Phencyclidine reduces postischemic neuronal necrosis in rat hippocampus without changing blood flow

Sauer, Dirk; Nuglisch, Jörg; Rossberg, C; Mennel, H. D.; Beck, Thomas; Bielenberg, Gerhard Wilhelm; Krieglstein, Josef

doi:10.1016/0304-3940(88)90701-x

Cited by 41 publications

(29 citation statements)

References 19 publications

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“…More recent studies from the same laboratory, using only 10 min of ischemia in rats, revealed a 2 1% reduction of CA 1 damage in the APH versus vehicle-treated hippocampi (Swan et al, 1988). Other studies in the rat have also noted protection against transient forebrain ischemia with the noncompetitive NMDA antagonists, MK-801 (Gill et al, 1987b;Church et al, 1988;Rod and Auer, 1989;Swan and Meldrnm, 1990), or phencyclidine (Sauer et al, 1988).…”

Section: Discussionmentioning

confidence: 97%

The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats

1991

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The neuroprotective effects of dizocilipine maleate (MK-801), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor/channel, were tested in the 4-vessel occlusion rat model of forebrain ischemia. Adult Wistar rats, treated intraperitoneally with MK-801 or saline using several different treatment paradigms were subjected to 5 (n = 208) or 15 (n = 62) min of severe, transient forebrain ischemia. In saline-treated animals, 15 min of ischemia (n = 13) produced extensive and consistent loss of pyramidal neurons in the CA1 zone of hippocampus. The degree and distribution of cell loss were not reduced by single dose preischemic administration of MK-801 at 1 (n = 7), 2.5 (n = 4), or 5 mg/kg (n = 8). In other animals subjected to 15 min of forebrain ischemia, multiple doses of MK-801 (5, 2.5, and 2.5 mg/kg) given immediately and at approximately 8 and 20 hr after cerebral reperfusion (n = 5) did not alter CA1 injury compared to saline-treated controls (n = 5). Five minutes of forebrain ischemia in saline-treated animals, (n = 82) resulted in significantly fewer (p less than 0.001) dead CA1 pyramidal cells and a greater variance compared to animals subjected to 15 min of ischemia. Power analysis of the preliminary saline-treated animals subjected to 5 min of ischemia (n = 22) indicated that 60 animals per group were necessary to detect a 15% difference between MK-801 and vehicle-treated groups. Multidose treatment with MK-801 (1 mg/kg) given 1 hr prior to 5 min of ischemia (n = 60) and again at approximately 8 and 16 hr after recirculation failed to attenuate hippocampal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 97%

The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats

1991

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“…Thus it may be possible that the improvement of cerebral blood flow in this period of reperfusion can ameliorate the histological consequences of cerebral ischemia. On the other hand, it was reported that some calcium and NMDA-receptor-anta gonists exert a cerebroprotective effect on hip pocampal neurons without changing the post ischemic blood flow (12)(13)(14). Taking these data into consideration, it is concluded that the amelioration of hypoperfusion by vin pocetine alone cannot explain its neuroprotec tive effect.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it was demonstrable that N-methyl-D-aspartate-receptor-antago nists (NMDA-antagonists) or calcium-antago nists were able to protect hippocampal neu rons against ischemic damage (9 12). These neuroprotectants have been suggested to act directly on the cerebral parenchyma (12)(13)(14). Vinpocetine, a derivative of vincamine, also revealed protective activities in several models of hypoxia, anoxia and cerebral ischemia (15), but, to our knowledge, no information is available about the mechanism by which this drug is acting.…”

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confidence: 99%

Protective Effect of Vinpocetine against Brain Damage Caused by Ischemia.

Rischke

Krieglstein

1991

Jpn.J.Pharmacol

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ABSTRACT-The effects of vinpocetine against hippocampal neuronal damage and on local cerebral blood flow (LCBF) were examined in a rat model of forebrain ischemia (10-min occlusion of the carotid arteries and hypotension). Histological evaluation of neuronal loss in the hippocampus was performed 7 days after ischemia . LCBF was measured before ischemia as well as after 2 min and 1 hr of recirculation . Vinpocetine (10 mg/kg) administered pre or post-ischemically reduced the hippocampal neuronal necrosis, while pre-ischemic administration of 2 or 20 mg/kg vinpocetine was ineffec tive. Since vinpocetine increased the LCBF after 1 hr of recirculation, it cannot be ex cluded that blood flow improvements contribute to its neuroprotective activity . On the other hand, there is no clear evidence that an elevation of post-ischemic hypoperfu sion could protect neurons against ischemic damage. It is, therefore, suggested that vinpocetine acts directly on brain cells.

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“…The prevailing view is that the neuroprotective properties of NMDA antagonists are not directly linked to improvements in cerebral tissue perfusion (Sauer et al, 1988;Park et al, 1989), although this view has not gone unchallenged (Buchan et al, 1989). However, the cerebral circulatory and met abolic effects of NMDA antagonists in anesthetized animals appear to differ from those in conscious animals Nehls et al, 1990), and the anesthetic de pendence of these responses will complicate the elucidation of their contribution, if any, to im proved outcome after cerebral ischemia.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent investigations on the role of the NMDA J Cereb Blood Flow Metab, Vol. 10, No.5, 1990 receptor in the genesis of neuronal damage have been dominated by studies with brain-penetrating noncompetitive NMDA blockers, either highly po tent and selective antagonists such as MK-801 or less potent and selective agents such as phencycli dine, TCP, and dextrophan (Gotti et al, 1988;Ozyurt et al, 1988;Park et al, 1988a,b;Sauer et al, 1988;Steinberg et al, 1988). Investigations of the antiischemic effects of systemic administration of selective, competitive NMDA antagonists in re liable animal models are more limited.…”

Section: Discussionmentioning

confidence: 99%

Focal Cerebral Ischemia in the Cat: Pretreatment with a Competitive NMDA Receptor Antagonist, D-CPP-ene

Bullock

Graham

Chen

et al. 1990

J Cereb Blood Flow Metab

106

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Summary:The effects of the competitive N methyl-o-aspartate (NMD A) receptor antagonist 0-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (o-CPP-ene; SDZ EAA 494) upon ischemic brain damage have been examined in anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of the middle cerebral artery (MCA) and the animals were killed 6 h later. The amount of early ischemic brain dam age was assessed in coronal sections at 16 predetermined stereotaxic planes. Pretreatment with o-CPP-ene (15 mg/ kg i. v. followed by continuous infusion at 0.17 mg/kg/min Excessive activation of glutamate receptors ap pears to be a crucial factor in the sequence of cel lular events leading to irreversible ischemic damage to neurons (Meldrum, 1985;Rothman and Olney, 1986). There is now considerable evidence that treatment with glutamate receptor antagonists, par ticularly antagonists of the N-methyl-D-aspartate (NMDA) receptor subtype, can reduce ischemic

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Phencyclidine reduces postischemic neuronal necrosis in rat hippocampus without changing blood flow

Cited by 41 publications

References 19 publications

The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats

The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats

Protective Effect of Vinpocetine against Brain Damage Caused by Ischemia.

Focal Cerebral Ischemia in the Cat: Pretreatment with a Competitive NMDA Receptor Antagonist, D-CPP-ene

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