Research Interests:Preclinical Studies of Neonatal Hypoxic-Ischemic Brain Injury
The primary focus of our research is on identifying metabolic alterations after hypoxic-ischemic injury that contribute to secondary energy failure and long-term damage to the developing brain. Neonatal hypoxic-ischemic (H/I) brain injury is a major cause of mortality and abnormal neurodevelopmental outcomes that range from mild learning disabilities to mental retardation.
Our studies use the well-characterized Vannucci 7 day-old rat pup model of neonatal hypoxic-ischemic brain injury. Our results reveal a close relationship between the extent of oxidative stress and impaired cerebral energy metabolism in early periods of recovery following H/I. Specific mechanisms of metabolic failure identified by our studies include loss of activity of the enzymes pyruvate dehydrogenase complex (PDHC), α-ketoglutarate dehydrogenase (KGDH), pyruvate carboxylase (PC) and impaired activity of the malate-aspartate shuttle in brain (as evidenced by loss of mitochondrial NAD(H) and a decrease in aralar1, the mitochondrial aspartate-glutamate carrier).
We are using a powerful combination of biochemical methods, in vivo 31P and 1H magnetic resonance spectroscopy (MRS), T2 and diffusion weighted imaging (DWI), diffusion tensor imaging (DTI) and ex vivo 13C-NMR spectroscopy to test mechanistic and translational hypotheses about injury and neuroprotection. Phosphorus (31P) and proton (1H) magnetic resonance spectroscopy (MRS) are used to detect energy failure and changes in clinically relevant metabolites in vivo after neonatal H/I injury. We are combining longitudinal in vivo MRS and imaging (T2, diffusion weighted imaging (DWI), and diffusion tensor imaging (DTI) to determine tissue damage) after H/I, with biochemical studies of enzymatic or metabolite transport deficits to better identify the extent to which the altered mitochondrial enzymes and bioenergetics contribute to in vivo energy failure and long term impairment. We are determining the efficacy of administration of acetyl-L-carnitine (ALCAR) after injury in protecting the brain from acute changes in energy status, and for long term protection of energy metabolism and neurotransmitter synthesis.
Collaborators and co-investigators
Gary Fiskum: Studies on the effect of ALCAR in limiting oxidative stress-induced inactivation of key brain enzymes and proteins, and the effect of both ALCAR and sulforaphane in increasing antioxidant defenses are being done in collaboration with Gary Fiskum in the Department of Anesthesiology.
Margaret M. McCarthy: Alterations in GABAergic neurons and the protective effect of ALCAR and estradiol after hypoxic/ischemic injury are being studied in collaboration with Margaret McCarthy, Ph.D. in the Department of Physiology.
Rao Gullapalli/Center for Translational Imaging: Studies using in vivo MRI and MRS are being done in collaborating with Rao Gullapalli, Ph.D., MBA, Department of Diagnostic Radiology who is the Director of the Core for Translational Research in Imaging at Maryland (C-TRIM) facility. These studies involve determining in vivo alterations in brain energetics and diagnostically relevant metabolites (using 31P and 1H MRS), and structural changes after injury using T2 and DWI and DTI to test mechanistic and translational hypotheses about injury and neuroprotection.
Preclinical Studies of Pediatric Traumatic Brain Injury
Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in children and is characterized by energy failure which is associated with poor outcome. The impaired oxidative cerebral energy metabolism is due in part to impaired activity of the pyruvate dehydrogenase complex (PDHC) in brain which links the glycolytic pathway to oxidative metabolism in brain. Recent studies done in collaboration with Susanna Scafidi, M.D. (division of Pediatric Critical Care) showed that from 5-6 hours after controlled cortical impact TBI injury to 21 day old rats there was impaired oxidative energy metabolism, impaired neurotransmitter synthesis, and impaired metabolism via the pyruvate carboxylase pathway in astrocytes, which is a key pathway in developing brain. In studies done in collaboration with Dr. Courtney Robertson and Pediatric Critical Care Fellow Paula Casey we found that 1H spectra of brain showed early and sustained alterations in cerebral metabolism after traumatic brain injury. This study was the first to determine changes in diagnostically relevant metabolites which are used clinically to assess the structural and metabolic integrity of brain, at 4-24 hr, and 7 days after injury using 1H NMR spectroscopy. The young rat model of controlled cortical impact traumatic brain injury simulates injury to a toddler age child. Study such injury in developing brain is crucial because any injury superimposed on the metabolic demands of the rapidly developing brain can have far reaching consequences and lead to poor developmental outcome.
