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Department of Pharmacology and Toxicology Michigan State University East Lansing, Michigan 48824
Address all correspondence and requests for reprints to: Anne M. Dorrance, Department of Pharmacology and Toxicology, B346 Life Sciences Building, Michigan State University, East Lansing, Michigan 48824. E-mail: dorranc3{at}msu.edu.
Stroke is a leading cause of morbidity and mortality in the Western world (1). Eighty-eight percent of strokes are ischemic, and despite extensive research in the field, therapeutic options for their treatment are few (2). The only Food and Drug Administration-approved pharmacotherapy is tissue plasminogen activator (tPA); this drug breaks down the blood clot and restores perfusion to the brain. The problem is that tPA has to be administered within 3 h of the ischemic insult and can only be given to patients with confirmed ischemic strokes. These tight restrictions result in only 3% patients receiving this therapy (3). Stroke risk increases with age (4), and as the baby boomers reach retirement and beyond, we are threatened with an epidemic that we can do little about.
There are several mechanisms through which the outcome of cerebral ischemia can be improved. As is the case with tPA, one can intervene to improve blood flow acutely and perhaps save the cells in the ischemic penumbra where blood flow is reduced but not lost. One could also administer a neuroprotective agent to prevent apoptosis or necrosis of the cells in the penumbra. Sadly, to date every promising neuroprotective agent has failed in phase III clinical trials (5). Most recently the free radical-trapping agent NXY-059 failed in its second round of phase III testing (6). The reasons for these failures are much too wide and deep to discuss here, but they have been eloquently reviewed by others (7). The general failure of the neuroprotective agents has led the field to question whether trying to prevent cell death is the correct approach to stroke therapy; this introspection has resulted in two new avenues for stroke research. Studies are currently evaluating the usefulness of drugs that promote neurogenesis and angiogenesis as treatments for acute ischemic stroke and the notion that one agent could stimulate both is tantalizing. The paper by Oyamada et al. (8) in this issue of Endocrinology documents that spironolactone, the mineralocorticoid receptor (MR) antagonist, has the potential to do just this. This adds to the ever-increasing number of actions of MR antagonists that occurs outside of the kidney and without any direct effect on sodium and/or water homeostasis.
The link between aldosterone, MR activation, and stroke is evident. In the 1960s, Conn (9) found that patients with primary aldosteronism had an increased risk of stroke. Similarly, patients with increased plasma aldosterone caused by glucocorticoid-remediable hypertension have what appears to be a blood pressure-independent increased risk of stroke (10). The link between mineralocorticoids and stroke has also been established in experimental animals. Administration of MR antagonists to stroke-prone spontaneously hypertensive rats fed a high-salt or stroke-prone diet prevents spontaneous hemorrhagic strokes (11). Chronic spironolactone treatment in to stroke-prone spontaneously hypertensive rats also has beneficial effects on the outcome of acute ischemic strokes that appear to be linked to improvements in vessel structure that have the potential to enhance blood flow (12, 13). Based on these studies, the therapeutic potential of spironolactone for stroke has been, until now, limited to prevention as opposed to cure. The current paper (8) expands on the usefulness of spironolactone as a stroke therapy and presents the possibility that it could be beneficial when administered after ischemia.
The basis for testing the potential therapeutic effects of spironolactone after stroke comes from the observation that MR expression is increased in astrocytes migrating into the ischemic striatum. Astrocytes play an integral role in the repair process in cerebral ischemia by removing debris and secreting neurotrophic factors. This finding alone is noteworthy, but the authors also showed that the MR is physiologically relevant by treating mice that were undergoing ischemia with spironolactone. Firstly, they showed that spironolactone reduced reactive oxygen species (ROS) production in the ischemic striatum. Increased oxidative stress is thought to be one of the key determinants of the ischemic damage and this finding fits well with some of the general thinking on how spironolactone has its beneficial effects on the cardiovascular system (14). The study also showed that spironolactone reduces apoptosis in the ischemic striatum and causes a small but significant reduction in the area of the brain damaged by ischemia. These effects can be attributed to a combination of neurogenesis and angiogenesis. Analysis of neuroprotective and angiogenic factors in the striatum showed that basic fibroblast growth factor and vascular endothelial growth factor were significantly elevated in astrocytes from the spironolactone-treated mice. Interestingly, that basic fibroblast growth factor was evaluated for ischemic stroke therapy in phase III clinical trails and failed (5). The authors continued their elegant assessment of the effects of spironolactone in the brain by testing whether vascular density and blood flow were altered in the infarcted area. As one could have predicated from the increase in vascular endothelial growth factor expression, they found an increase in vessel density and blood flow in the ischemic striatum from the spironolactone-treated mice. Based on analysis of Evan’s blue leakage, the authors believe that new vessels in the brain are fully formed 14 d after ischemia. The authors also observed an increase in the number of neuroblasts in the ischemic area after spironolactone treatment, suggesting that neurogenesis is actively occurring. However, it is difficult to dissect whether this is a direct effect of MR antagonism on neurogenesis or a product of the increased blood flow and therefore nutrient and growth factor delivery. The beneficial effects of spironolactone in the mice occurred without a significant reduction in blood pressure. This should probably be considered a positive because there is no consensus in the stroke field as to the benefits of lowering blood pressure after ischemia (15).
