Temporal profile of the effects of pretreatment with brief cerebral ischemia on the neuronal damage following secondary ischemic insult in the gerbil: cumulative damage and protective effects

doi:10.1016/0006-8993(91)90831-F

Brain Research

Volume 553, Issue 2, 12 July 1991, Pages 238-242

https://doi.org/10.1016/0006-8993(91)90831-F Get rights and content

Abstract

We examined the response of the gerbil brain to secondary ischemic insult following pretreatment with brief ischemia at intervals of 5 min, 1 and 6 h, 1, 2, 4, 7 and 14 days. Two minutes of bilateral carotid artery occlusion produced no histopathological brain damage, whereas 3 min of occlusion caused a moderate to severe reduction in the number of hippocampal CA1 pyramidal cells. Two-minute occlusion followed by 3-min occlusion at 5-min, 1- and 6-h intervals resulted in almost complete destruction of CA1 neurons. Additional neuronal damage was observed in the striatum at a 1-h interval and in the thalamus and the neocortex at 1- and 6-h intervals. The neuronal damage was most severe at a 1-h interval. Two-minute ischemia followed by 3-min ischemia at intervals of 1, 2, 4 and 7 days, however, caused a marked protective effect, and the hippocampal CA1 neurons were preserved. The protective effect was not observed at a 14-day interval and following pretreatment with 1-min ischemia. Thus, pretreatment with brief ischemia leads to complex responses of the brain to secondary ischemia insult; cumulative damage at intervals of 1–6 h and protective effects at intervals of 1–7 days.

