Chronic Dexamethasone Pretreatment Aggravates Ischemic Neuronal Necrosis

Abstract

Summary: This study addresses the question of whether the cyclooxygenase inhibitors indomethacin and diclo fenac and the glucocorticosteroid dexamethasone ame liorate neuronal necrosis following cerebral ischemia. In addition, since these drugs inhibit the production of pros taglandins and depress phospholipase A2 activity, respec tively, the importance of free fatty acids (FFAs) on the development of ischemic neuronal damage was assessed. Neuronal damage was determined in the rat brain at I week following 10 min of forebrain ischemia. The cy c100xygenase inhibitors, whether given before or after ischemia, failed to alter the brain damage incurred. An imals given dexamethasone were divided into three groups and the drug was administered at a constant dosage of 2 mg/kg: (a) 2 days, 1 day, and 3 h intraperito neally before (chronic pretreatment), (b) 3 h intraperito neally before (acute pretreatment), and (c) 5 min intrave nously and 6 h and 1 day intraperitoneally after (chronic posttreatment) induction of ischemia. Acute pretreat ment did not affect the histopathological outcome. Chronic posttreatment of animals with dexamethasoneThe pathophysiology of ischemic brain damage has been extensively explored. So far, though, cur rent information is largely descriptive. Thus, al though numerous articles have been devoted to cir culatory and metabolic events in global as well as regional ischemia, be it complete or incomplete, the molecular mechanisms of neuronal necrosis have remained largely elusive.During recent years, several lines of evidence suggest that mechanisms that lead to irreversible brain cell damage following cerebral ischemia could 395ameliorated the damage inflicted on the caudate nucleus, but had no effect on other brain areas investigated. Unexpectedly, the chronic pretreatment aggravated the brain damage and caused seizures following ischemia.Histopathological data showed massive neuronal damage in these brains. The accumulation of FFA levels during ischemia was markedly suppressed, and the decrease in the energy charge was curtailed by chronic pretreatment with dexamethasone. However, brain glucose levels in control animals and lactic acid concentrations following 10 min of ischemia were significantly higher both in the cerebral cortex and in the hippocampus of dexametha sone-treated animals. These results suggest that aggrava tion of neuronal necrosis by chronic dexamethasone pre treatment could be ascribed to lactic acidosis due to hyperglycemia in combination with an action of dexamethasone on glucocorticoid receptors in the brain.

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

“…In fact, studies about steroid-induced alterations of protein synthesis, dating back to the late seventies (Etgen et al, 1979) have so far supplied evidence for a role in several of these general cell processes: (1) The synthesis of GPDH was found to be increased by acute stress or corticosterone, with a delay of only 2 hr (Nichols et al, 1988(Nichols et al, , 1989Schlatter et al, 1990); (2) In hippocampal tissue glucocorticoids enhanced the amount of synapsin-1, a phosphoprotein which is involved in the control of neurotransmitter release (Nestler et al, 1981); the effect was apparent after 1 day, but reached a maximum after 7 days. By contrast, the mRNA for GAP43, another protein associated with transmitter release (Dekker et al, 1989), was not changed after 4 days corticosterone treatment (Nichols and Finch, 1991); t3~ Corticosteroid hormones may play a role in free radical formation, since they were shown to inhibit prostaglandin synthesis in the brain (Weidenfeld et at., 1987); however, lipid peroxidation was not altered (Koide et al. 1986).…”

“…calpains, endonucleases, phospholypase C, oxygen radical formation and severe acidosis eventually leads to delayed neuronal death (Siesjo and Bengtsson, 1989;Choi, 1988Choi, , 1990Meyer, 1989;Erecinska and Silver, 1989). Glucocorticoid hormones do not seem to reduce cellular metabolism to an extent that they are damaging by themselves, but they can clearly exacerbate the vulnerability to excitotoxins (Sapolsky, 1985), hypoxia/ischemia (Sapolsky and Pulsinelli, 1985;Koide et al, 1986) and hypoglycemia (Sapolsky, 1985) in hippocampal tissue. They do so regardless of their peripheral catabolic actions, since the aggrevation of induced lesions was also observed in isolated brain preparations Tombaugh et al, 1992).…”

Social stress exacerbates stroke outcome by suppressing Bcl-2 expression

“…In humans, post-stroke cortisol concentrations are predictive of stroke outcome; high cortisol is associated with increased morbidity and mortality (10)(11)(12). Furthermore, experimental manipulations in rats that increase blood corticosterone concentrations during or after cerebral ischemia also increase infarct volume (13), whereas surgical or pharmacological suppression of corticosterone concentrations is neuroprotective (14,15). It has been proposed that rather than killing neurons directly, exposure to high concentrations of corticosteroids typically induces a physiological state that renders neurons more susceptible to subsequent neurologic insults (16).…”

Intrathecal Corticoids in Permanent Focal Cerebral Ischemia in Rats. Part I: A New Therapeutic Approach in the Acute Phase

“…However, the authors stated that steroid administration might prevent death in patients harboring massive infarcts (Norris and Hachinski, 1986). In other studies, administration of glucocorticoids resulted in no or even detrimental effects on infarction size (Koide et al, 1986;Slivka and Murphy, 2001). Koide et al (1986) found that glucocorticoids administered intraperitoneally did not improve (acute pretreatment and post-treatment) but even aggravated (long-term pretreatment) infarction size in transient focal forebrain ischemia in rats.…”

“…They are used empirically to reduce inflammation and edema in the clinical setting, for example, after brain injury and in multiple sclerosis (Hoffmann et al, 2003;Rhodes, 2003). Interestingly, there are a few experimental and clinical studies available on the effects of glucocorticoids in acute cerebral ischemia reporting controversial results (Abraham et al, 2001;Akdemir et al, 2005;Bertorelli et al, 1998;de Courten-Myers et al, 1994;Koide et al, 1986;Lapchak et al, 2000;Limbourg et al, 2002;Norris and Hachinski, 1986;Patten et al, 1972;Slivka and Murphy, 2001;Tuor et al, 1993).…”