Estrogen Decreases Infarct Size After Temporary Focal Ischemia in a Genetic Model of Type 1 Diabetes Mellitus Editorial Comment

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Stroke (Impact Factor: 5.72). 12/2000; 31(11):2701-6. DOI: 10.1161/01.STR.31.11.2701
Source: PubMed


It is unclear how genetic type 1 diabetes mellitus (DM) influences infarct size when blood glucose is tightly controlled. The aim of this study was to determine the effect of genetic type 1 DM, as occurs in BB rats, on infarct size after transient unilateral middle cerebral artery occlusion (MCAO) in male and female rats. In addition, studies suggest that male type 1 DM rats have a higher incidence of end-organ complications than do females. A second aim of this study was to determine the effect of chronic 17beta-estradiol (E(2)) administration on infarct size in male BB rats.
Diabetic male (MDiab, n=14) and female (FDiab, n=8) BB rats were studied and compared with background strain Wistar rats (MWist, n=16; FWist, n=14). Two additional male cohorts (MWist+E(2), n=15; MDiab+E(2), n=14) received subcutaneous 25 microg E(2) implants 7 to 10 days before MCAO. Rats underwent 1 hour of MCAO followed by 22 hours of reperfusion. Physiological variables were controlled among groups, and the intraischemic laser Doppler flow signal was reduced similarly in all animals. Infarction volume was evaluated by 2,3,5-triphenyltetrazolium chloride staining and image analysis.
Preischemic blood glucose was 94+/-5, 127+/-13, 90+/-15, 63+/-18, 122+/-8, and 81+/-14 mg/dL in MWist, FWist, MDiab, FDiab, MWist+E(2), and MDiab+E(2) rats, respectively (mean+/-SE). Intraischemic laser Doppler flow was reduced to 20% to 25% of baseline in all groups. Striatal infarct size (percentage of ipsilateral caudate putamen) was increased in male diabetic rats relative to nondiabetic MWist rats (41+/-3% versus 28+/-3%). Striatal injury was not increased in FDiab rats, and infarction volume was smaller than that in FWist rats (23+/-4% in FWist versus 13+/-3% in FDiab). Chronic estrogen treatment reduced cortical and striatal infarction in MDiab+E(2) rats compared with untreated MDiab rats.
Type 1 DM is associated with increased infarct size after temporary MCAO, despite tight control of blood glucose. The deleterious effect of DM is evident only in males rats; female diabetic BB rats sustain small infarcts. Chronic E(2) treatment reduced injury in the male BB rat, providing neuroprotection even in the presence of DM. These data suggest that genetic diabetes even with mild glucose elevation plays a role in determining neuropathology in experimental stroke. However, factors such as reproductive steroids also determine outcome in DM stroke.

Full-text preview

Available from:
  • Source
    • "Consensus was reached to include 61 studies, of which 45 were included in the previous systematic analysis [6,8,9,21-62] while 16 were not [11,63-77]. The previous systematic analysis [12] included not only focal cerebral ischemia, but also global ischemia, which is really not a model of ischemic stroke, but rather models the effects of cardiac arrest on the brain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for. The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats. We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.
    Full-text · Article · Feb 2014 · BMC Neuroscience
  • Source
    • "Sex differences in stroke outcome are also well recognized in preclinical models. Females have a smaller infarct and better cerebral blood flow than age-matched males both in normoglycemic (Alkayed et al., 1998) and diabetic (Toung et al., 2000) animals. However, although female mice sustain a much smaller infarct as compared to age matched males (Manwani et al., 2011), aged females showed significantly more mortality and poorer stroke outcomes as compared to older males. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stroke is one of the leading causes of adult disability and the fourth leading cause of mortality in the US. Stroke disproportionately occurs among the elderly, where the disease is more likely to be fatal or lead to long-term supportive care. Animal models, where the ischemic insult can be controlled more precisely, also confirm that aged animals sustain more severe strokes as compared to young animals. Furthermore, the neuroprotection usually seen in younger females when compared to young males is not observed in older females. The preclinical literature thus provides a valuable resource for understanding why the aging brain is more susceptible to severe infarction. In this review, we discuss the hypothesis that stroke severity in the aging brain may be associated with reduced functional capacity of critical support cells. Specifically, we focus on astrocytes, that are critical for detoxification of the brain microenvironment and endothelial cells, which play a crucial role in maintaining the blood brain barrier. In view of the sex difference in stroke severity, this review also discusses studies of middle-aged acyclic females as well as the effects of the estrogen on astrocytes and endothelial cells.
    Preview · Article · Jun 2013 · Neurochemistry International
  • Source
    • "Diabetes impairs outcome in rodent models of focal cerebral ischemia (Bomont and MacKenzie 1995). Interestingly, brain injury and inflammation in diabetic models can be reversed by angiotensin II type 1 receptor (AT(1)-R) antagonist, PPARγ agonist, administration of 17β-estradiol, IGF-1, aspirin and niacin (B3 vitamin) even at high blood glucose levels, highlighting the potential role of inflammatory mechanism in diabetes-induced exacerbation of brain injury (Kusaka et al. 2004; Toung et al. 2000; Tureyen et al. 2007; Rizk et al. 2007; Wang et al. 2009; Ye et al. 2011). Brain injury and neurological outcome are exacerbated after cerebral ischemia in rodent models of hypertension, which can mostly (although not uniformly (Porritt et al. 2010)) be reversed by blood pressure lowering drugs (Elewa et al. 2007; Kozak et al. 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases -such as atherosclerosis, obesity, diabetes or infection - similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti-inflammatory/immunomodulatory therapeutic approaches.
    Full-text · Article · May 2013 · Journal of Neuroimmune Pharmacology
Show more