Ischemic CA-1 pyramidal cell loss is prevented by preischemic colchicine destruction of dentate gyrus granule cells

Ff, Johansen; Mb, Jørgensen; Nh, Diemer

doi:10.1016/0006-8993(86)90878-4

Cited by 121 publications

(28 citation statements)

References 14 publications

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“…Since the major excitatory input to the hippocampus is from the entorhinal cortex, it can be assumed that ritanserin exerts its neuroprotective effects by depression of the entorhinal output. This hypothesis is supported by studies demonstrating that both lesions of the entorhinal afferent 46 -47 and destruction of the entorhinal cortex 48 protect CA1 pyramidal neurons from ischemic degeneration. Therefore, 5-HT 2 antagonists may protect by depressing CA1 neuronal hyperexcitation by inhibiting the action of neurons in the dentate gyrus and/or entorhinal cortex.…”

supporting

confidence: 68%

Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats.

Globus

Wester

Busto

et al. 1992

Stroke

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Background and Purpose: Serotonin, via 5-HT 2 receptors, exerts an excitatory effect on CA1 neurons and may play a role in ischemia-induced excitotoxic damage. To evaluate the role of serotonin in ischemia, both neurochemical and histopathological studies were performed.Methods: Neurochemical studies included rats that were subjected to 12.5 or 20 minutes of normothermic ischemia by two-vessel occlusion plus hypotension, and extracellular serotonin levels were measured in the hippocampus (12.5 minutes' ischemia, n=5) or striatum (20 minutes' ischemia, n = 13) by microdialysis. In the histopathological study the effect of 8 mg/kg ritanserin, a 5-HT 2 antagonist, administered continuously from 30 minutes prior to ischemia until 1 hour of recirculation was evaluated in five rats subjected to 10 minutes of ischemia. After 3 days, the numbers of normal-appearing neurons in the CA1 subregions were counted.Results: Ischemia of 12.5 minutes' duration induced a fourfold increase in serotonin in the hippocampus (mean±SEM baseline, 1.86±0.25 pmol/ml perfusate; during ischemia, 8.14±0.89 pmol/ml; p<0.05 by analysis of variance). Twenty minutes of ischemia induced a 25-fold increase in serotonin in the dorsolateral striatum (baseline, 0.98±0.15 pmol/ml; ischemia, 24.4±5.93 pmol/ml; p<0.001). The histopathological study demonstrated severe ischemic damage in all CA1 subregions of nontreated animals (medial, 34±16 normal-appearing neurons, middle, 52.2±22.9 neurons; lateral, 56.6+21.8 neurons). Treatment with ritanserin significantly attenuated ischemic damage (medial, 117.6±6.5 neurons; middle, 131.4±4.9 neurons; lateral, 130±7.5 neurons; p<0.01 different from nontreated).Conclusions: Taken together, these results suggest that serotonin plays a detrimental role, mediated by 5-HT, receptors, in the development of ischemic damage. (Stroke 1992(Stroke ,23:1595(Stroke -1601 KEY WORDS • cerebral ischemia • ritanserin • serotonin • rats

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supporting

confidence: 68%

Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats.

Globus

Wester

Busto

et al. 1992

Stroke

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“…A number of observations are consistent with the suggestion that increased excitatory activity in spe cific neuronal pathways may play a significant role in postischemic neuronal injury (Suzuki et al, 1983;Benveniste et al, 1984;Wieloch et al, 1985;Roth man and Olney, 1986;Johansen et al, 1986;J�rgensen et al, 1987;Chang et al, 1989). The an ticonvulsant, MK-801, is a potent noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype (Wong et al, 1986) with demonstrated protective effects against glutamate toxicity and hypoxic/ischemic injury in vitro (Gold berg et al, 1987;Hahn et al, 1988).…”

supporting

confidence: 66%

Localization of 70 kDa Stress Protein mRNA Induction in Gerbil Brain after Ischemia

