Injuries to the CNS caused by ischemia, anoxia, epilepsy, AIDS associated dementia, Huntington's disease, and trauma are thought to be mediated either directly or indirectly by excitotoxicity. Concomitant with increases in total intracellular calcium ([Ca2+]i), glutamate receptor overstimulation produces a triphasic fluctuation in intracellular hydrogen ion concentration, an initial transient acidification followed by a longer alkalinization and eventually a progressive acidification. The progressive acidification has been associated with glutamate-induced neurotoxicity. These changes in intracellular pH (pHi) may act in concordance with [Ca2+]i to promote excitotoxic neurodegenerative changes. The experiments proposed in this application are designed to increase understanding of the normal hydrogen ion regulatory processes in cultured hippocampal neurons and to determine how disruption of these processes and abnormal fluctuations in pHi contribute to neuronal damage from excitotoxic, hypoxic, and related insults. The long term objectives of the research are to understand the sequence of events underlying glutamate- and hypoxia-induced neuronal death by studying activation of membrane receptors and intracellular biochemical pathways.
The specific aims for this project include 1) to test the hypothesis that the slow, progressive acidification observed several hours after glutamate receptor overstimulation directly mediates the ensuing toxicity. 2) To test the hypothesis that normal hippocampal neurons contain a minimum of 3 acid/base regulatory mechanisms, a Na+/H+ antiporter, a Na-dependent HCO3-/Cl- exchanger and a passive HCO3-/Cl- exchanger and do not contain a Na+/HCO3- symporter. 3) To test the hypothesis that of the cellular hydrogen ion regulatory mechanisms, operation of the Na+/H+ antiporter and the Na-dependent HCO3-/Cl-- exchanger are compromised following excitotoxic insult and the passive HCO3-/Cl- exchanger is not. And 4) to test the hypothesis that the Na+- dependent acid/base regulatory mechanisms are compromised following excitotoxic insult due to rundown of the Na gradient.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Neurological Sciences Subcommittee 1 (NLS)
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Brustovetsky, Nickolay; Dubinsky, Janet M; Antonsson, Bruno et al. (2003) Two pathways for tBID-induced cytochrome c release from rat brain mitochondria: BAK- versus BAX-dependence. J Neurochem 84:196-207
Brustovetsky, Nickolay; Brustovetsky, Tatiana; Jemmerson, Ronald et al. (2002) Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J Neurochem 80:207-18
Brustovetsky, N; Brustovetsky, T; Dubinsky, J M (2001) On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem 76:425-34
Araki, E; Forster, C; Dubinsky, J M et al. (2001) Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke 32:2370-5
Lakkaraju, A; Dubinsky, J M; Low, W C et al. (2001) Neurons are protected from excitotoxic death by p53 antisense oligonucleotides delivered in anionic liposomes. J Biol Chem 276:32000-7
Brustovetsky, N; Dubinsky, J M (2000) Limitations of cyclosporin A inhibition of the permeability transition in CNS mitochondria. J Neurosci 20:8229-37
Brustovetsky, N; Dubinsky, J M (2000) Dual responses of CNS mitochondria to elevated calcium. J Neurosci 20:103-13
Dubinsky, J M; Brustovetsky, N; Pinelis, V et al. (1999) The mitochondrial permeability transition: the brain's point of view. Biochem Soc Symp 66:75-84
Brustovetsky, N; Dubinsky, J M (1999) EDTA-induced monovalent fluxes through the Ca2+ uniporter in brain mitochondria. Ann N Y Acad Sci 893:258-60
Dubinsky, J M; Levi, Y (1998) Calcium-induced activation of the mitochondrial permeability transition in hippocampal neurons. J Neurosci Res 53:728-41

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