Propyl pyrazole triol (PPT) is a selective estrogen receptor α (ERα) agonist that can shield neurons from oxidative stress and inflammatory damage through ERα activation in the nervous system[1]. The binding affinity of Propyl pyrazole triol to the two ERs (ERα and ERβ) shows more than a 400-fold preference for ERα[2]. Propyl pyrazole triol is shown as estradiol to modulate hippocampal N-methyl-d-aspartate (NMDA) receptors and AMP-activated protein kinase (AMPK) receptors in the cortex and striatum of ovariectomized rats[3].
In vitro, adult rat dorsal root ganglion neurons were exposed to 1, 10, or 100nM Propyl pyrazole triol. A 1h treatment elicited a concentration-dependent rise in AMPK phosphorylation, whereas a 24h exposure to 10nM Propyl pyrazole triol significantly increased total neurite outgrowth, elevated nuclear activating transcription factor 3 (ATF3) expression, and improved multiple parameters of mitochondrial function[4]. Treatment of aortic smooth-muscle cells with 100µM Propyl pyrazole triol raised cyclic GMP (cGMP) from a basal level of 0.84±0.28 to 2.05±0.3pmol/mg protein, while 50µM Propyl pyrazole triol reduced the intracellular calcium signal by 70.6±9.95%[5].
In vivo, starting two days after ovariectomy, rats received daily subcutaneous injections of 1mg/kg Propyl pyrazole triol for 14 days, which prevented the loss of uterine weight, blocked the rise in [3H]α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) binding in the striatum and nucleus accumbens, and reduced GluR2 mRNA in the prefrontal cortex and striatum[6]. Male rats received daily subcutaneous injections with 1mg/kg Fadrozole 1h before mating for 29 days and were given an additional single 1mg/kg Propyl pyrazole triol subcutaneous injection on Days 13 and 29 showed more mounting but reached sexual satiety sooner[7].
References:
[1] Zhang K, Hou B, Yan T, et al. Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genes. Exp Gerontol. 2025;200:112676.
[2] Vijaykumar D, Al-Qahtani MH, Welch MJ, et al. Synthesis and biological evaluation of a fluorine-18 labeled estrogen receptor-alpha selective ligand: [18F] propyl pyrazole triol. Nucl Med Biol. 2003;30(4):397-404.
[3] Morissette M, Le Saux M, D'Astous M, et al. Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain. J Steroid Biochem Mol Biol. 2008;108(3-5):327-338.
[4] Mishra P, Albensi BC, Fernyhough P. Estradiol activates the CaMKKβ/AMPK pathway to enhance neurite outgrowth in cultured adult sensory neurons. Mol Cell Neurosci. 2025;133:104008.
[5] Alda JO, Valero MS, Pereboom D, et al. Endothelium-independent vasorelaxation by the selective alpha estrogen receptor agonist propyl pyrazole triol in rat aortic smooth muscle. J Pharm Pharmacol. 2009;61(5):641-646.
[6] Le Saux M, Estrada-Camarena E, Di Paolo T. Selective estrogen receptor-alpha but not -beta agonist treatment modulates brain alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. J Neurosci Res. 2006;84(5):1076-1084.
[7] Corre PHC, Mainwaring JM, Peralta KKZ, et al. Low dose of propyl-pyrazole-triol, an agonist of estrogen receptor alpha, administration stimulates the Coolidge effect in fadrozole-treated male rats. Horm Behav. 2024;161:105520.
Propyl pyrazole triol (PPT)是一种选择性雌激素受体α（ERα）激动剂，可通过在神经系统激活ERα，保护神经元免受氧化应激与炎症损伤[1]。其对ERα和ERβ的亲和力差异达400倍以上，显著偏好ERα[2]。与雌二醇类似，Propyl pyrazole triol可调节去卵巢大鼠海马N-甲基-d-天冬氨酸（NMDA）受体及大脑皮层与纹状体内的AMP活化蛋白激酶（AMPK）受体[3]。
在体外，成年大鼠背根神经节神经元分别暴露于1、10或100nM的Propyl pyrazole triol。1小时处理即可浓度依赖性地升高AMPK磷酸化水平；而24小时10nM的Propyl pyrazole triol处理显著促进总神经突生长、提高核内转录激活因子3（ATF3）表达，并改善多项线粒体功能指标[4]。对主动脉平滑肌细胞给予100µM的Propyl pyrazole triol，可使环磷酸鸟苷（cGMP）由基线0.84±0.28升至2.05±0.3pmol/mg蛋白；50µM的Propyl pyrazole triol则可降低细胞内钙信号70.6±9.95%[5]。
在体内，大鼠于卵巢切除术后第2天开始每日皮下注射1mg/kg的Propyl pyrazole triol，连续14天，可阻止子宫重量丢失和纹状体与伏隔核中[3H]α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）结合的增加，并降低前额叶皮层与纹状体中GluR2 mRNA的表达[6]。雄性大鼠于交配前29天每日皮下注射1mg/kg芳香化酶抑制剂Fadrozole，并于第13、29天额外单次皮下注射1mg/kg的Propyl pyrazole triol，大鼠爬背次数增加但更快达到性饱足[7]。