Systems pharmacology modeling in neuroscience: Prediction and outcome of PF-04995274, a 5-HT4 partial agonist, in a clinical scopolamine impairment trial

Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT4 modulation in providing beneficialeffects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and5-HT4 activity as output. The serotonergic model was calibrated using bothinvivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated usingdata reported for working memory tasks in healthyhumans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer’s disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT4 activation on working memory and to prospectively simulate the response of PF- 04995274, a 5-HT4partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low in- trinsic activity 5-HT4agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD patients.

环境相关浓度的氟西汀和帕罗西汀对章鱼脑组织五羟色胺能系统的影响

近年来,随着抑郁症患者数量激增,抗抑郁性药物的使用量显著增加。由于药物具有特殊活性,常会对非目标生物的生理功能产生不良影响,干扰这些生物的生长发育,对其健康产生严重威胁。因此,本研究选取通过抑制五羟色胺(serotonin,5-HT)转运体提高突触间隙5-HT水平发挥治疗作用的SSRI(selective serotonin reuptake inhibitor)类抗抑郁代表性药物氟西汀和帕罗西汀,探讨2种药物对章鱼脑组织5-HT能神经递质系统功能的影响。野生成体短蛸章鱼(O.ochellatus)于环境浓度的氟西汀、帕罗西汀溶液中连续暴露14 d,收集脑组织。通过qPCR和Western blot技术分析药物对章鱼脑组织5-HT能神经递质系统主要功能分子转录及表达水平的影响。结果显示,氟西汀和帕罗西汀引起章鱼脑组织中5-HT能系统重要功能分子转录及表达水平异常,表现为5-HTR1、5-HTR1B、5-HTR2A、SERT mRNA转录水平降低及5-HTR1、5-HTR1B、5-HTR2A、SERT蛋白表达水平升高,且具有药物特异性和剂量依赖性。此外,氟西汀与帕罗西汀混合暴露对章鱼脑5-HT能系统的影响程度弱于两者单独暴露,提示2种药物在干扰章鱼脑5-HT能系统正常功能过程中可能存在拮抗作用,通过比较二者的半衰期,认为氟西汀对于水生生态系统的影响更大。本研究结果表明,SSRI类抗抑郁药物氟西汀和帕罗西汀暴露可引起章鱼脑组织5-HT能神经系统主要功能分子转录与表达水平异常,可能干扰其正常功能,严重威胁章鱼健康。本研究为进一步研究抗抑郁症药物对章鱼神经系统的不良影响提供科学依据,为研究其他药物对海洋生物的健康损害效应提供参考。

单胺类神经递质在药物成瘾中的作用机制

药物成瘾是一种慢性复发性大脑疾病,各种成瘾性药物通过作用于奖赏系统,最终引起神经递质释放的改变,产生奖赏效应。其中,单胺类神经递质5-羟色胺(5-hydroxytryptamine,5-HT)、去甲肾上腺素(noradrenergic,NE)和多巴胺(dopamine,DA)在药物成瘾中起到重要作用,该文就单胺类神经递质在药物成瘾中的作用及机制进行综述。