Abstract
Human umbilical cord blood derived CD34+ stem cells are reported to mediate therapeutic effects in stroke animal models. Estrogen was known to protect against ischemic injury. The present study wished to investigate whether the protective effect of CD34+ cells against ischemic injury can be reinforced with complemental estradiol treatment in female ovariectomized rat and its possible mechanism. Experiment 1 was to determine the best optimal timing of CD34+ cell treatment for the neuroprotective effect after 60-min middle cerebral artery occlusion (MCAO). Experiment 2 was to evaluate the adjuvant effect of 17β-estradiol on CD34+ cell neuroprotection after MCAO. Experiment 1 showed intravenous infusion with CD34+ cells before MCAO (pre-treatment) caused less infarction size than those infused after MCAO (post-treatment) on 7T magnetic resonance T2-weighted images. Experiment 2 revealed infarction size was most significantly reduced after CD34+ + estradiol pre-treatment. When compared with no treatment group, CD34+ + estradiol pre-treatment showed significantly less ADC reduction at 2 h and 2 d, less CBF reduction at 2 h and less hyperperfusion at 2 d. The immunoreactivity of c-Fos, c-Jun and GFAP was attenuated, and BDNF showed significant recovery from 2 h to 2 d after MCAO, especially after CD34+ + estradiol pre-treatment. The present study suggests pre-treatment with CD34+ cells with complemental estradiol can be most protective against ischemic injury, which may act through stabilization of cerebral hemodynamics and normalization of the expressions of immediate early genes and BDNF.
Highlights
Stroke is ranked as one of the leading causes of death, and the poststroke neurological disability is the most important problem to cause handicap worldwide
The present study suggests pre-treatment with CD34+ cells with complemental estradiol can be most protective against ischemic injury, which may act through stabilization of cerebral hemodynamics and normalization of the expressions of immediate early genes and Brain-derived neurotrophic factor (BDNF)
The result showed the infarction volume was significantly smaller in CD34+ pre-treatment group (84.94 ± 37.14 mm3) than no treatment group (177.22 ± 28.39 mm3, p = 0.011) on T2-weighted images obtained at 2 d after middle cerebral artery occlusion (MCAO) (Fig 1)
Summary
Stroke is ranked as one of the leading causes of death, and the poststroke neurological disability is the most important problem to cause handicap worldwide. Brain-derived neurotrophic factor (BDNF) is known to be protective against neuronal damage in in vivo and in vitro studies [7,8]. Combined intravenous treatment with HUCB cells and mannitol was found to significantly increase cerebral BDNF, which correlated positively with reduced cerebral infarction and improved behavioral functions in a MCAO rat model [9]. Estrogen administered before or after ischemia has demonstrated protective effect against ischemic damage in normal rats [10,11] and in ovariectomized rats [12,13], and is found to selectively attenuate the injury-induced increase of c-Fos after MCAO [14]
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