The relationship of structural ischemic brain damage to neurobehavioural deficit: The effect of postischemic MK-801.

Abstract

Global cerebral ischemia is well known to cause neuronal necrosis in selectively vulnerable sectors of the hippocampus. Since the hippocampus of the rat is involved in spatial navigation, learning, and memory, selective deficits in these abilities may arise from ischemic brain damage. Previous studies have shown (a) a detectable neurobehavioural deficit due to ischemic brain damage limited to half of the CA1 sector of the hippocampus and (b) a reduction of ischemic neuronal necrosis with the noncompetitive N-methyl-D-Aspartate (NMDA) antagonist MK-801. This study was designed to determine the relationship between the improvement in structural brain damage in postischemically treated rats and any improvement in ncurobchavioural performance, using a learning-set water task.Seventeen male Wistar rats received 10.5 min of forebrain ischemia induced by carotid clamping and hypotension. Brain temperature was estimated with probes in the temporal is muscle. Ten of these animals received no therapy (controls), and seven animals received 5 mg/kg MK-801 iv, 20 min postischemia. Six additional rats underwent a sham operation. Postischemic hypothermia was prevented with heating lamps. Four controls and one MK-801 treated animal died. The survivors were then tested on a place learning-set task in a swimming pool paradigm, and quantitative histopathologic analysis of their entire brains was done.The learning-set task revealed defects in spatial navigation, reflected as increased errors and latency in the performance of the untreated control rats. The performance of the MK-801 treated group progressively approached that of sham-operated rats over the course of testing and was significantly better than controls. Importantly, no long-term detrimental effect of MK-801 on the learning-set task performance was seen.Quantitative ncuropathology revealed significantly less damage in the MK-801 treated group in all major brain regions. In the hippocampus, MK-801 treated animals showed hippocampal damage limited to the vulnerable portion of the pyramidal cell band comprising 48.8% of the CAI pyramidal cells, as opposed to 72.4% in untreated controls. Extrahippocampal damage was evident only in untreated control animals. MK-801 totally prevented neuronal necrosis in both the cerebral cortex and striatum and also prevented infarction in the neoconex and thalamus.Three conclusions emerge from the study. First, postischemic MK-801 mitigates structural brain damage in several brain regions in the absence of concomitant hypothermia. Second, neurobehavioural performance appears to be improved by MK-801 when performance trends are examined, but is somewhat less sensitive than quantitated hislopathology due to compounding interanimal variation in performance abilities. Third, neurobehavioural testing can reveal significant differences corresponding to histologic improvement, but only when the treatment gives robust histologic protection against neuronal necrosis.

Neuroprotective Treatment With FK506 Reduces Hippocampal Damage and Prevents Learning and Memory Deficits After Transient Global Ischemia in Rat

“…Our findings agree with the Bachevalier and Meunier study who reviewed the relationship between hippocampal cell loss and cognitive deficits due to brain ischemia (28), also Rod, Kiyota and Milani (29)(30)(31). However findings of Green and Nunn did not show any correlation between these two parameters (1,32).…”

Combination therapy with nimodipine and dizocilpine in a rat model of transient forebrain ischemia.

“…The degree of histological protection was sufficient to be accompanied by improved performance on tasks of learning and memory carried out before histological analysis. 33 Based on the results discussed above, it is possible to reconcile apparently discrepant findings in the literature concerning the effect of MK-801 in global ischemia. It is clear that in temperature-controlled studies obviating hypothermia, MK-801 gives no significant protective effect in global ischemia.…”

“…The results showed that MK-801 did not reduce neuronal necrosis in the septal, densely ischemic CA1 pyramidal cells to a degree reaching statistical significance. 33 However, sections at coronal levels in the temporal hippocampus, incompletely ischemic due to continuing vertebrobasilar supply, did show significant protection. This was enough to significantly reduce overall necrosis at all levels of the hippocampus.…”

“…33 Neurobehavioral testing was done to gain a functional assessment of efficacy in addition to histology. The results showed that MK-801 did not reduce neuronal necrosis in the septal, densely ischemic CA1 pyramidal cells to a degree reaching statistical significance.…”

Protective effect of synaptic inhibition during cerebral ischemia in rats and rabbits.

“…Neurobehavioral performance in the water maze and also the radial arm maze appears to correlate with estimates of neuronal loss in the CA1 layer of the hippocampus. 42 Previously, we demonstrated a similar learning deficit after damage to structures other than the hippocampus, primarily the cortex. 29 It is not clear why extensive cortical damage interferes with visualspatial memory when the hippocampus is spared, although others have obtained similar results using different experimental models.…”