Britzolaki Aikaterini, Cronin Claire C, Flaherty Patrick R, Rufo Riely L, Pitychoutis Pothitos M
Department of Biology, University of Dayton, Dayton, OH, USA.
Department of Biology, University of Dayton, Dayton, OH, USA; Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA; Integrative Science and Engineering (ISE) Center, University of Dayton, Dayton, OH, USA.
Behav Brain Res. 2021 Feb 5;399:112984. doi: 10.1016/j.bbr.2020.112984. Epub 2020 Nov 1.
Intracellular calcium (Ca) homeostasis is a vital process to nerve cell survival and function with an intricate regulatory network. It is well established that the endoplasmic reticulum (ER) is a major intraneuronal Ca storage and that the sarco/endoplasmic reticulum (SR/ER) calcium (Ca)-ATPase (SERCA) pump is a key regulator of cytosolic Ca levels. SERCA pumps play a critical role in brain pathophysiology, thus SERCA comprises an emerging pharmacological target for the treatment of brain diseases. Interestingly, preclinical studies in rodents suggest that chronic pharmacological activation of SERCA2 by the quinoline derivative CDN1163 comprises a potential pharmacotherapeutic target in Alzheimer's and Parkinson's diseases. As little is known about the behavioral and neurochemical consequences of CDN1163 administration, in the current study we investigated the potential effects of acute (i.e., at 1 h) and chronic (i.e., 17 days) CDN1163 administration (i.e., 10 mg/kg and 20 mg/kg; intraperitoneally) on locomotor activity and relevant affective behaviors, as well as on monoaminergic neurotransmission in naïve C57BL/6J mice of both sexes. Interestingly, chronic, but not acute, CDN1163 administration induced anxiogenic and depressive-like behavioral effects in mice, as assessed in the open field (OF) test and the forced swim test (FST), respectively. In addition, chronic CDN1163 administration induced sustained sex- and brain region-dependent noradrenergic and serotonergic neurochemical effects ex vivo. Taken together, present findings support the critical role of SERCA-dependent Ca handling in regulating behavior and neurochemical activity, and further highlight the need to consider sex in the development of SERCA-targeting pharmacotherapies for the treatment of debilitating brain disorders.
细胞内钙（Ca）稳态是神经细胞存活和功能的重要过程，其调控网络错综复杂。内质网（ER）是神经元内主要的钙储存部位，肌浆网/内质网（SR/ER）钙（Ca）-ATP酶（SERCA）泵是胞质钙水平的关键调节因子，这一点已得到充分证实。SERCA泵在脑病理生理学中起关键作用，因此SERCA成为治疗脑部疾病的新兴药理学靶点。有趣的是，啮齿动物的临床前研究表明，喹啉衍生物CDN1163对SERCA2的慢性药理学激活是阿尔茨海默病和帕金森病的潜在药物治疗靶点。由于对CDN1163给药的行为和神经化学后果知之甚少，在本研究中，我们调查了急性（即1小时）和慢性（即17天）腹腔注射CDN1163（即10mg/kg和20mg/kg）对未接触过药物的雌雄C57BL/6J小鼠的运动活动、相关情感行为以及单胺能神经传递的潜在影响。有趣的是，分别通过旷场（OF）试验和强迫游泳试验（FST）评估发现，慢性而非急性CDN1163给药在小鼠中诱导出焦虑样和抑郁样行为效应。此外，慢性CDN1163给药在体外诱导出持续的、依赖性别和脑区的去甲肾上腺素能和5-羟色胺能神经化学效应。综上所述，目前的研究结果支持了SERCA依赖的钙处理在调节行为和神经化学活性中的关键作用，并进一步强调在开发针对SERCA的药物疗法以治疗衰弱性脑部疾病时需要考虑性别因素。
