Neuroprotective effects of SKF 10,047 in cultured rat cerebellar neurons and in gerbil global brain ischemia (original) (raw)
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Neuroprotective mechanism of (+)SKF 10,047 in vitro and in gerbil global brain ischemia
Stroke, 1992
Background and Purpose: The A'-methyl-D-aspartate receptor is believed to mediate part of the ischemic neuronal damage caused by the excitatory amino acid glutamate. (+)SKF 10,047, the prototypic er-agonist, interacts with the A'-methyl-D-aspartate receptor. Therefore, we studied the neuroprotective effect of (+)SKF 10,047 on cultured rat cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia. Methods: Mechanisms of neuroprotection were studied in vitro by measuring calcium influx into cultured rat cerebellar granule cells loaded with fura 2-AM. In vivo neuroprotection of gerbil CA1 hippocampal neurons was studied in a posttreatment regimen following 5 minutes of bilateral carotid artery occlusion and 7 days of reperfusion. Results: In primary cultured rat cerebellar granule cell neurons, (+)SKF 10,047 in a dose-dependent manner diminished intracellular calcium levels of iV-methyl-D-aspartate-stimuIated neurons by a maximum of 87% (TI=8), with a 50% inhibitory concentration of 0.8 fiM. (+)SKF 10,047 did not prevent subsequent calcium influx stimulated by kainic acid or KC1, nor did it interfere with modulation of the kainate response by quisqualic acid. Neuroprotection of 64% (p=0.006, n = 15) of gerbil CA1 hippocampal neurons was achieved by posttreatment injection followed by minipump infusion. Conclusions: Neuroprotection by (+)SKF 10,047 most likely involves interaction at the A'-methyl-Daspartate receptor. These results suggest that the benzomorphan class of cr-agonists may provide neuroprotection in cerebral ischemia and stroke.
Neuroscience, 1995
While N-methyl-D-aspartate antagonists have been shown to attenuate neuronal damage in focal cerebral ischemia, few studies have examined whether continuous or multiple dose treatment is necessary for maximum efficacy. We studied the effect of a loading dose only or load plus maintenance infusion using several non-competitive N-methyl-D-aspartate antagonists (dextromethorphan, dextrorphan, MK-801) and the levorotatory enantiomer of dextromethorphan (levomethorphan) in a rabbit model of focal cerebral ischemia. Forty-seven anesthetized rabbits underwent occlusion of the left internal carotid, anterior cerebral and middle cerebral arteries for 2 h followed by 4 h of reperfusion. Drugs were administered 10 min after occlusion. Dextromethorphan and dextrorphan protected against ischemic edema only when given as load plus maintenance (29% and 31% reduction, respectively), while both load only and load plus maintenance of MK-801 protected against edema (26% and 31% reduction, respectively). Levomethorphan load plus maintenance also protected against ischemic edema (25% reduction). However, dextromethorphan and dextrorphan both required maintenance infusion to protect against ischemic neuronal damage (24% and 27% reduction in area of ischemic neuronal damage, respectively), while levomethorphan failed to protect against neuronal injury even when given as load plus maintenance. Administration of MK-801 as load plus maintenance reduced ischemic neuronal damage by 23%, but this difference was not quite statistically significant.
Journal of Cerebral Blood Flow & Metabolism, 1993
We investigated the neuroprotective potential of MK-801 (dizocilpine), a noncompetitive N-methyl-D aspartate (NMDA) antagonist, in the setting of three 5-min periods of global cerebral ischemia separated by I-h intervals in halothane-anesthetized rats. Each isch emic insult was produced by bilateral carotid artery oc clusions plus hypotension (50 mm Hg). Brain temperature was maintained at normothermic levels (36.5-37.0°C) throughout the experiment. MK-801 (3 mg/kg) (n = 6) or saline (n = 6) was injected intraperitoneally 45 min fol lowing the end of the first ischemic insult. Following 7-day survival, quantitative neuronal counts of perfusion fixed brains revealed severe ischemic damage in hippo campal CAl area, neocortex, ventrolateral thalamus, and striatum of untreated rats. By contrast, significant pro tection was observed in MK-801-treated rats. In area CAl of the hippocampus, numbers of normal neurons were increased 11-to 14-fold by MK-801 treatment (p < 0.01). The ventrolateral thalamus of MK-801-treated rats It has been well established that repetitive epi sodes of global brain ischemia separated by inter vals of 1 h markedly enhance the extent and inten sity of neuronal injury when compared with equiv alent single periods of ischemia (Mrsulja et aI., 1977; Tomida et aI., 1987; Vass et aI., 1988; Ikeda et aI., 1989; Kato et aI., 1989; Nakano et aI., 1989; Araki et aI., 1990; Hossmann et aI., 1990; Nowak et aI., 1990; Lin et aI., 1992). Glutamate has been pos tulated to play a key role in the pathophysiology of ischemic injury Mel-
The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat
