Oestradiol and Insulin‐Like Growth Factor‐1 Reduce Cell Loss after Global Ischaemia in Middle‐Aged Female Rats

Abstract

Whereas the ability of oestradiol and insulin-like growth factor-1 (IGF1) to afford neuroprotection against ischemia-induced neuronal death in young female and male rodents is well established, the impact of IGF1 in middle-aged animals is largely unknown. This study assessed the efficacy of oestradiol and IGF1 in reducing neuronal death after transient global ischemia in middle-aged female rats following an 8-week hormone withdrawal. Rats were ovariohysterectomized (OVX) and implanted 8 weeks later with an osmotic mini-pump delivering IGF1 or saline into the lateral ventricle. Some rats also received physiological levels of oestradiol by subcutaneous pellet. Two weeks later, rats were subjected to global ischemia or sham operation. Surviving hippocampal CA1 neurones were quantified. Ischemia produced massive CA1 cell death compared to sham-operated animals evident at 14 days. Significantly more neurones survived in animals treated with either oestradiol or IGF1, but simultaneous treatment produced no additive effect. IGF1, an endogenous growth factor, may be a clinically useful therapy in preventing human brain injury, with neuroprotective equivalence to oestradiol but without the harmful side effects.

Effects of global ischemia and estradiol pretreatment on phosphorylation of Akt, CREB and STAT3 in hippocampal CA1 of young and middle-aged female rats

“…Middle-aged rats underwent pellet implantation (0.1 mg, 60d sustained release; Innovative Research of America) or sham surgery 8 weeks after OVX. In recent reports (De Butte-Smith et al, 2009; Traub et al, 2009) we found that estradiol was effective in rescuing CA1 pyramidal neurons from ischemia-induced cell death in middle-aged rats that were OVX for 8 weeks before experimentation. Hence, we used the 8 week OVX duration as these animals would be similar to women who are 5–10 years post-menopause.…”

“…In contrast, we recently demonstrated that estradiol pretreatment is neuroprotective in middle-aged females that are OVX for 8 weeks prior to insult (De Butte-Smith et al, 2009; Traub et al, 2009). Hence, the current study investigated the effects of estradiol on the phosphorylation status of several key molecular targets involved in neuronal survival, such as Akt, CREB, and STAT3, in middle-aged female rats subjected to global ischemia 8 weeks after OVX.…”

“…We recently reported that estradiol retains its neuroprotective actions after global ischemia in middle-aged female rats even after 8 weeks of ovarian hormone deprivation (De Butte-Smith et al, 2009; Traub et al, 2009). Both acute (Raval et al, 2009) and chronic (Jover-Mengual et al, 2007) pretreatment with estradiol elevates p-CREB in young female rats subjected to global ischemia.…”

“…Neuroprotective treatments such as estradiol (Jover-Mengual et al, 2010; Wilson et al, 2002) and ischemic preconditioning (Zhan et al, 2010) promote phosphorylation of Akt and subsequent phosphorylation and inactivation of downstream targets implicated in cell death. The ability to markedly elevate p-Akt at 3 h after ischemia in older females may contribute to the hormone’s efficacy in reducing CA1 cell death after global ischemia (De Butte-Smith et al, 2009; Traub et al, 2009). …”

“…It is now well established that endogenous and exogenous estrogens exert profound neuroprotective effects in animal models of global ischemia (Etgen et al, 2011; Brown et al, 2009; Lebesgue et al, 2009; Suzuki et al, 2009). Recently, we reported that estradiol retains its neuroprotective actions after global ischemia in middle-aged female rats, even after long-term hormone withdrawal (De Butte-Smith et al, 2009; Lebesgue et al, 2010; Traub et al, 2009). To date, the molecular mechanisms underlying estradiol protection against global ischemia-induced neuronal death in middle-aged rats are unclear.…”