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Targeting the purine salvage pathway in in vitro models of cerebral ischemia
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Zur Nedden, Stephanie (2011) Targeting the purine salvage pathway in in vitro models of cerebral ischemia. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2565790~S1
Abstract
An interruption of the blood supply to the brain, as occurs during ischemic stroke,
results in a rapid decline of ATP levels and a subsequent loss of neuronal function
and viability. Under physiological conditions the brain reuses ATP degradation
metabolites, such as hypoxanthine, via the purine salvage pathway, to restore its
ATP pool. However, the massive degradation of ATP during ischemia results in the
accumulation and loss of diffusible purine metabolites and thereby leads to a
reduction in the post-ischemic ATP pool size, leaving the brain more vulnerable to
secondary ischemic insults (recurrent strokes) and less able to deploy reparative
mechanisms. The aim of this study was to improve the recovery of post-ischemic
ATP levels by enhancing the purine salvage pathway, with substances that are
already known to be tolerated in humans.
Using acute hippocampal rat brain slices, I found that 1 mM Ribose (Rib) and 50 μM
Adenine (Ade), two main metabolites of the purine salvage pathway, significantly
increased the tissue ATP levels under basal conditions. Rib/Ade pre-treatment results
in accelerated decline of synaptic transmission after onset of oxygen/glucose
deprivation (OGD), due to increased adenosine release. However, this intervention
does not delay the onset of anoxic depolarisation, or improve the recovery of
synaptic transmission after prolonged ischemic periods. Pre-treatment of brain slices
with 1 mM creatine, which increases phosphocreatine levels and thereby buffers the
rapid decline of ATP levels upon energy shortage, significantly delays the onset of
AD and helps to improve the recovery of synaptic transmission. By using cultured
cerebellar granule cells, for more protracted studies on cell viability after OGD, I
show that addition of Rib/Ade after ischemia helps to improves cell viability.
Therefore my results suggest that both, delaying the decline of ATP upon onset of
OGD (pre-treatment with creatine), or enhancing the post-ischemic recovery of ATP
(post-treatment with Rib/Ade) are useful strategies to improve cell survival and
function after in vitro ischemia.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology | ||||
Library of Congress Subject Headings (LCSH): | Adenosine triphosphate, Cerebral ischemia, Ribose, Adenine, Creatine | ||||
Official Date: | June 2011 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | School of Life Sciences | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Frenguelli, Bruno G. ; Doney, Alexander S. | ||||
Sponsors: | Research into Ageing (Charitable trust) | ||||
Extent: | xxii, 268, [21] leaves : ill., charts | ||||
Language: | eng |
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