Gibbs R B
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, 1004 Salk Hall, Pittsburgh, PA 15261, USA.
Brain Res. 1998 Mar 23;787(2):259-68. doi: 10.1016/s0006-8993(97)01511-4.
Recent studies suggest that hormone replacement therapy can help to reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women. We have hypothesized that these effects are due, in part, to the ability for estrogen and progesterone to enhance hippocampal function, as well as the functional status of cholinergic projections to the hippocampus and cortex, by influencing the expression of specific neurotrophins and neurotrophin receptors. In the present study, quantitative in situ hybridization techniques were used to determine whether the levels of trkA mRNA in the basal forebrain, and nerve growth factor (NGF) mRNA and brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus, are significantly affected by physiological changes in circulating gonadal steroids. Gonadally intact animals were sacrificed at different stages of the estrous cycle and ovariectomized animals were sacrificed at different times following the administration of either estrogen or estrogen plus progesterone. In gonadally intact animals, significant fluctuations in the levels of trkA mRNA in the medial septum (MS), and BDNF mRNA in regions CA1 and CA3/4 of the hippocampus, were detected across the estrous cycle. In animals that received hormone replacement, a significant increase (30.4%) in trkA mRNA was detected in the MS of animals sacrificed 24 h following estrogen administration. Levels of trkA mRNA in the MS declined to control levels over the next 48 h; however, a single injection of progesterone administered 48 h after estradiol appeared to prevent any further decline in trkA mRNA over the next 24 h. In addition, significant increases in BDNF mRNA were detected in the dentate granule cell layer (73.4%), region CA1 (28. 1%), and region CA3/4 (76.9%) of animals sacrificed 53 h after receiving estrogen and 5 h after receiving progesterone. No significant changes in trkA mRNA were detected in the nucleus basalis magnocellularis, and no significant changes in NGF mRNA were detected in the hippocampus. These data demonstrate that levels of trkA mRNA in the MS, and BDNF mRNA in the hippocampus, are affected by physiological changes in the levels of circulating gonadal steroids and are elevated in response to acute hormone replacement. The relevance of these effects to the ability for estrogen replacement to enhance cholinergic activity and hippocampal function, and thereby reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women, is discussed.
近期研究表明，激素替代疗法有助于降低绝经后女性患阿尔茨海默病相关痴呆症的风险并减轻其严重程度。我们推测，这些作用部分归因于雌激素和孕激素能够通过影响特定神经营养因子和神经营养因子受体的表达，增强海马体功能以及海马体与皮质之间胆碱能投射的功能状态。在本研究中，运用定量原位杂交技术来确定循环性腺类固醇的生理变化是否会显著影响基底前脑trkA mRNA的水平，以及海马体中神经生长因子（NGF）mRNA和脑源性神经营养因子（BDNF）mRNA的水平。在发情周期的不同阶段处死性腺完整的动物，并在给予雌激素或雌激素加孕激素后的不同时间处死去卵巢的动物。在性腺完整的动物中，整个发情周期内检测到内侧隔区（MS）中trkA mRNA水平以及海马体CA1区和CA3/4区中BDNF mRNA水平存在显著波动。在接受激素替代的动物中，雌激素给药后24小时处死的动物的MS中trkA mRNA显著增加（30.4%）。在接下来的48小时内，MS中trkA mRNA水平降至对照水平；然而，在雌二醇给药48小时后单次注射孕激素似乎可防止trkA mRNA在接下来的24小时内进一步下降。此外，在接受雌激素53小时和孕激素5小时后处死的动物的齿状颗粒细胞层（73.4%）、CA1区（28.1%）和CA3/4区（76.9%）中检测到BDNF mRNA显著增加。在大细胞基底核中未检测到trkA mRNA的显著变化，在海马体中未检测到NGF mRNA的显著变化。这些数据表明，MS中trkA mRNA水平以及海马体中BDNF mRNA水平受循环性腺类固醇水平的生理变化影响，并在急性激素替代后升高。本文讨论了这些作用与雌激素替代增强胆碱能活性和海马体功能从而降低绝经后女性患阿尔茨海默病相关痴呆症的风险及严重程度的能力之间的相关性。
