Effects of chronic NMDA-NR2b inhibition in the median eminence of the reproductive senescent female rat.
Effects of chronic NMDA-NR2b inhibition in the median eminence of the reproductive senescent female rat.
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DOI：
10.1111/jne.12087
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发表时间：
2013-10
影响因子：
3.2
通讯作者：
Gore AC
中科院分区：
文献类型：
--
作者：
Kermath BA;Riha PD;Sajjad A;Gore AC
下丘脑-垂体-性腺 (HPG) 轴的促性腺激素释放激素 (GnRH) 神经元驱动生殖功能，并在向生殖衰老过渡期间经历与年龄相关的激活减少。正中隆起 (ME) 的 GnRH 分泌减少，部分原因是通过 NMDA 受体 (NMDAR) 的谷氨酸能信号减弱，并且可能是由于随着年龄的增长，NMDAR 化学计量发生变化，有利于 NR2b 亚基表达，而不是 NR2a 亚基表达。我们之前已经证明，用艾芬地尔（一种 NR2b 特异性拮抗剂）对含有 NR2b 的受体进行系统性抑制，可以刺激年轻和中年女性黄体生成素（用作 GnRH 的代表）释放参数。在这里，我们在生殖衰老中年雌性大鼠的正中隆起 (ME) 的 GnRH 末端或视前区的 GnRH 周围长期施用艾芬地尔（一种 NR2b 特异性拮抗剂），以确定 NR2b 拮抗剂是否可以恢复生殖功能的各个方面。测量了 ME 中对动情周期、血清激素以及 GnRH、NR2b 和磷酸化 NR2b (Tyr-1472) 蛋白表达的影响。对 ME（而非视前区）进行慢性艾芬地尔治疗，通过增加促发情天数的百分比来改变发情周期。这伴随着外部 ME 区 GnRH 荧光强度的增加以及在治疗过程中与 pNR2b 共同标记的 GnRH 末端比例的增加。正如生物网络分析所揭示的，我们还观察到无周期女性中蛋白质免疫荧光、血清激素水平和生殖生理学其他方面之间关系的变化。总之，这些数据支持 NMDAR-NR2b 表达和磷酸化状态在生殖衰老中发挥作用的假设，并强调 ME 作为生殖衰老的主要参与者。
Gonadotrophin-releasing hormone (GnRH) neurones of the hypothalamic-pituitary-gonadal (HPG) axis drive reproductive function and undergo age-related decreases in activation during the transition to reproductive senescence. Decreased GnRH secretion from the median eminence (ME) partially arises from attenuated glutamatergic signaling via the NMDA receptor (NMDAR), and may be due to changing NMDAR stoichiometry to favor NR2b over NR2a subunit expression with aging. We have previously shown that the systemic inhibition of NR2b-containing receptors with ifenprodil, an NR2b-specific antagonist, stimulates parameters of luteinising hormone (used as a proxy for GnRH) release in both young and middle-aged females. Here, we chronically administered ifenprodil, an NR2b-specific antagonist, at the site of GnRH terminals in the median eminence (ME) or at GnRH perikarya in the preoptic area, in reproductively senescent middle-aged female rats to determine whether NR2b antagonism could restore aspects of reproductive functionality. Effects on oestrous cyclicity, serum hormones, and protein expression of GnRH, NR2b, and phosphorylated NR2b (Tyr-1472) in the ME were measured. Chronic ifenprodil treatment in the ME, but not the preoptic area, altered oestrous cyclicity by increasing the percentage of days spent in pro-oestrus. This was accompanied by increased GnRH fluorescence intensity in the external ME zone and a greater proportion of GnRH terminals that co-labelled with pNR2b with treatment. We also observed changes in the relationships between protein immunofluorescence, serum hormone levels, and other aspects of reproductive physiology in acyclic females, as revealed by bionetwork analysis. Together, these data support the hypothesis that NMDAR-NR2b expression and phosphorylation state play a role in reproductive senescence and highlight the ME as a major player in reproductive aging.
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影响因子：
4.1
作者：
Kermath BA;Gore AC
通讯作者：
Gore AC
影响因子：
4.8
作者：
Gore, AC;Yeung, G;Oung, T
通讯作者：
Oung, T
影响因子：
4.7
作者：
Grimwood, S;Richards, P;Hutson, PH
通讯作者：
Hutson, PH
DOI：
10.1073/pnas.88.21.9743
发表时间：
1991-11-01
影响因子：
11.1
作者：
JUNIER, MP;MA, YJ;OJEDA, SR
通讯作者：
OJEDA, SR
影响因子：
3.2
作者：
Carreño FR;Walch JD;Dutta M;Nedungadi TP;Cunningham JT
通讯作者：
Cunningham JT