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The p38 MAPK/NF-κB pathway mediates GLT-1 up-regulation during cerebral ischemic preconditioning-induced brain ischemic tolerance in rats
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Our previous finding suggests that p38 MAPK contributes to the GLT-1 upregulation during induction of brain ischemic tolerance by cerebral ischemic preconditioning (CIP), however, the underlying mechanism is still unclear. Here, we investigated the molecular mechanisms underlying the CIP-induced GLT-1 upregulation by using Western blotting, Co-immunoprecipitation (Co-IP), electrophoretic mobility shift assay (EMSA) and thionin staining in rat hippocampus CA1 subset. We found that application of BAY11-7082 (an inhibitor of NF-κB), or dihydrokainate (an inhibitor of GLT-1), or SB203580 (an inhibitor of p38 MAPK) could attenuate the CIP-induced neuronal protection in hippocampus CA1 region of rats. Moreover, CIP caused rapid activation of NF-κB, as evidenced by nuclear translocation of NF-κB p50 protein, which led to active p50/p65 dimer formation and increased DNA binding activity. GLT-1 was also increased after CIP. Pretreatment with BAY11-7082 blocked the CIP-induced GLT-1 upregulation. The above results suggest that NF-κB participates in GLT-1 up-regulation during the induction of brain ischemic tolerance by CIP. We also found that pretreatment with SB203580 caused significant reduction of NF-κB p50 protein in nucleus, NF-κB p50/p65 dimer nuclear translocation and DNA binding activity of NF-κB. Together, we conclude that p38 MAPK/NF-κB pathway participates in the mediation of GLT-1 up-regulation during the induction of brain ischemic tolerance induced by CIP.
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Citation Excerpt :
The sections were stained with thionin. The number of surviving pyramidal neurons in CA1 hippocampus within 1 mm linear length was counted according to the description previously (Kato et al., 1991; Kitagawa et al., 1990), which was named as neuronal density. Primary astrocyte cultures were prepared as previously described with some modifications (Ji et al., 2013; Li et al., 2017).
The previous studies have shown that glial glutamate transporter-1 (GLT-1) participates in cerebral ischemic injury in rats. However, the mechanism involved remains to be elucidated. This study was undertaken to investigate whether p38 MAPK was involved in regulating GLT-1 in the process. At first, it was observed that global brain ischemia for 8 min led to obvious delayed neuronal death, GLT-1 down-regulation and p-p38 MAPK up-regulation in CA1 hippocampus in rats. Then, whether p-p38 MAPK was involved in regulating GLT-1 during cerebral ischemic injury was studied in vitro. Astrocyte-neuron co-cultures exposed to oxygen and glucose deprivation (OGD) were used to mimic brain ischemia. It was observed that lethal OGD (4-h OGD) decreased GLT-1 expression and increased p-p38 MAPK expression in astrocytes. The p-p38 MAPK protein rised from 0 min to 48 h that is the end time of the observation, and the peak value was at 12 h, which was 12.45 times of the control group. Moreover, pre-administration of p38 MAPK inhibitor SB203580 or its siRNA dose-dependently increased GLT-1 expression, and meanwhile alleviated the neuronal death induced by lethal OGD. The above results indicated that p38 MAPK signaling pathway participated in regulating GLT-1 during OGD injury in vitro. Finally, back to in vivo experiment, it was found that pre-administration of SB203580 by intracerebroventricular injection dose-dependently reversed the down-regulation of GLT-1 expression and attenuated the delayed neuronal death normally induced by global brain ischemia in CA1 hippocampus in rats. Taken together, it can be concluded that the mechanism of GLT-1 mediating cerebral ischemic injury depends on the activation of p38 MAPK.
The role of adenosine in up-regulation of p38 MAPK and ERK during limb ischemic preconditioning-induced brain ischemic tolerance
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Our previous studies have demonstrated that limb ischemic preconditioning (LIP) induced brain ischemic tolerance and up-regulated the expression of p38 MAPK and ERK in the hippocampal CA1 region in rats. The present study was undertaken to investigate the role of adenosine in brain protection and up-regulation of p38 MAPK and ERK induced by LIP. It was found that adenosine A1 receptor antagonist DPCPX dose-dependently inhibited the protective effect of LIP. The up-regulation of p38 MAPK and ERK induced by LIP could be blocked by DPCPX. Furthermore, we observed the effect of adenosine on the brain ischemia. The results showed that pre-administration of adenosine could partly mimic the neuroprotective effect on the brain, up-regulate the expression of p38 MAPK and ERK. Based on the above results, it can be concluded that adenosine participated in brain protection and up-regulation of the expression of p38 MAPK and ERK during the induction of brain ischemic tolerance after LIP.
Isoflurane post-conditioning down-regulates expression of aquaporin 4 in rats with cerebral ischemia/reperfusion injury and is possibly related to bone morphogenetic protein 4/Smad1/5/8 signaling pathway
2018, Biomedicine and Pharmacotherapy
Aquaporins (AQPs) are water-channels that play important roles in brain water homeostasis and cerebral edema induced by brain injury. This study aimed to investigate the relationship between AQP4, bone morphogenetic protein 4 (BMP4)/Smad1/5/8 signaling pathway and isoflurane post-conditiong, which has effects on brain edema in rats with cerebral ischemia/reperfusion (I/R) injury.
Cerebral I/R injury was induced in rats by using the middle cerebral artery occlusion (MCAO) model for 90 min, followed by 24 h of reperfusion. Isoflurane post-conditioning (ISO) group received 90 min ischemia and underwent 1.5% isoflurane post-conditioning for 60 min after initiating reperfusion. Neurobehavior, brain water content, thionine staining and 2, 3, 5-triphenyl tetrazolium chloride staining were evaluated to measure levels of brain edema and damage. Expressions of AQP4, BMP4, Smad1/5/8 and phosphorylated Smad1/5/8 were detected by using Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence (IF) staining.
Compared with the Sham group, neurological behavior score, brain infarct volume and water content of MCAO model rats increased with reperfusion injury. However, in the ISO group, cell edema and damage of brain was significantly ameliorated (P < 0.01). qRT-PCR showed less AQP4 mRNA expression in the hippocampal tissue of the ISO group than in the I/R group (P < 0.01). Western blot and immunofluorescence results showed similar changes in protein levels of both groups. Related protein expressions showed expressions of BMP4 and Smad1/5/8 increased in the ISO group (P < 0.01), whereas total Smad1/5/8 expression didn’t change in all groups. When BMP4 inhibitor (LDN193189) was injected, expression levels of AQP4 increased and neuronal density decreased (P < 0.05). By contrast, expression levels of BMP4 did not change significantly after pre-injection of AQP4 inhibitor (TGN020) (P > 0.05), but neuronal density increased (P < 0.05).
Isoflurane post-conditioning may inhibit occurrence of brain edema and reduce cerebral I/R injury through down-regulating expression of AQP4, This process may be related to the activation of BMP4/Smad1/5/8 signaling pathway.
Neuroprotection of edaravone on the hippocampus of kainate-induced epilepsy rats through Nrf2/HO-1 pathway
2018, Neurochemistry International
Epilepsy is a severe and chronic neurological disease. Edaravone is an effective free radical scavenger and has been reported to prevent neuronal loss induced by Kainate (KA). However, the molecular mechanisms by which edaravone inhibits KA-induced neuron injury remain elusive. Seventy adult male Wistar rats were randomly divided into 7 groups. For KA treatment, Kainate (4 μg/kg) were administrated in the right hippocampus CA3 region with sereotactic technique. And for edaravone treatment, the rats were intraperitoneal injection with edaravone (10 mg kg ^{- 1} d ^{– 1}). All rats were sacrificed on the seven day after the injection of KA. Histological changes of the hippocampus, CA1, CA3 and CA4 were observed under thionine staining. Histological changes of CA1 and CA3 were divided into the following 4 grades (histological grade,HG) under light microscope. The release of inflammatory cytokines was measured by ELISA assay. The inflammatory proteins and Nrf2 and HO-1 expression were determined by quantitative real time PCR (qRT-PCR) and Western blots analysis. Treatment with edaravone increased the neuronal density and decreased the neuronal damage degree in the CA1, CA3 subfield induced by KA. Besides, edaravone reduced the downregulation of the mRNA and protein expression levels of Nrf2 and HO-1 induced by KA. Moreover, edaravone decreased the levels of NF-κB (P65) and proinflammatory cytokines TNF-α, IL-1β and IL-6 and the inflammatory proteins expression levels, HMGB1, nNOS, iNOS and eNOS in the hippocampus. However, introduction of Nrf2-siRNA and HO-1 inhibitor (Znpp) reversed the effects of edaravone on KA-injected rats. Edaravone can protect hippocampal neurons from damage in KA-induced epilepsy rats through Nrf2/HO-1 pathway.