Exciting as they are, the results presented by Oyamada et al. (8) appear at odds with other studies of the direct effects of aldosterone, or perhaps more appropriately, MR activation, on neurons. Several studies show that MR activation is required for neuronal survival, at least in the hippocampus and dentate gyrus (16, 17, 18). The B-cell leukemia/lymphoma-2 (Bcl-2) gene is neuroprotective; MR blockade reduces basal Bcl-2 (19) and MR activation increases its expression (20). It is, however, important to remember that these studies were carried out in normal brain and that the signaling milieu is likely very different after ischemia. In keeping with the results of the current study, others (21) have found that MR expression is increased in the hippocampus after transient global ischemia, but MR blockade 1 h before the induction of ischemia resulted in increased cell death. These studies assessed the effects of activation of neuronal MRs. In the present study, the receptors that appear to be important are on astrocytes, and the effects on neurons seem to be secondary.
Before becoming too excited that the prayers of stroke neurologists everywhere have been answered, there are still questions that remain to be addressed. In the current study, spironolactone was administered 48 h before the induction of ischemia. Although this short treatment is unlikely to affect vessel structure, it could affect ROS production in the vessels and therefore vasodilation. Thus, it is imperative that we examine whether spironolactone is effective when administered after ischemia, and if so, how long can one wait to give the drug and still have it be beneficial? A time of less than 3 h really puts us in no better a position than we are at present with tPA, although the possibility that spironolactone could be used as an additive therapy with tPA should not be ruled out. It is also essential that we test the effect of spironolactone after longer durations of ischemia. In the current study, neuronal damage was induced by a 20-min middle cerebral artery occlusion. This is, relatively speaking, a very short occlusion time and the injury produced was quite mild.
It will also prove to be important to assess exactly which receptor the spironolactone is binding to. Although the results showing an increase in MR expression and a beneficial effect of spironolactone suggest the two are linked, one cannot rule out the potential role of the androgen receptor. Recent studies have suggested that testosterone, binding to the androgen receptor, which is also antagonized by spironolactone, has deleterious effects on the outcome of cerebral ischemia (22); thus, it is possible that androgen receptor antagonism could also be beneficial. Spironolactone is also a progesterone receptor agonist. Although estrogen has fallen from favor, progesterone is rapidly gaining support as a potential stroke therapy (23). The use of the more selective MR antagonist, eplerenone, would go a long way to addressing these questions.
Of course one cannot discuss the MR without considering the effects of the 11β hydroxysteroid dehydrogenase (11β HSD) enzymes. It remains to been seen whether the astrocytes expressing the MR in this study also express 11β HSD 1 or 2; thus, it is unclear what the ligand is for the MR. Although under normal conditions aldosterone is excluded from the brain, no studies have assessed what happens when the blood brain barrier is disrupted after ischemia. It is even unclear at present whether spironolactone crosses the blood brain barrier to have potential pre-stroke effects. The binding of ligands to, and activation of, the MR is rapidly becoming a complex issue. Cortisol (or corticosterone in rodents) binds to the MR with the same affinity as aldosterone, and in many areas of the brain cortisol is the ligand of choice. Recent studies in the heart and vasculature suggest that ROS not only inhibit the 11β HSD 2 enzyme but are required to convert cortisol from a ligand that merely occupies the receptor to one that activates it (24, 25). It is unknown whether this phenomena exists in the brain, but it seems possible, given the oxidative stress produced by ischemia, that the MR could be ripe for activation by cortisol and that the 11β HSD enzymes, if present, will be inhibited.
One thing that continues to be true is the amazing resurgence of interest in MR antagonism: it should be remembered that these drugs had largely fallen from favor until the publication of the RALES trial in 1999 (26). In a short 10 yr, MR antagonists have moved from being little-used drugs because of their troublesome side effects to being potential therapies for cardiovascular disease and now stroke. I hope and believe that this is only the beginning of the story.
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Abbreviations: Bcl-2, B-cell leukemia/lymphoma-2; 11β HSD, 11β hydroxysteroid dehydrogenase; MR, mineralocorticoid receptor; ROS, reactive oxygen species; tPA, tissue plasminogen activator.
Received May 15, 2008.
Accepted for publication May 27, 2008.
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