correlated blood flow changes with the occurrence of tissue hypoxia and the development of neuronal injury. 2. To identify molecular mediators involved in the modulation of cerebral blood flow in the rat model of GBS neonatal meningitis. Using specific inhibitors/agonists, we will focus on the role of nitric oxide as potentially beneficial vasodilator and on endothelin as potentially harmful vasoconstrictor. 3. To examine the contribution of excitatory amino acids (EAA)to neuronal injury in the infant rat model of GBS meningitis by determining whether animals treated with different EAA antagonists have reduced brain injury compared to control animals. 4. To characterize glial cell activation and the expression of selected cytokines (IL-1beta, TNF-alpha, IL-6, TGF-beta) in the GBS meningitis rat model. We will also examine the contribution of cytokines to the development of brain injury in the model: 5. To analyze in primary cultures in vitro which of the factors that play a role in the pathophysiology of meningitis lead to cytokine expression in glial cells, either by direct stimulation of glia or through thee effect on neurons. We will also examine whether the cytokines induced in glial cells have a beneficial or harmful effect on neuronal injury caused by EAA and ischemic conditions.
Showing the most recent 10 out of 93 publications
