Pathologic alterations in mitochondrial populations following experimental brain injury / Jonathan Lifshitz.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Lifshitz, Jonathan.

Contributor:

McIntosh, Tracy Kahl, 1953- advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Neurosciences.

Academic Dissertations as Topic.

Medical Subjects:

Neurosciences.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Physical Description:

xiii, 184 pages : illustrations ; 29 cm

Production:

2002.

Summary:

The enduring cognitive deficits and histopathology associated with traumatic brain injury (TBI) may arise from acute damage to the mitochondrial populations in vulnerable brain regions, which initiates the metabolic dysfunction observed in clinical and experimental TBI. The aim of this thesis was to determine the extent of damage to the mitochondrial population isolated from the parieto-temporal cortex and hippocampus 3 hours and 24 hours following fluid percussion brain injury in the rat. Significantly less mitochondrial protein was isolated from the injured compared to the uninjured parieto-temporal cortex, while comparable protein yields were obtained from the hippocampus. Respiratory function was unaffected by TBI, despite significantly greater percentages of ultrastructural morphological damage in isolated mitochondrial populations from injured than uninjured brain. In light of the decreased protein yields, the 40--60% reductions in tissue ATP concentrations in injured brain suggest the in vivo elimination of mitochondria. Furthermore, mitochondrial populations may be hypersensitive to calcium following injury and burst in response to calcium exposure, as inferred from the reduced calcium-induced swelling rates, ballooned morphologies observed by electron microscopy, shifts in mean mitochondrial sizes, and redistributed population compositions in comparison to populations from uninjured brain. After injury, Cyclosporin A (CsA) can inhibit calcium-induced swelling by preventing the formation of the mitochondrial permeability transition (MPT) pore, suggesting that conformational changes to a pathological high conductance MPT pore state have not occurred in response to TBI. Furthermore, oxidation or homoplasmic deletion of the mitochondrial genome was not observed in conjunction with the alterations in morphology and calcium-sensitivity, as the post-traumatic increases in free radicals and calcium may suggest. Thus, in vivo TBI may result in the damage and elimination of mitochondria from the selectively vulnerable parieto-temporal cortex and hippocampus, with the remaining population retaining sensitivity to calcium and CsA. With a considerable understanding of post-injury mitochondrial populations, therapeutic interventions targeted to the mitochondria may delay or prevent secondary cascades that lead to long-term disability.

Notes:

Supervisor: Tracy Kahl McIntosh.

Thesis (Ph.D. in Neuroscience) -- University of Pennsylvania, 2002.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3054972.

OCLC:

244972763