N. N. Rizk1, E. Abbott1, M. Rizk2, A. Fischer1,2, J. Dunbar2 1Beaumont Health System Research Institute,General Surgery,Royal Oak, MI, USA 2Wayne State University,Physiology,Detroit, MI, USA
Introduction: The physiologic differences between men and women are well characterized so their clinical manifestations in pathologic states should potentially exhibit differences. Much of preclinical research utilizes male animal models to develop treatment modalities for clinical applications assumed to extrapolate to both genders. In this study we evaluated normal and diabetic female rats response to stroke and reperfusion injury and compared to our previously characterized outcomes in male rats.
Methods: We utilized middle cerebral artery occlusion (MCAO) and reperfusion model in normal and diabetic Wistar female animals. Following 24-hour MCAO and 2-hour MCAO followed by 24-hour reperfusion interval, several CNS parameters were examined, lesion volume (Triphenyltetrazolium Chloride), up regulation of apoptosis [TUNEL immunoreactivity in the sensori-motor cortex (layers-5 and 6) and the hippocampal pyramidal cell layers (CA1 and CA3 sectors)], as well as the percent survival.
Results: The two parameters in which the female animals differed significantly from their male counter parts were i) in lesion volume following restoration of blood flow with 2-hour MCAO and ii) in mortality following 24-hour MCAO and in following restoration of blood flow with 2-hour MCAO. Restoration of blood flow following 2-hour MCAO significantly decreased lesion volume in the normal and diabetic female animals (13.95 ± 8.16* and 20.32 ± 6.85*, respectively). In comparison to the male counterparts, lesion volumes following reperfusion were significantly less for normal male rats and significantly more for the diabetic male animals (3.8 ± 2.36# and 31.25 ± 2.5#, respectively). Twenty-hour MCAO and restoration of blood flow with 2-hour MCAO proved to be significantly more detrimental to the female animals with lower survival (normal 65%, diabetic 55% survival, p<0.05) in comparison to the male animals (normal 90%, diabetic 65% survival, p<0.05). There was a significant increase in TUNEL immunoreactive cells in the diabetic animals following reperfusion injury compared with the control counterpart. There were no appreciable differences in TUNEL immunoreactivity between male and female diabetic animals following reperfusion.
Conclusion:This paper highlights the dramatically different outcomes and metrics in different genders in animal models. Thus one gender alone may not translate into clinically relevant data applicable to both genders. We have demonstrated that both male and female diabetic animals have an exaggerated response to stroke and to restoration of blood flow but differ in their outcome with a significantly more detrimental outcome for the female sex. Understanding the exaggerated vascular response to injury in the female animal model is important in developing gender specific treatment modalities.