# Project II- Impact of Hypoxia-Ischemia and/or inflammation on Metabolism in Cerebellum

> **NIH NIH P01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $256,470

## Abstract

Neonatal hypoxia-ischemia (H/I) leads to rapid energy failure in cortical, subcortical and hippocampal regions
due to lack of oxygen and glucose delivery to brain. This is followed by a transient normalization during
reperfusion and a later secondary energy failure (~2-6 hours after H/I) that ultimately leads to brain injury, and
poor neurodevelopmental outcome. Inflammation occurring prior to H/I can exacerbate injury. Acute alterations
in metabolism and prolonged metabolic dysregulation after neonatal H/I leave the brain vulnerable and unable
to support processes essential for normal development. We will use a well-characterized model of perinatal H/I
at term (postnatal (PN) day 10 rat pup) with and without prior inflammation. The effects of H/I on cerebellum
have not been carefully explored even though the rapidly developing cerebellum is particularly vulnerable to
inflammation and perinatal injury. We will combine high field 1H-NMR and 13C-NMR spectroscopy of energy
metabolism and neurotransmitter synthesis with matrix-assisted laser desorption/ionization-mass spectrometry
imaging (MALDI-MSI) determination of metabolites, lipids, proteins in specific layers of the cerebellum. Our
studies will be the first determination of alterations in metabolism via astrocyte and neuron specific pathways
and synthesis of glutamate and GABA in cerebellum after H/I. Molecular and metabolic alterations and long-
term functional outcomes will determine the therapeutic potential of hypothermia and drug therapy. We
hypothesize that neonatal H/I leads to energy failure in the cerebellum that contributes to impaired function of
brain cells including acute and long-term alterations in energy metabolism and neurotransmitter synthesis. We
hypothesize that the combined effect of inflammation and H/I exacerbates cerebellar damage and dysregulated
metabolism in male and female brain. Our Specific Aims test these hypotheses: 1. Determine the effect of H/I
at PN10 with and without prior inflammation on energy metabolism in cerebellum of male and female rat pups.
2. Determine the alterations in neurotransmitters, metabolites, lipids and proteins in Purkinje, molecular and
granule cell layers, deep nuclei and white matter of the cerebellum of male and female pups after H/I with and
without prior inflammation. 3. Determine the protective effect of hypothermia, choline and ceftriaxone alone,
and these compounds in combination with hypothermia against changes in neuronal and glial metabolism and
specific molecular changes in the Purkinje, molecular and granule cell layers, deep nuclei and myelin. Novel,
clinically relevant information about the timing and targets of injury and alterations in neuron and astrocyte
specific metabolic pathways in brain and alterations of metabolites, nucleotides, membrane and signaling
lipids, and proteins in cerebellar layers and deep nuclei will be obtained using the unique combination of 1H-
NMR and 13C-NMR in conjunction with MALDI-MSI and LC/M...

## Key facts

- **NIH application ID:** 9979922
- **Project number:** 5P01HD085928-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** MARY C MCKENNA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $256,470
- **Award type:** 5
- **Project period:** 2016-08-17 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979922

## Citation

> US National Institutes of Health, RePORTER application 9979922, Project II- Impact of Hypoxia-Ischemia and/or inflammation on Metabolism in Cerebellum (5P01HD085928-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979922. Licensed CC0.

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