Experimental Stroke in the Female Diabetic, db/db, Mouse

Abstract

Diabetic hyperglycemia increases brain damage after cerebral ischemia in animals and humans, although the underlying mechanisms remain unclear. Gender-linked differences in ischemic tolerance have been described but have not been studied in the context of diabetes. In the current study, we used a model of unilateral common carotid artery ligation, combined with systemic hypoxia, to study the effects of diabetes and gender on hypoxic-ischemic (HI) brain damage in the genetic model of Type II diabetes, the db/db, mouse. Male and female, control and db/db, mice were subjected to right common carotid artery ligation followed by varying periods of hypoxia (8% oxygen/92% nitrogen) to assess mortality, infarct volume, and tissue damage by light microscopic techniques. End-ischemic regional cerebral blood flow (CBF) was determined using [14C] iodoantipyrine autoradiography. Glycolytic and high energy phosphate compounds were measured in blood and brain by enzymatic and fluorometric techniques. Gender and diabetes had significant effects on mortality from HI and extent of brain damage in the survivors. Female mice were more resistant than their male counterparts, such that the severity (mortality and infarction size) in the male diabetics > female diabetics - male controls > female controls. Endischemic CBF and depletion of cerebral high energy reserves were comparable among all groups. Surprisingly, female diabetic mice were more hyperglycemic and demonstrated a greater prolonged lactacidosis than the males; however, they were more resistant to damage. The results suggest a unique pathophysiology of hypoxia-ischemia in the female diabetic brain.

A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture

“…For example, stroke is a sexually dimorphic disease, starting from male and female differences in stroke incidence and outcome in humans, to experimental studies that clearly show differences in ischemic sensitivity between male and female animals. This sex difference in ischemic brain injury persisted in genetic in vivo models of hypertension (Alkayed, et al, 1998) and diabetes (Hurn and Macrae, 2000;Toung, et al, 2000;Vannucci, et al, 2001;Sieber, et al, 2001), suggesting that fundamental molecular mechanisms of ischemic cell death may be gender dependent. These differences are in part due to the protective effect of the female sex hormone estrogen (Hurn and Macrae, 2000;McCullough, et al, 2003;Liu, et al, 2004), since ovariectomy increases ischemic brain damage in female rats (Alkayed, et al, 1998) and mice (McCullough, et al, 2005), and estrogen replacement is protective against cerebral ischemia in ovariectomized rats (Rusa, et al, 1999) and mice (McCullough, et al, 2005) and in reproductively senescent male and female rats (Alkayed, et al, 2000).…”

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

“…A variety of data suggest in vivo, and more recently in vitro, that the female brain (Zhang et al, 1998;Alkayed et al, 1998;Vannucci et al, 2001;Carswell et al, 2000) and female neurons (Zhang Figure 9 The effects of the selective poly-ADP ribose polymerase (PARP-1) inhibitor PJ-34 in wild-type (WT) mice of both genders. Treatment with PJ-34 at ischemic onset reduced total infarction in male mice compared with saline-treated controls (*Po0.001).…”

Deficiency of PAR4 Attenuates Cerebral Ischemia/Reperfusion Injury in Mice

“…For this purpose, the hemispheric infarct volume in each section was calculated by subtracting the area of normal TTC-stained tissue in the hemisphere ipsilateral to the ligation from the contralateral nonischemic area to generate the infarct fraction (%) as described byLin et al (1993) and Swanson et al (1990). Cerebral edema was determined by the percent increase of the ipsilateral/contralateral hemisphere area (Vannucci et al, 2001). …”