Novel neurosteroid anesthetics and developmental synaptogenesis
新型神经类固醇麻醉剂和发育突触发生
基本信息
- 批准号:10456624
- 负责人:
- 金额:$ 52.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-12 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAgeAgonistAlphaxoloneAnalgesicsAnesthesia proceduresAnestheticsAnimalsApoptoticBase of the BrainBehavioralBrainCell DeathChildChildhoodClinicalCommunicationComplementDataDevelopmentDrug InteractionsDrug KineticsElectrophysiology (science)EquilibriumExhibitsExposure toFamilyGeneral AnesthesiaGeneral anesthetic drugsGoalsHealth ProfessionalHippocampal FormationHippocampus (Brain)HumanImpaired cognitionImpairmentInfantInhalation AnestheticsInjectableKetamineMaintenanceMedicineMental DepressionMitochondriaModelingModernizationMonkeysMorphologyMusMutant Strains MiceN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNeuronsOutcomePharmaceutical PreparationsPlayPregnant WomenPreparationPropertyPropofolProtective AgentsRattusRegimenReportingRiskRodentRoleSafetySliceSteroidsSynaptic TransmissionSystemT-Type Calcium ChannelsTestingbehavioral impairmentcellular targetingchannel blockerscognitive developmentdesigndevelopmental neurotoxicityfunctional disabilityfunctional outcomesgamma-Aminobutyric Acidhypnoticin vivolong-term sequelaeneuronal excitabilityneuronal survivalneurosteroidsneurotoxicnew therapeutic targetnonhuman primatenovelpostnatalpostsynapticpresynapticpupreceptorside effectsteroid analogsynaptic functionsynaptogenesistranslational studyvoltageyoung adult
项目摘要
Summary
Exposure of young children to general anesthetics (GAs) is common in medicine; however, emerging data
suggest that this practice may be detrimental to brain development, resulting in long-term cognitive
impairments. Since currently used GAs known to be neurotoxic to the immature brain exert their action by
modulating two main receptor systems – GABA and NMDA – we suggest the general hypothesis that novel
anesthetics with different cellular targets might be safe and promising alternative. One such alternative
is a family of neuroactive steroids with blocking action on low-voltage-activated T-type calcium channels known
to be important for neuronal excitability and synaptic transmission. Our long-term goal is to develop novel GAs
that will provide the same reliability and efficacy as currently available ones but without devastating long-term
consequences. We are off to a promising start since T-channel-blocking neuroactive steroids are not only
powerful analgesics but also effective hypnotics. Most importantly, compared with other injectable (and
inhaled) anesthetics, they appear to be much less harmful to the developing brain based on our
preliminary pathomorphological and functional findings. Our rationale is that the design of safer
anesthetics for use in children should be guided by the presently available understanding of the mechanisms
responsible for developmental neurotoxicity of currently used GAs. To that end, we will use ex vivo and in vivo
rat models of GA-induced developmental neurotoxicity to address the specific hypothesis that novel
neuroactive steroids with blocking action on T-channels, unlike clinically-used GAs, are effective and safe
anesthetics for use during critical stages of brain development. Aim #1: Characterizes anesthetic properties of
novel neuroactive steroid analogs that are T-channel blockers (e.g. 3-OH and ECN) and GABAA agonists
(e.g. ACN, CDNC24 and alphaxalone) and compares their anesthesia profile in rats and mice with commonly
used injectable anesthetic, propofol. Preliminary data suggest that 3-OH is safe and effective and, compared
with ketamine, it exhibits higher efficacy and potency when administered to rat pups (at post-natal day 7). Aim
#2: Examines neurotoxic potential of neuroactive steroid analogs vis-à-vis propofol (known to cause significant
developmental neurotoxicity) by focusing on morphological and functional features of GA-induced impairments
of synaptogenesis (e.g. acute apoptotic cell death, delayed impairment in synapse formation/maintenance,
integrity of mitochondria, neuronal survival and impairment in synaptic transmission). Aim #3: Scrutinizes long-
term functional outcomes of an early exposure to novel neuroactive steroid analogs with particular focus on
neuronal communication in hippocampal ex vivo slice preparation and in vivo assessment of cognitive
development. Our preliminary findings suggest a lack of cognitive impairment after an early exposure to 3-
OH. Aim #4: Takes rodent studies to the next level by examining the anesthetic properties and safety of a
chosen neuroactive steroid (as determined in Aims 1-3) in infant non-human primates.
总结
项目成果
期刊论文数量(0)
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Vesna Jevtovic-Todorovic其他文献
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{{ truncateString('Vesna Jevtovic-Todorovic', 18)}}的其他基金
Novel neurosteroid anesthetics and developmental synaptogenesis
新型神经类固醇麻醉剂和发育突触发生
- 批准号:
10201697 - 财政年份:2019
- 资助金额:
$ 52.95万 - 项目类别:
Novel neurosteroid anesthetics and developmental synaptogenesis
新型神经类固醇麻醉剂和发育突触发生
- 批准号:
10673850 - 财政年份:2019
- 资助金额:
$ 52.95万 - 项目类别:
Novel neurosteroid anesthetics and developmental synaptogenesis
新型神经类固醇麻醉剂和发育突触发生
- 批准号:
10017289 - 财政年份:2019
- 资助金额:
$ 52.95万 - 项目类别:
Novel neurosteroid anesthetics and perioperative analgesia
新型神经类固醇麻醉剂和围手术期镇痛
- 批准号:
9333664 - 财政年份:2017
- 资助金额:
$ 52.95万 - 项目类别:
Novel neurosteroid anesthetics and perioperative analgesia
新型神经类固醇麻醉剂和围手术期镇痛
- 批准号:
9926278 - 财政年份:2017
- 资助金额:
$ 52.95万 - 项目类别:
Molecular mechanisms of glycosylation of Cav3.2 channels in pain pathway
疼痛通路中Cav3.2通道糖基化的分子机制
- 批准号:
9127411 - 财政年份:2016
- 资助金额:
$ 52.95万 - 项目类别:
Molecular mechanisms of glycosylation of Cav3.2 channels in pain pathway
疼痛通路中Cav3.2通道糖基化的分子机制
- 批准号:
9471872 - 财政年份:2016
- 资助金额:
$ 52.95万 - 项目类别:
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