Effects of postischemic hypothermia, postischemic hyperthermia, MK-801 (Dizocilpine) and PBN (N-tert-Butyl-alpha-phenylnitrone) on behavioral and histopathological deficits associated with transient global ischemia in rats

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)



First Committee Member

Edward J. Green - Committee Chair


After stroke, and several other injuries to the central nervous system (CNS), there is a core of tissue which is irreversibly damaged and undergoes neuronal cell death. This damage leads to neurologic deficits, some of which recover significantly over time. There is, also, a marginally affected region (the "penumbral" region) which remains vulnerable for the first few hours, days, or even weeks following the infarct. Excitotoxicity, temperature increases, and the release of oxygen-derived free radicals, are some of the mechanisms which have been implicated in this "penumbral" expansion and much research has concentrated on the development of therapeutic interventions which might target this delayed neuronal death. In a model of transient forebrain ischemia, intraischemic hypothermia has been shown to reduce chronically the consequences of the insult, while short periods of postischemic hypothermia have failed to protect certain brain areas from neuronal death. This suggests the involvement of a delayed or secondary injury mechanism. Recent studies in this laboratory have found partial histopathological protection after transient forebrain ischemia, when followed by immediate postischemic hypothermia in combination with delayed treatment with the non-competitive N-methyl-D-aspartate antagonist MK-801 (dizocilpine). Preliminary data has also shown reduced histopathology after transient forebrain ischemia, following the administration of the spin trapping agent N-tert-Butyl-alpha-phenylnitrone (PBN). The present studies were designed to determine the individual and combined effects of immediate postischemic hypothermia, delayed postischemic hyperthermia, MK-801 administration and PBN administration with respect to histopathology and/or behavior at acute and chronic time points following transient forebrain ischemia in rats. A combination of postischemic hypothermia and delayed MK-801 injections provided partial protection from ischemic-associated hyperactivity in the open field, and robust protection from spatial navigational deficits in the water maze. Evidence for significant protective effects of MK-801 or hypothermia alone was observed in the water maze, during the final trial blocks each day. Likewise, postischemic hypothermia and delayed PBN injections provided partial protection from hippocampal CA1 cell loss. Evidence for significant protective effects of the combination of hypothermia and PBN were observed during aquisition training in the water maze. Furthermore, only animals in the normothermic ischemia group differed significantly from shams in the amount of time spent in the previous platform location quadrant during the probe trial. These results support the notion that these treatments have neuroprotective effects at chronic survival intervals, and indicate that the therapeutic window for attenuating ischemic damage is considerably longer than was previously thought.


Biology, Neuroscience; Psychology, Psychobiology; Health Sciences, Medicine and Surgery; Psychology, Physiological

Link to Full Text


Link to Full Text