Annals of Neurology, 1988
Excessive activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in the sequence of neurochemical events that results in irreversible neuronal damage in cerebral ischemia. The effects of the NMDA antagonist (+) -5-methyl-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) upon the amount of ischemic brain damage has been assessed quantitatively in the lightly anesthetized rat. Focal cerebral ischemia was produced by the permanent occlusion of one middle cerebral artery (MCA), and the animals were killed 3 hours after the arterial occlusion. MK-801 (0.5 mg/kg) was administered intravenously either 30 minutes prior to MCA occlusion or 30 minutes after the induction of ischemia. Pretreatment with MK-801 reduced the volume of ischemic damage both in the cerebral cortex (by 38% compared with untreated rats with MCA occlusion; p < 0.01) and in the caudate nucleus (by 18% compared with controls; p < 0.05). Treatment with MK-801, initiated 30 minutes after MCA occlusion, reduced the volume of ischemic damage in the cerebral cortex (by 52% compared with controls; p < 0.01). The volume of ischemic damage in the caudate nucleus was minimally influenced by MK-801 treatment initiated after MCA occlusion. The antiischemic effects of MK-801 were readily demonstrable despite the hypotension that MK-801 induced in rats anesthetized with halothane (0.5%), nitrous oxide (70%), and oxygen (30%). The potency of MK-801 in reducing ischemic brain damage, even when administered after the induction of ischemia, highlights the potential use of NMDA receptor antagonists for the treatment of focal cerebral ischemia in humans.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1990
Several laboratories have reported a significant reduction of ischemia-induced injury to hippocampal neurons in rodents treated with competitive and noncompetitive N-methyl-D-aspartate (NMDA) receptor-channel antagonists. This study examined the effects of the noncompetitive antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) in Mongolian gerbils subjected to 5 min of bilateral carotid artery occlusion. In adult female gerbils, single doses of MK-801 injected 1 hr prior to ischemia significantly (p less than 0.01) reduced damage to CA1 hippocampal neurons. However, the drug rendered the postischemic animals comatose and hypothermic for several hours compared with the saline-treated animals. In subsequent experiments, animals pretreated with MK-801 and maintained normothermic during and after forebrain ischemia demonstrated no amelioration of hippocampal damage. Gerbils not treated with MK-801, but kept hypothermic in the postischemic period t...
Brain Research, 1995
Substantiating evidence has raised the possibility that o-ligands may have therapeutic potential as neuroprotective agents in brain ischemia. It has been suggested that the neuroprotective capacity of cr ligands is related primarily to their affinity for the NMDA receptor complex and not to any selective action at the ~ binding site. However, ~ specific ligands, devoid of significant affinity for the NMDA receptor, are also neuroprotective via an inhibition of the ischemic-induced presynaptic release of excitotoxic amino acids. In the present study, we have investigated the potential neuroprotective effect of a comprehensive series of ~r ligands, with either significant (o-/PCP) or negligible (~r) affinity for the PCP site of the NMDA receptor, in order to delineate a selective ~r site-dependent neuroprotective effect. For this aim, we have employed two different neuronal culture toxicity paradigms implicating either postsynaptic-mediated neurotoxicity, (brief exposure of cultures to a low concentration of NMDA or Kainate) or pre-and postsynaptic mechanisms (exposure to hypoxic/hypoglycemic conditions). Only ~r ligands with affinity for the NMDA receptor [(+ ) and (-) cyclazocine, (+) pentazocine, (+) SKF-10047, ifenprodil and haloperidol] were capable of attenuating NMDA-induced toxicity whereas the ~r [(+)BMY-14802, DTG, JO1784, JO1783, and (+)3-PPP] and K-opioid [CI-977, U-50488H] ligands, with very low affinity for the NMDA receptor, were inactive. The rank order of potency, based on the 50% protective concentration (PCs0) value, of o-/PCP ligands against NMDA-mediated neurotoxicity correlates with their affinity for the PCP site of the NMDA receptor, and not with their affinity for the o-site. In addition ~/PCP, o-or K-opioid ligands failed to attenuate kainate-mediated neurotoxicity. On the other hand, ~r/PCP, o-and K-opioid ligands were potent inhibitors of hypoxia/hypoglycemia-induced neurotoxicity, although their neuroprotective potency did not correlate with their affinity for either the or or PCP binding sites. In conclusion, the ability of o-and K-opioid ligands to attenuate hypoxia/hypoglycemia, but not NMDA or kainate-induced toxicity, suggests that these drugs exert their neuroprotective role by a predominantly presynaptic mechanism possibly by inhibiting ischemic-mediated glutamate release.