Clinically, stroke is a leading cause of death and disability. Information that elucidates the pathogenesis and leads to effective therapy of this condition would have important socio- economic implications. This study is part of a long-range investigation into the cellular pathophysiology of cerebral ischemia and potentially beneficial treatments for the cerebral insufficiencies of stroke. Cerebral ischemia results in an increase in lactic acid that has been linked to the production of irreversible changes in brain cell structure and function, especially in animals that have ben treated with glucose before the ischemic event. Preliminary studies in this laboratory have shown that pre- or postischemic treatment with dichloroacetate (DCA) significantly reduces the levels of cerebral lactic acid in a stroke model in both fasted and fed rats. If cerebral lactic acid is a major contributor to cellular functional and structural pathophysiology of this condition, treatment with DCA should ameliorate these effects. Therefore, the objectives of this study are: (a) to analyze and correlate elevated lactate and the effects of treatment with DCA on survival, neurological function, distribution of brain metabolites, energy levels, and presence of edema, as well as cell viability, activity, and ultrastructure in a stroke model in the fasted and fed rat; (b) to determine the effects of DCA on pyruvate dehydrogenase (PDH), the enzyme by which DCA is hypothesized to mediate its lactate lowering effect; and, (c) to determine how PDH mediates this effect in a stroke model in the fasted and fed rat. This model combines bilaterial carotid ligation and systemic hypotension to produce partial global ischemia for 10 min that is followed by reperfusion for varying periods of time prior to sacrifice. The following techniques will be used to accomplish the aims of this study: (a) neurological (survival and locomotor testing); (b) physiological (mean arterial blood pressure, electroencephalograph and somatosensory evoked response recordings); (c) biochemical (brain metabolite analysis, energy charge calculation, blood Pa02, PH, and HC03, and serum metabolites); (d) biophysical (tissue specific gravity); and (e) neuropathological (Evans Blue extravasation; enzyme histo- and cytochemistry; and, routine light and electron microscopy using morphometry). The data of this study will contribute to the development of an effective treatment of stroke and a more complete definition of the role of lactic acid in the pathogenesis of irreversible damage caused by in incomplete cerebral ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS025635-03
Application #
3477223
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1990-08-01
Budget End
1991-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Medrano, S; Gruenstein, E; Dimlich, R V (1994) Substance P receptors on human astrocytoma cells are linked to glycogen breakdown. Neurosci Lett 167:14-8
Dimlich, R V; Nielsen, M M (1992) Facilitating postischemic reduction of cerebral lactate in rats. Stroke 23:1145-52;discussion 1152-3
Medrano, S; Gruenstein, E; Dimlich, R V (1992) Histamine stimulates glycogenolysis in human astrocytoma cells by increasing intracellular free calcium. Brain Res 592:202-7
Tomsig, J L; Gruenstein, E; Dimlich, R V (1991) Inhibition of lactate-induced swelling by dichloroacetate in human astrocytoma cells. Brain Res 568:92-100
Keller, J T; Dimlich, R V; Zuccarello, M et al. (1991) Influence of the sympathetic nervous system as well as trigeminal sensory fibres on rat dural mast cells. Cephalalgia 11:215-21
Dimlich, R V; Keller, J T; Strauss, T A et al. (1991) Linear arrays of homogeneous mast cells in the dura mater of the rat. J Neurocytol 20:485-503
Dimlich, R V; Tornheim, P A; Kindel, R M et al. (1990) Effects of a 21-aminosteroid (U-74006F) on cerebral metabolites and edema after severe experimental head trauma. Adv Neurol 52:365-75
Dimlich, R V; Showers, M J; Shipley, M T (1990) Densitometric analysis of cytochrome oxidase in ischemic rat brain. Brain Res 516:181-91
Olson, J E; Mishler, L; Dimlich, R V (1990) Brain water content, brain blood volume, blood chemistry, and pathology in a model of cerebral edema. Ann Emerg Med 19:1113-21
Dimlich, R V; Timerding, B L; Kaplan, J et al. (1989) Effects of sodium dichloroacetate dose. Brain metabolites associated with cerebral ischemia. Ann Emerg Med 18:1172-80

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