Pelligrino D A, Santizo R, Baughman V L, Wang Q
Neuroanesthesia Research Laboratory, University of Illinois at Chicago, 60607, USA.
Neuroreport. 1998 Oct 5;9(14):3285-91. doi: 10.1097/00001756-199810050-00026.
The effects of chronic 17beta-estradiol (E2) depletion, via ovariectomy (OVX), and its repletion, on cortical cerebral blood flow (CBF) and EEG activities during forebrain ischemia, as well as post-ischemic recovery and neuropathology, were assessed and compared with results obtained in normal female rats. We also examined whether neuronal nitric oxide synthase (nNOS) activity is affected by OVX and E2 replacement and whether NOS-derived NO supports vasodilation during ischemia. OVX females displayed a significantly lower CBF during ischemia (10% of baseline) than did normal females (23% of baseline). In OVX rats, given chronic low-dose E2 treatment (0.1 mg kg(-1) day(-1)), intra-ischemic CBF was similar to normal females (25% of baseline). However, at supraphysiologic E2 doses (> or = 0.5 mg kg(-1) day(-1)), that benefit was diminished or lost. Intra-ischemic EEG power reductions and post-ischemic survival rates, neurological dysfunction, and histopathology displayed similar relative differences among groups as the CBF findings. Intra-ischemic CBF was reduced by nNOS inhibition, with ARL 17477, in normal and low-dose E2-treated OVX rats (4-8% baseline). The repressed intra-ischemic vasodilating function in OVX rats may be due to reductions in nNOS activity, because untreated OVX rats showed a 50% lower cortical nNOS activity than that in normal rats and in rats treated with low or high dose (5 mg kg(-1) day(-1)) E2. However, the inability to restore vasodilating function despite normalization of nNOS activity indicates that another mechanism is responsible for the repression of vasodilatory function in the high-dose group. These findings suggest that E2, at levels within the physiological range, promotes ischemic neuroprotection via improving vasodilating capacity. One possible mechanism may relate to E2 enhancing brain nNOS expression and activity.
通过卵巢切除术（OVX）造成慢性17β-雌二醇（E2）耗竭及其补充对雌性大鼠前脑缺血期间皮质脑血流量（CBF）和脑电图活动以及缺血后恢复和神经病理学的影响，并与正常雌性大鼠的结果进行比较。我们还研究了神经元型一氧化氮合酶（nNOS）活性是否受OVX和E2替代的影响，以及一氧化氮合酶衍生的NO是否在缺血期间支持血管舒张。OVX雌性大鼠在缺血期间的CBF（基线的10%）显著低于正常雌性大鼠（基线的23%）。在接受慢性低剂量E2治疗（0.1 mg·kg⁻¹·天⁻¹）的OVX大鼠中，缺血期间的CBF与正常雌性大鼠相似（基线的25%）。然而，在超生理剂量的E2（≥0.5 mg·kg⁻¹·天⁻¹）时，这种益处减弱或丧失。缺血期间脑电图功率降低以及缺血后存活率、神经功能障碍和组织病理学在各实验组间表现出与CBF结果相似的相对差异。在正常和低剂量E2治疗的OVX大鼠中，用ARL 17477抑制nNOS可降低缺血期间的CBF（基线的4 - 8%）。OVX大鼠缺血期间血管舒张功能受抑制可能是由于nNOS活性降低，因为未治疗的OVX大鼠皮质nNOS活性比正常大鼠以及接受低剂量或高剂量（5 mg·kg⁻¹·天⁻¹）E2治疗的大鼠低50%。然而，尽管nNOS活性恢复正常但血管舒张功能仍无法恢复，这表明高剂量组中血管舒张功能受抑制还有另一种机制。这些发现表明，生理范围内的E2通过提高血管舒张能力促进缺血性神经保护。一种可能的机制可能与E2增强脑nNOS表达和活性有关。