Ongoing studies done in collaboration with Susanna Scafidi, M.D., Division of Pediatric Critical Care include determining alterations in key brain enzymes and proteins after injury including pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and pyruvate carboxylase. Several novel neuroprotective strategies are being tested at different time points after injury. A variety of spectroscopic, biochemical, immunohistochemical and imaging methods are used to test mechanistic and translational hypotheses about injury and neuroprotection. Cell-specific antibodies are used to determine loss of and/or changes to neurons, astrocytes and myelin after injury to developing brain. The Scafidi lab uses an array of behavioral tests are employed to determine alterations in motor skills and learning and memory including beam walking to assess motor function, Y-maze for assessing hippocampal function, Morris water maze for determining alterations in hippocampal function and learning, Moss wheel to assess learning and motor function, and novel object recognition tests.
Alterations in Glutamate and Glutamine Metabolism in Fragile X Syndrome
Studies using 13C-NMR spectroscopy to determine alterations in glutamate and GABA synthesis and neuronal-astrocytic interactions in Fmr1 knockout mouse model of fragile X syndrome. The effect of inhibiting the metabotropic glutamate receptor mGluR5 on metabolism and glutamate synthesis is also being determined.
Lab Techniques and Equipment:
- Perinatal hypoxic/ischemic brain injury in 6 day old rat brain (Rice-Vannucci model)
- Intrauterine inflammation/infection models (LPS and Ureaplasma)
- Ex vivo 13C-NMR spectroscopy studies of neuronal and glial specific brain metabolism
- 1,6-13C]glucose - neuronal metabolism and neuronal --> and glial trafficking
- [1,2-13C]acetate - astrocytic metabolism and glial --> neuronal trafficking
- 1H NMR of NAA, lactate, choline & creatine
- Pediatric TBI (collaboration with Courtney Robertson, M.D. and Susanna Scafidi, M.D.)
- Studies of neuroprotection in vivo
- MRI, DTI, DWI, SWI and 1H and 31P-MRS using the 7T small animal magnet
- Ultracentrifugation -- isolation of synaptosomes and synaptic and nonsynaptic mitochondria for metabolic studies and enzymes
- Mitochondrial enzymes
- pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, aspartate aminotransferase, glutamate dehydrogenase
- Fmr1 knockout mouse colony (fragile X syndrome)
NIH Program Project Grant 2P01 HD016596-25
FRAXA Research Foundation
(See complete list of publications from NIH Program Project Grant 2P01 HD016596-25)
Search My Publications in Pub Med
McKenna M.C., Tildon J.T., Couto R., Stevenson J.H., Caprio F.C. (1990) The metabolism of malate by cultured rat brain astrocytes. Neurochem. Res. 15, 1211-1220.
Malik P., McKenna M.C. and Tildon J.T. (1992) Regulation of malate dehydrogenases from neonatal, adolescent and mature rat brain. Neurochem. Res. 18, 247-257.
Tildon J.T., McKenna M.C., Stevenson J.H., and Couto R. (1993) Transport of L-lactate by cultured rat brain astrocytes. Neurochem. Res. 18, 177-184.
McKenna M.C., Tildon J.T., Stevenson, J.H. Jr., Boatright R., Huang S. (1993) Differences in the regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes. Dev. Neurosci. 15, 320-329.
McKenna M.C., Tildon J.T., Stevenson J.H. and Hopkins I.B. (1994) Compartmentation of energy substrate metabolism in cortical synaptic terminals from weanling and mature rat brain. Dev. Neurosci. 16, 291-300.
Tildon J.T., McKenna M.C., Stevenson J.H. (1994) Transport of 3-hydroxy-[3-14C]butyrate by cultured rat brain astrocytes. Neurochem. Res. 19:1119-1124.
