Deleterious effect of  β-estradiol in a rat model of transient forebrain ischemia

Oestrogen is a complex hormone whose role as a neuroprotectant in experimental stroke has been published in numerous studies. However, although some clinical studies report a reduction in stroke incidence by oestrogen replacement therapy in postmenopausal women, others have found increased mortality and morbidity after stroke. Diathermy occlusion of the proximal middle cerebral artery (MCAO), one of the most reproducible rodent stroke models, has consequently been employed to investigate physiologic and supraphysiologic doses of 17b-oestradiol on ischaemic brain damage. Lister Hooded rats were ovariectomised (OVX) and a 21-day release pellet (placebo, 0.025 or 0.25 mg 17b-oestradiol) implanted in the neck. At 2 weeks after OVX, animals underwent MCAO and were perfusion fixed 24 hours later. Neuronal perikaryal damage was assessed from haematoxylin and eosin-stained sections and in adjacent sections, axonal pathology was assessed with amyloid precursor protein and Neurofilament 200 (NF-200) immunohistochemistry. 17b-Oestradiol induced a dose-dependent increase in neuronal perikaryal damage, 0.025 and 0.25 mg 17b-oestradiol increased damage by 20% (Po0.05) and 27.5% (Po0.01) compared with placebo. 17b-Oestradiol did not influence axonal pathology compared with placebo. Our results suggest that 17b-oestradiol treatment can exacerbate brain damage in experimental stroke. Thus, further investigation into the role of oestrogen and the mechanisms which mediate its effects in stroke is required.

Section: Discussionmentioning

confidence: 99%

Detrimental Effects of 17β-Oestradiol after Permanent Middle Cerebral Artery Occlusion

Bingham

Macrae

Carswell

2005

“…Neurodamage has been reported using both permanent (Bingham et al, 2005;Carswell et al, 2004;Gordon et al, 2005) and transient (Harukuni et 2005) and also using the four-vessel occlusion method of global ischemia (Harukuni et al, 2001). Neuroprotection has been shown using all described methods.…”

Section: Induction Of Ischemic Brain Lesionsmentioning

confidence: 95%

Dose-Related Neuroprotective versus Neurodamaging Effects of Estrogens in Rat Cerebral Ischemia: A Systematic Analysis

Ström

Theodorsson

2009

Numerous studies of the effects of estrogens for stroke prevention have yielded conflicting results in human and animal studies alike. We present a systematical analysis of study design and methodological differences between 66 studies where estrogens' impact on ischemic brain damage in rat models has been investigated, providing evidence that the differences in results may be explained by high estrogen doses produced by slow-release pellets. These pellets have been used in all studies showing increased neurologic damage because of estrogens. Our data indicate that the increased neurologic damage is related to the pellets' plasma concentration profile with an early, prolonged, supraphysiological peak. Neither the method of inducing the ischemic brain lesions, the choice of variables for measuring outcome, the measured plasma concentrations of estrogens at the time of ischemia nor rat population attributes (sex, strain, age, and diseases) are factors contributing to the discrepancies in results. This suggests that the effects of estrogens for stroke prevention are concentration related with a complex dose-response curve, and underscores the importance of carefully validating the experimental methods used. Future studies of hormonereplacement therapy in women may have to take dosage and administration regimens into account.

“…Therefore, testosterone may not be involved in the reduction of pathology with estrogen treatment. In contrast to these positive studies with 17␤-estradiol treatment, some studies have shown an exacerbation of injury with this treatment paradigm (Carswell et al, 2004;Harukuni et al, 2001). Carswell and colleagues report that low or high dose 17␤-estradiol pre-treatment for two weeks before permanent MCAO produces an increase in damaged tissue compared to placebo treatment in ovariectomised rats.…”

Section: Gendermentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

552

358

Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.