Elsevier

Neuroscience Research

Volume 54, Issue 4, April 2006, Pages 319-327
Neuroscience Research

Mineralocorticoid and glucocorticoid receptor expressions in astrocytes and microglia in the gerbil hippocampal CA1 region after ischemic insult

https://doi.org/10.1016/j.neures.2005.12.012Get rights and content

Abstract

In the present study, we observed expression and changes of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the gerbil hippocampal CA1 region, but not in the CA2/3 region, after 5 min of transient forebrain ischemia. In blood, corticosterone levels were increased biphasically at 30 min and 12 h after ischemia/reperfusion, and thereafter its levels were decreased. In the sham-operated group, MR and GR immunoreactivities were weakly detected in the CA1 region. By 3 days after ischemia, MR and GR were not significantly altered in the CA1 region: at 12 h after ischemia, GR was expressed in a few neurons in the CA1 region, whereas MR was not expressed in any neurons after ischemic insult. From 4 days after ischemia, MR and GR immunoreactivities were detected in astrocytes and microglia in the CA1 region, and at 7 days after ischemia, MR and GR immunoreactivities peaked in the hippocampal CA1 region. At this time, 55% of astrocytes and 30% of microglia showed MR immunoreactivity, and 20% of astrocytes and 40% of microglia showed GR immunoreactivity. Western blot analyses showed that the pattern of changes in MR and GR protein levels was similar to the immunohistochemical changes observed after transient forebrain ischemia. From 4 days after ischemia, MR and GR protein levels were increased time-dependently after ischemia. In conclusion, enhanced MR and GR expressions in astrocytes and microglia were detected in the hippocampal CA1 region 4–7 days after ischemia/reperfusion. At this time, GR immunoreactivity was abundant in microglia, whereas MR immunoreactivity was prominent in astrocytes. The specific distribution of corticosteroid receptors in the astrocytes and microglia may be associated with the differences of MR and GR functions against ischemic damage.

Introduction

The hippocampus is involved in episodic, declarative, spatial and contextual learning and memory. It is a particularly vulnerable and sensitive region of the brain that expresses high levels of adrenal steroid “stress” hormone receptors (McEwen, 1999, Bohbot et al., 2000). Corticosteroid hormones entering the brain can bind to two intracellular receptor types that regulate the transcriptions of responsive genes, i.e., (i) high affinity mineralocorticoid receptors and (ii) glucocorticoid receptors; the latter are bound with approximately 10-fold lower affinity. Glucocorticoid hormones terminate stress response via a negative feedback action at the levels of the pituitary, hypothalamus and limbic brain areas, the latter of which includes the hippocampus, amygdala and septum (Kawata et al., 2001, Kellendonk et al., 2002).

Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) are abundantly expressed in the hippocampus, which makes this region a prime target for glucocorticoid action (Aronsson et al., 1988, Reul et al., 1989, De Kloet, 1995). Moreover, excessive GR activation increases hippocampal neuronal vulnerability to neuronal insults such as excitotoxicity, oxidative stress and ischemia (Sapolsky et al., 1988, Goodman et al., 1996, McCullers et al., 2002). Furthermore, protection from delayed neuronal death in transient global ischemia, focal ischemia and kainate-induced excitotoxic damage occurs when stress-induced glucocorticoid release is prevented by administering metyrapone, an inhibitor of steroid 11β hydroxylation (Smith-Swintosky et al., 1996). It has been reported that hypoxic injury-induced impairment in synaptic transmission in the CA1 region in vitro was exacerbated by concomitant corticosteroid treatment and alleviated by pretreatment with metyrapone (Kruggers et al., 1999, Kruggers et al., 2000). This result suggests that synaptic function along with cellular integrity is preserved after hypoxic injury by preventing the ischemia-evoked rise in corticosteroid levels.

Although the actions of glucocorticoids may be important in ischemic damage, changes in the expressions of MR and GR have not been determined in the ischemic hippocampus. Therefore, we examined the ischemia-related changes of MR and GR in the gerbil hippocampus after 5 min of transient forebrain ischemia.

Section snippets

Experimental animals

This study used the progeny of Mongolian gerbils (Meriones unguiculatus) obtained from the Experimental Animal Center, Hallym University, Chunchon, South Korea. The animals were housed at constant temperature (23 °C) and relative humidity (60%) with a fixed 12 h light/12 h dark cycle and free access to food and water. Procedures involving animals and their care were conformed to the institutional guidelines, which are in compliance with current international laws and policies (NIH Guide for the

Delayed neuronal death in the CA1 region

In the present study, we confirmed delayed neuronal death in the hippocampal CA1 region using NeuN immunohistochemistry. In the sham-operated group, neurons in hippocampal subfields were well-stained with NeuN antibody (Fig. 1A and B). One and 2 days after ischemic insult, there were no significant changes in NeuN immunoreactivity in CA1 pyramidal cells (Fig. 1C–F). We confirmed the delayed neuronal death in CA1 pyramidal cells 4 days following 5 min of transient forebrain ischemia. There was a

Discussion

In the present study, we confirmed delayed neuronal death in the gerbil hippocampal CA1 region 4 days after 5 min of transient forebrain ischemia using NeuN immunohistochemistry. Kirino (1982) had reported that the pyramidal cells of the hippocampal CA1 region showed delayed neuronal death 4 days after 5 min of transient forebrain ischemia in gerbils. However, the pattern of delayed neuronal death was controversial. In recent studies, the delayed neuronal death was intermingled with apoptosis and

Acknowledgements

The authors would like to thank Mr. Seok Han, Mr. Seung Uk Lee and Ms. Hyun Sook Kim for their technical help for this study. This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A020007).

References (39)

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