McKenna M.C., Tildon J.T., Stevenson J.H., Huang X. and Kingwell K.G. (1995) Regulation of mitochondrial and cytosolic malic enzymes from cultured rat brain astrocytes. Neurochem. Res. 20, 1491-1501.
Alves P.M., McKenna M.C. and Sonnewald U. (1995) Lactate metabolism in astrocytes studies by 13C NMR spectroscopy. Neuro Report 6, 2201-2204.
McKenna M.C., Sonnewald U., Huang X., Stevenson J.H. and Zielke H.R. (1996) Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes. J. Neurochem. 66, 386-393.
McKenna M.C., Tildon J.T., Stevenson J.H., and Huang X. (1996) New insights into the compartmentation of glutamate and glutamine metabolism in astrocytes. Dev. Neurosci. 18, 380-390.
McKenna, M.C., Sonnewald, U., Huang, X., Stevenson, J.H., Johnsen, S., and Zielke, H.R. (1998) α-ketoisocaproate (α-KIC) alters the production of both lactate and aspartate from [U-13C]glutamate in astrocytes: A 13C NMR study. J. Neurochem. 70:1001-1008.
McKenna M.C., Tildon J.T., Stevenson J.H., Hopkins I.B., Huang X. and Couto R. (1998) Lactate transport by cortical synaptosomes from adult rat brain: characterization of kinetics and inhibitor specificity. Dev. Neurosci. 20:300-309.
Hanu R., McKenna M.C., O’Neill A., Resneck W.G. and Bloch R.J. Monocarboxylic acid transporters, MCT1 and MCT2, in cortical astrocytes in vitro and in vivo. Am. J. Physiol. 278:C921-C930.
McKenna M.C., Stevenson J.H., Huang X., Tildon J.T., Zielke C.L. and Hopkins I.B. Mitochondrial malic enzyme activity is much higher in mitochondria from cortical synaptic terminals compared with mitochondria from primary cultures of cortical neurons or cerebellar granule cells. Neurochem. Int. 36: 451-459.
McKenna M.C., Stevenson J.H., Huang X., and Hopkins I.B. Differential distribution of the enzymes glutamate dehydrogenase and aspartate aminotransferase in cortical synaptic mitochondria contributes to metabolic compartmentation in cortical synaptic terminals. Neurochem. Int. 37: 229-241.
McKenna, M.C., Hopkins I., Carey A. (2001) Alpha-cyano-4-hydroxycinnamate decreases both glucose and lactate metabolism in neurons and astrocytes: implications for lactate as an energy substrate for neurons. J. Neurosci. Res. 66:747-754.
Sonnewald, U., McKenna, M.C. (equal co-authors) (2002) Metabolic compartmentation in cortical synaptosomes: Influence of glucose and preferential incorporation of endogenous glutamate into GABA. Neurochem. Res. 27:43-50.
McKenna, M.C. (2003) Glutamate metabolism in primary cultures of rat brain astrocytes: Rationale and initial efforts toward developing a compartmental model. Invited chapter for book on Mathematical Modeling in Nutrition and the Health Sciences. (Boston, R., Novotny, J. and Green M., Eds). Advances in Experimental Biology and Medicine 537, 2003, Kluwer Plenum Academic Publishing, New York, pp. 317-341. (Peer Reviewed Book Chapter).
McKenna, M.C. and Sonnewald, U. (equal co-authors) (2005) GABA alters the metabolic fate of [U-13C]glutamate in cultured cortical astrocytes. J. Neurosci. Res. 79: 81-87.
McKenna, M.C., Hopkins, I.B., Lindauer, S.L., Bamford, P. (2006) Aspartate aminotransferase in synaptic and nonsynaptic mitochondria: Differential effect of compounds that influence transient hetero-enzyme complex (metabolon) formation. Neurochemistry International 48:629-636.
McKenna, M.C., Waagepteresen H.S., Schousboe, A, Sonnewald U. (2006) Neuronal and astrocytic shuttle mechanisms for cytosolic-mitochondrial transfer of reducing equivalents: current evidence and pharmacological tools. Biochem Pharmacol 71(4):399-407. Epub 2005 Dec 20.
