Estrogen treatment post experimental stroke does not influence recovery of function

Introduction

Stroke is the leading cause of disability worldwide. Consequently, the development of therapeutic intervention to aid recovery is essential. The ovarian hormone estrogen has both beneficial and detrimental effects on infarct volume in rodent stroke models. Estrogen has a number of beneficial effects beyond neuroprotection that may make it a candidate for stroke rehabilitation therapy. Specifically, estrogen has been shown to promote synaptogenesis ¹ , and enhance behavioural performance ² . It may be possible to harness these effects to promote recovery following experimental stroke. This study was designed to assess whether estrogen treatment, administered after infarct evolution is complete, improves recovery of function post-stroke.

Materials and Methods

Female Lister Hooded rats were ovariectomized and tested for limb asymmetry using the spontaneous forelimb use (cylinder) test. Fourteen days after ovariectomy rats received a diathermy-induced middle cerebral artery occlusion (MCAO). Since infarct size is maximal by 48 hours in this model, at this time infarct volumes were manually delineated through the use of a RARE T2 weighted magnetic resonance imaging (MRI) scan (TR/TE of 5086/73 msec, 600 μm slice thickness) on a 7T/30 Bruker BioSpec system and corrected for edema ³ . Rats were also implanted with high dose slow release pellets of either 17β-estradiol (0.25 mg, n=7) or placebo (n=6). Animals were tested for functional recovery at days 4, 18 and 28 post-MCAO.

Results

There were no differences in infarct size between the groups prior to treatment (unpaired t-test P=0.81): estrogen 29%±2.4 and placebo 31%±4.1 (mean± SEM of hemispheric volume). A repeated measures ANOVA revealed significant behavioural deficit post MCAO in the cylinder (Figure 1). Rats increased use of their intact (ipsilateral) forelimb from 20% pre-surgically to 40% post-surgically (F(3,36)=21.729, P<0.001) at the expense of the impaired (contralateral) forelimb (from 20–10%). These deficits remained at 28 days, indicating no recovery of function over time. Estrogen treatment had no significant influence on limb use (F(1,11)=2.827, P=0.9869).

Figure 1

Percent use of each forelimb (ipsilateral-good- dark gray, contralateral-bad- light gray), and a combination of the two limbs (both- white), prior to and at 4, 18 and 28 days post MCAO (means ± SEM), P=placebo and E=estrogen-treated animals.

Conclusions

This is the first study to assess the effects of post-stroke estrogen treatment on recovery. Estrogen had no significant influence on behavioural deficit, indicating that in this form and dose, estrogen does not provide a potential therapy for improving recovery.