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References (24)

Prevention of delayed neuronal death in gerbil hippocampus by a novel vinca alkaloid derivative (vinconate)

Mol. Chem. Neuropathol.

Regional impairment of protein synthesis following brief cerebral ischemia in the gerbil

Acta Neuropathol.

Neuronal damage and calcium accumulation following brief cerebral ischemia in the gerbil

Brain Research

Fimbria-fornix lesions: the temporal profile for protection of CA1 hippocampus against ischemic injury

J. Cereb. Blood Flow Metabol.

Transient hyperthermia protects against subsequent forebrain ischemia cell damage in the rat

Neurology

Effects of normothermic versus mild hyperthermic forebrain ischemia in rats

Stroke

Selective gene expression in focal cerebral ischemia

J. Cereb. Blood Flow Metabol.

Delayed c-fos proto-oncogene expression in the rat hippocampus: an in situ hybridization study

Brain Research

Neuronal damage following repeated brief ischemia in the gerbil

Brain Research

Neuronal damage following nonlethal but repeated cerebral ischemia in the gerbil

Acta Neuropathol.

Sequential cerebral blood flow changes in short-term cerebral ischemia in gerbils

Stroke

Role of the excitotoxic mechanism in the development of neuronal damage following repeated cerebral ischemia in the gerbil: protective effects of MK-801 and pentobarbital

Brain Research

Cited by (305)

Melissa officinalis extract suppresses endoplasmic reticulum stress-induced apoptosis in the brain of hypothyroidism-induced rats exposed to γ-radiation

The p38 MAPK/NF-κB pathway mediates GLT-1 up-regulation during cerebral ischemic preconditioning-induced brain ischemic tolerance in rats

The mechanism of GLT-1 mediating cerebral ischemic injury depends on the activation of p38 MAPK

The role of adenosine in up-regulation of p38 MAPK and ERK during limb ischemic preconditioning-induced brain ischemic tolerance

Isoflurane post-conditioning down-regulates expression of aquaporin 4 in rats with cerebral ischemia/reperfusion injury and is possibly related to bone morphogenetic protein 4/Smad1/5/8 signaling pathway

Neuroprotection of edaravone on the hippocampus of kainate-induced epilepsy rats through Nrf2/HO-1 pathway