Nowak

1991

J Cereb Blood Flow Metab

198

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Induction of mRNA encoding the 70 kDa stress/heat shock protein, hsp70, was evaluated in postischemic gerbil brain by in situ hybridization using an oligonucleotide probe selective for stress-inducible members of this gene family. Expression of hsp70 sequences was most pronounced in hippocampal CA1 neurons that fail to accumulate immunoreactive hsp70 protein, and that are selectively lost following ischemia. Hybridizable RNA continued to be expressed in CA1 through at least 48 h, essentially until the onset of cell death in this model. In contrast, dentate granule cells and CA3 neurons destined to survive the insult showed transient induction of hsp70 mRNA during the first 24 h of recirculation that disappeared prior to the detection of maximal hsp70 immunoreactivity in these cell populations. Pre treatment with a single injection of MK-801 (10 mg/kg) considerably attenuated the induction of hsp70 mRNA in hippocampus at 6 h of recirculation, an effect apparently mediated by persistent drug-induced hypothermia. The drug did not prevent the later, selective appearance of hsp70 hybridization in CA1 neurons at 24 h, nor did it protect against the subsequent loss of these cells. These results demonstrate a prolonged postischemic stress response at the transcriptional level in vulnerable hippocampal neurons, and suggest its utility as a marker for neuronal pathophysiology associated with mechanisms mediating delayed neuronal death.

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“…This may seem surprising, as pre vious lesion studies indicate that deafferentation of hippocampal neurons may alleviate ischemic cell death (Wieloch et al, 1985;Johansen et al, 1986;J�rgensen et al, 1987;Benveniste et al, 1989;Kaplan et al, 1989;Buchan and Pulsinelli, 1990). It should be noted in this regard that the average level of Glu-LI in the terminals predominantly reflects the size of the vesicular pool (Ji et al, 1991).…”

Section: Redistribution Of Glutamatementioning

confidence: 99%

Redistribution of Glutamate and Glutamine in Slices of Human Neocortex Exposed to Combined Hypoxia and Glucose Deprivation in vitro

Aas

Berg-Johnsen

Hegstad

et al. 1993

J Cereb Blood Flow Metab

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Summary: This study was undertaken to elucidate the roles of neurons and glial cells in the handling of gluta mate and glutamine, a glutamate precursor, during cere bral ischemia. Slices (400--6 00 fLm) from human neocortex obtained during surgery for epilepsy or brain tumors were incubated in artificial cerebrospinal fluid and subjected to 30 min of combined hypoxia and glucose deprivation (an in vitro model of brain ischemia). These slices, and con trol slices that had not been subjected to "ischemic" con ditions, were then fixed and embedded. Ultrathin sec tions were processed according to a postembedding im munocytochemical method with polyclonal antibodies raised against glutamate or glutamine, followed by colloi dal gold-labeled secondary antibodies. The gold particle densities over various tissue profiles were calculated from electron micrographs using a specially designed computer program. Combined hypoxia and glucose dep rivation caused a reduced glutamate immunolabeling in neuronal somata, while that of glial processes increased. Following 1 h of recovery, the glutamate labeling of neu ronal somata declined further to very low values, com pared to control slices. The glutamate labeling of glial cells returned to normal levels following recovery. InThe pathogenesis of ischemic brain damage is not fully understood, and a number of neurotoxic sub stances has been implicated (Krause et aI. , 1988; Siesjo, 1988;Ginsberg, 1990; Siesjo et aI. , 1990 503axon terminals, no consistent change in the level of glu tamate immunolabeling was observed. Immunolabeling of glutamine was low in both nerve terminals and neuronal somata in normal slices and was reduced to nondetectable levels in nerve terminals upon hypoxia and glucose dep rivation. This treatment was also associated with a re duced glutamine immunolabeling in glial cells. Reversed glutamate uptake due to perturbations of the transmem brane ion concentrations and membrane potential proba bly contributes to the loss of neuronal glutamate under "ischemic" conditions. The increased glutamate labeling of glial cells under the same conditions can best be ex plained by assuming that glial cells resist a reversal of glutamate uptake, and that their ability to convert gluta mate into glutamine is compromised due to the energy failure. The persistence of a nerve terminal pool of glu tamate is compatible with recent biochemical data indi cating that the exocytotic glutamate release is contingent on an adequate energy supply and therefore impeded dur ing ischemia.

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Ischemic CA-1 pyramidal cell loss is prevented by preischemic colchicine destruction of dentate gyrus granule cells

Cited by 121 publications

References 14 publications

Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats.

Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats.

Localization of 70 kDa Stress Protein mRNA Induction in Gerbil Brain after Ischemia

Redistribution of Glutamate and Glutamine in Slices of Human Neocortex Exposed to Combined Hypoxia and Glucose Deprivation in vitro

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