Studies in Project III address the hypothesis that insults that disrupt the supply or metabolism of glucose in brain will lead to acute impairment in energy metabolism, neuronal/glial metabolic trafficking and neurotransmitter biosynthesis and may also result in long term damage to developing brain. The neural cell death associated with hypoxia/ischemia, hypoglycemic episodes and some inborn errors may be due in part to prolonged alterations in metabolism that result in ongoing cellular damage even after the initial insult has ceased. Recent clinical studies have found that recurrent hypoglycemic episodes in children lead to mild to severe learning impairment. Retardation or early death is associated with inborn errors that impair the oxidative metabolism of glucose or prevent the use of pyruvate from glucose metabolism in anaplerotic pathways in brain. We will also address the hypothesis that it is crucial for the brain to maintain the proper balance of production and utilization of lactate since this monocarboxylic acid is a substrate for developing brain, possibly for neurons in adult brain. Elevated brain lactate is a prominent feature in many disorders that lead to mental retardation, and is associated with poor neurodevelopmental outcome high-risk infants. Although monocarboxylic acids (ketone bodies and lactate) are key substrates used by developing brain for energy, neurotransmitter and lipid biosynthesis, a continuous supply of glucose is critical for the developing brain. There is also an interesting reciprocal relationship between brain energy status and the synthesis of kynurenic acid, an endogenous neuromodulator at excitatory synapses. Thus, mice lacking a major biosynthetic enzyme of kynurenic acid, KAT II, show impaired glucose and lactate metabolism and increased susceptibility to excitotoxic damage in developing brain. The following specific aims will test these hypotheses and provide valuable new information about alterations in brain metabolism, mitochondrial function and neuronal/glial interactions subsequent to injury in developing brain. 1. Determine the consequences of chronic overproduction of lactate on the disposition of lactate in the brain of KAT II knockout mice; 2. Use labeled substrates to determine metabolism, neuronal/glial trafficking and neurotransmitter synthesis by ex vivo 13C-NMR spectroscopy in hypoglycemic, hypoxic/ischemic and KAT II knockout mouse brain; 3. Determine acute changes in the functional metabolism of brain mitochondria after hypoglycemic or hypoxic/ischemic injury; and 4. Test the ability of the neuroprotective compound acetyI-L-carnitine to ameliorate the metabolic alterations in hypoxic/ischemic brain. The information obtained from these studies, together with other segments of the Program Project, will provide new insights into the mechanisms of damage in the immature brain and will aid in the development of neuroprotective strategies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
2P01HD016596-20A1
Application #
7013467
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
2004-02-17
Project End
2009-01-31
Budget Start
2004-02-17
Budget End
2005-01-31
Support Year
20
Fiscal Year
2004
Total Cost
$297,647
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Jaber, Sausan M; Bordt, Evan A; Bhatt, Niraj M et al. (2018) Sex differences in the mitochondrial bioenergetics of astrocytes but not microglia at a physiologically relevant brain oxygen tension. Neurochem Int 117:82-90
Ferreira, Gustavo C; McKenna, Mary C (2017) L-Carnitine and Acetyl-L-carnitine Roles and Neuroprotection in Developing Brain. Neurochem Res 42:1661-1675
Tang, Shiyu; Xu, Su; Lu, Xin et al. (2016) Neuroprotective Effects of Acetyl-L-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats. Dev Neurosci 38:384-396
Demarest, Tyler G; Schuh, Rosemary A; Waddell, Jaylyn et al. (2016) Sex-dependent mitochondrial respiratory impairment and oxidative stress in a rat model of neonatal hypoxic-ischemic encephalopathy. J Neurochem 137:714-29
Waddell, Jaylyn; Hanscom, Marie; Shalon Edwards, N et al. (2016) Sex differences in cell genesis, hippocampal volume and behavioral outcomes in a rat model of neonatal HI. Exp Neurol 275 Pt 2:285-95
Demarest, Tyler G; McCarthy, Margaret M (2015) Sex differences in mitochondrial (dys)function: Implications for neuroprotection. J Bioenerg Biomembr 47:173-88
McKenna, Mary C; Rae, Caroline D (2015) A new role for ?-ketoglutarate dehydrogenase complex: regulating metabolism through post-translational modification of other enzymes. J Neurochem 134:3-6
Xu, Su; Waddell, Jaylyn; Zhu, Wenjun et al. (2015) In vivo longitudinal proton magnetic resonance spectroscopy on neonatal hypoxic-ischemic rat brain injury: Neuroprotective effects of acetyl-L-carnitine. Magn Reson Med 74:1530-42
Pershing, Michelle L; Bortz, David M; Pocivavsek, Ana et al. (2015) Elevated levels of kynurenic acid during gestation produce neurochemical, morphological, and cognitive deficits in adulthood: implications for schizophrenia. Neuropharmacology 90:33-41
McKenna, Mary C; Scafidi, Susanna; Robertson, Courtney L (2015) Metabolic Alterations in Developing Brain After Injury: Knowns and Unknowns. Neurochem Res 40:2527-43

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