Pola Roberto, Flex Andrea, Ciaburri Michele, Rovella Emilio, Valiani Angela, Reali Giada, Silveri Maria C, Bernabei Roberto
Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, L.go A. Gemelli 8, 00168 Rome, Italy.
Neurosci Lett. 2005 Jul 15;382(3):338-41. doi: 10.1016/j.neulet.2005.03.027. Epub 2005 Apr 7.
Cholinesterase inhibitors (ChEIs) are the most established treatment strategy in Alzheimer's disease (AD). However, the responsiveness to these drugs is widely heterogeneous and the majority of AD subjects do not respond to treatment. Paraoxonase-1 (PON-1) is a potent endogenous ChEI and has been widely studied for its ability to hydrolyze environmental neurotoxins. Serum levels and biological activity of PON-1 display wide inter-individual variability and are strongly influenced by a common polymorphism at position 192 of the PON-1 gene. Here, we evaluated whether this gene variation is associated with differences in the ability of AD subjects to respond to therapy with ChEIs. We found that individuals that respond to ChEIs had a significantly higher frequency of the R allele, compared to non-responders (P<0.05). This study indicates that the 192 Q/R polymorphism of the PON-1 gene might influence responsiveness to ChEIs, with potentially important implications for the treatment of AD. Mutations of genes encoding for endogenous modulators of the cholinergic system should merit further investigation as prognostic indicators of individual response to treatment in AD subjects.
胆碱酯酶抑制剂（ChEIs）是治疗阿尔茨海默病（AD）最成熟的治疗策略。然而，对这些药物的反应存在广泛的异质性，大多数AD患者对治疗无反应。对氧磷酶-1（PON-1）是一种有效的内源性胆碱酯酶抑制剂，因其水解环境神经毒素的能力而被广泛研究。PON-1的血清水平和生物活性存在广泛的个体间差异，并受到PON-1基因第192位常见多态性的强烈影响。在此，我们评估了这种基因变异是否与AD患者对ChEIs治疗反应的差异有关。我们发现，与无反应者相比，对ChEIs有反应的个体中R等位基因的频率显著更高（P<0.05）。这项研究表明，PON-1基因的192 Q/R多态性可能影响对ChEIs的反应，对AD的治疗可能具有重要意义。编码胆碱能系统内源性调节剂的基因突变作为AD患者个体治疗反应的预后指标值得进一步研究。
