Assessment of ischemic damage and neuroprotection in an experimental model of forebrain ischemia

Nurse, Suzanne (1995) Assessment of ischemic damage and neuroprotection in an experimental model of forebrain ischemia. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

In this dissertation, two treatments, intraischemic hypothermia and glutamate receptor blockade, were evaluated for neuroprotective efficacy against global ischemia. Since the standard assessment of ischemic damage using only histological outcome reveals nothing about function, I used multiple outcome measures including behaviour and electrophysiology, as well as a histological evaluation. In order to further increase the strength of this approach, multiple assessments were made in the same animals. -- Intraischemic hypothermia induced by selectively cooling the brain conveyed both long-lasting protection against functional loss as well as cell loss. These findings provide a strong argument for the implementation of hypothermia in cases where the occurrence of an ischemic episode can be predicted before it occurs (e.g. elective cardiac/neuro-surgery). However, most cases of ischemia, or stroke, occur without warning thereby precluding the use of intraischemic hypothermia. -- NBQX, a glutamate receptor antagonist which selectively blocks the AMP A receptor, is reportedly neuroprotective when treatment is delayed several hours postischemia. The same approach developed to evaluate intraischemic hypothermia was ·used to study NBQX. In the course of these studies it was found that NBQX induced a mild, prolonged, hypothermic action. Due to the ability of hypothermia to mitigate ischemic damage and the confounding effects of hypothermia in previous pharmacological studies of ischemia, it became important to determine whether the hypothermia induced by NBQX contributed to its mechanism of action. The results strongly suggest that NBQX conveys neuroprotection through a hypothermic action. These data raise important questions concerning current hypotheses of ischemic cell death, which currently focus primarily on involvement of the AMP A subtype of glutamate receptor. -- Finally, the behavioural changes that follow an ischemic episode were characterized with reference to variation in ischemic severity. Two types of behavioural alterations were noted: (1) an acute increase in activity following ischemia, and (2) a chronic increase in locomotor activity triggered by novel environments after the acute phase recovers. This second phase of increased locomotor activity was previously thought to reflect an impairment in spatial memory. Instead, it may be due to a form of behavioural sensitization not unlike that induced by stimulant drugs such as amphetamine.

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