Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke

Five groups of mice were subjected to thromboembolic stroke: adult males, aged males, adult females, aged females, and adult ovariectomized females. They were treated with phosphate saline (vehicle) or minocycline (6 mg/kg) immediately after stroke onset. Behavioral outcomes, infarct volumes and cerebral blood flow were assessed. The effect of minocycline on expression and activity of MMP-9 was analyzed.The model resulted in reproducible infarct in the experimental groups. As expected, adult females were significantly more resistant to cerebral ischemic injury than males. This advantage was abolished by aging and ovariectomy. Minocycline significantly reduced the infarct volume (P < 0.0001) and also improved neurologic score (P < 0.0001) in all groups. Moreover, minocycline treatment significantly reduced mortality at 24 hours post stroke (P = 0.037) for aged mice (25% versus 54%). Stroke up-regulated MMP-9 level in the brain, and acute minocycline treatment reduced its expression in both genders (P < 0.0001).In a thromboembolic stroke model minocycline is neuroprotective irrespective of mouse sex and age.Interest in sex differences during acute stroke is an area of growing interest. A consistent finding in rodent models of cerebral ischemia is that young females have smaller infarct sizes and better outcomes than young male rodents [1]. This female protection is lost after ovariectomy. However, the sex difference in stroke is only present when the brain is reperfused; in permanent occlusion the sex difference vanishes [2]. Moreover, in older rodents, the sex difference seen in younger animals is lost [3]. Reproductively senescent older female and male mice have similar infarct sizes after 2 hours of ischemia and 22 hours of reperfusion [4].The effect of sex on stroke outcome may also be hormone independent [3]. Recent studies suggest the existence of sex-divergent cell death pathways operating during cerebral ischemia [5]. The neuronal nitric oxide (NO)/Poly ADP ri