O’Brien, J., Kla, K.M., Hopkins, I.B., Malecki, E.A., McKenna, M.C. (2006) Kinetic parameters and lactate dehydrogenase isozyme activities support possible lactate utilization by neurons. Neurochemical Res. Epub Sept. 22, 2006; DOI 10.1007/s0064-006-9132-9.
McKenna, M.C., Rolf Gruetter, R., Sonnewald, U., Waagepetersen, H.S. and Schousboe, A.(2006) Energy Metabolism of the Brain. In Basic Neurochemistry, (Siegel, G., Albers, R.W., Brady, S., Price, D.L., eds.), Elsevier, London, pp. 531-557.
Richards, E.M., Fiskum, G., Rosenthal, R.E., Hopkins, I., McKenna, M.C. (2007) Hyperoxic Reperfusion Following Global Ischemia Decreases Hippocampal Energy Metabolism. Stroke 38:1578-1584.
McKenna, M.C. (2007) The glutamate/glutamine cycle is not stoichiometric: fates of glutamate in brain. J. Neurosci. Res. 85;15:3347-3358. Epub Sept 10; DOI 10.1002/jnr.21444.
Fiskum, G., Danilov, C.A., Mehrabian, Z., Bambrick, L.L., Kristian, T., McKenna, M.C., Hopkins, I., Rosenthal, R.E. (2008) Postischemic Oxidative Stress Promotes Mitochondrial Metabolic Failure in Neurons and Astrocytes. Ann. NY Acad. Sci. 1147:129-138.
Casey, P.A., McKenna, M.C., Fiskum, G., Saraswati, M., Robertson, C.L. (2008) Early and sustained alterations in cerebral metabolism after traumatic brain injury in immature rats. J Neurotrauma. 25:603-614. PMID: 18454682
Scafidi, S., O’Brien, J., Hopkins, I., Robertson, C., Fiskum, G., McKenna, M.C. Delayed cerebral oxidative glucose metabolism after traumatic brain injury in young rats. J. Neurochem. 109 (Suppl. 1) 189-197.
Robertson, C.L., Scafidi, S., McKenna, M.C. and Fiskum, G. (2009) Mitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury. Exp. Neurol. 218: 371–380.
Scafidi, S., Fiskum, G., Lindauer, S.L., Bamford, P., Shi, D., Hopkins, I., McKenna, M.C. # (2010) Metabolism of acetyl-L-carnitine for energy and neurotransmitter synthesis in the immature rat brain. Journal of Neurochemistry (in press)
Peer-Reviewed Special Issues of Journals Edited
McKenna, M.C. and Edmond, J. (1998) Energy Metabolism in Brain Function and Neuroprotection. Dev. Neurosci. 20(no 4-5):pp 265-494. S. Karger A.G., Basel.
Schousboe, A. and McKenna, M.C. (2001) Brain Energy Metabolism in Neurotransmission: Function and Dysfunction. Journal of Neuroscience Research 66 (5): pp. 737-1034, Wiley-Liss, New York.
McKenna, M.C. and Schousboe, A. (2005) Brain Energy Metabolism: Mitochondria, Transporters and Neurodegeneration. Journal of Neuroscience Research 79 (January 2005 issue), pp. 737-1034, John Wiley and Sons, New York.
Robertson, C.L. and McKenna, M.C. (2006) Pediatric Traumatic Brain Injury: from Molecular Mechanisms to Clinical Research. Dev. Neurosci. 28(4-5). Karger A.G., Basel.
McKenna, M.C. and Skoff, R. (2007) Special issue in honor of Tony and Celia Campagnoni. Neurochemical Research 32(2), pp. 133-388.
McKenna, M.C. and Schousboe, A. (2007) Integrating Molecular, Cellular and Metabolic Aspects of Neuron-Glial Interaction. Journal of Neuroscience Research 85(15): 5205-3504, John Wiley and Sons, New York.
Schousboe, A. and McKenna, M.C. (2009) Degeneration and Regeneration-The 3rd ISN Special Neurochemistry Conference 8th International Metting on Brain Energy Metabolism. Journal of Neurochemistry 109 (Supplement 1): 1-314. Blackwell, Oxford.
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