Targeting toll like receptor 4 (TLR4) and TLR2 to resolve EAE-associated paralysis, pain and cognitive deficits: efficacy of a clinically-relevant blood brain barrier permeable TLR4/TLR2 antagonist
靶向 Toll 样受体 4 (TLR4) 和 TLR2 以解决 EAE 相关的麻痹、疼痛和认知缺陷:临床相关血脑屏障可渗透性 TLR4/TLR2 拮抗剂的功效
基本信息
- 批准号:9153350
- 负责人:
- 金额:$ 33.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-15 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnti-Inflammatory AgentsAnti-inflammatoryBehavioralBindingBlood - brain barrier anatomyBrainCell DeathCellsCerebrospinal FluidCharacteristicsChronicClinicalClinical TrialsCognitive deficitsDemyelinationsDepartment of DefenseDevelopmentDiseaseDisease ProgressionDoseDrug abuseEncephalitisExperimental Autoimmune EncephalomyelitisFemaleFunctional disorderFundingGoalsGrantHeightHumanImmuneImmunohistochemistryImmunologic ReceptorsImpaired cognitionImpairmentInflammationInflammatoryInvestigationInvestigational DrugsInvestigational New Drug ApplicationIsomerismLifeLiteratureLysophosphatidylcholinesMapsModelingMotorMultiple SclerosisNaltrexoneOpioidOpioid ReceptorPainPain managementParalysedParesisPathologyPopulationProcessRattusRecruitment ActivityResearchRodentRoleSeriesSiteSocial InteractionSpecificitySpinalSpinal CordSymptomsSystemTLR2 geneTLR4 geneTestingTherapeuticTissuesTranslationsWorkbehavioral studychronic demyelinationclinically relevantcytokineglial activationimprovedmalemotor disordermultiple sclerosis treatmentneuroinflammationneuron lossnon-drugnovelpainful neuropathypre-clinicalreceptorremyelinationsmall moleculesocial cognitionsymptomatic improvement
项目摘要
PROJECT SUMMARY
Multiple sclerosis (MS) is a life-long, debilitating disease in both males and females. Symptoms include
loss of motor function, neuropathic pain, cognitive impairments, and impaired social interaction. MS is
furthermore associated with elevations in circulating and central (spinal cord and brain) levels of pro-
inflammatory cytokines and decreased levels of anti-inflammatory cytokines, suggesting a dysregulation of
immune and glial processes resulting in chronic inflammation. This ongoing inflammation is important in
demyelination, chronic glial activation, and neuronal death characteristic of the disease.
Targeted suppression of spinal cord neuroinflammation using anti-inflammatory strategies dramatically
improves symptoms of experimental autoimmune encephalomyelitis (EAE), a rat model of MS. Looking forward
toward translation, what is needed is not our current approaches that are injected intrathecally, but rather a
means to effectively treat EAE/MS via a clinically relevant, orally available, blood-brain barrier permeable small
molecule that targets EAE/MS pathology driven by neuroinflammation.
We have discovered, and extensively characterized, such a small molecule. This drug (the non-opioid
(+)-isomer of naltrexone; (+)-naltrexone) is rapidly moving toward FDA application for Investigational New Drug
status. This is a selective antagonist at toll-like receptor 4 (TLR4) and TLR2. As it fails to bind classical opioid
receptors, (+)-naltrexone does not interfere with the efficacy of opioids for pain control or normal functioning of
opioid receptor systems. Targeting TLR2 and TLR4 arises from an extensive literature demonstrating the
importance of these receptors in the neuroinflammatory processes and EAE/MS symptoms to be studied here.
A complimentary series of behavioral and immunohistochemistry studies are proposed in males and
females which will explore the ability of (+)-naltrexone to suppress EAE-induced (a) paresis/paralysis, (b)
neuropathic pain, (c) cognitive impairment, and (d) social interaction impairment, as well as (e) improve
survival, when (+)-naltrexone is systemically administered across days, comparing dosing early vs. late in the
EAE timecourse. The IHC studies will analyze brain and spinal cord tissues collected after early vs. late (+)-
naltrexone treatment (mapping onto the behavioral studies) to define whether (+)-naltrexone suppresses glial
activation, neuronal cell death, and demyelination, as well as stimulates remyelination, as predicted.
These studies create two complimentary Aims. Aim 1 explores a novel means of positively intervening in
EAE-induced motor dysfunction, neuropathic pain, deficits in social interaction and cognition, and loss of life by
targeting TLR4/TLR2 by systemic administration of (+)-naltrexone. Aim 2 transitions to an initial exploration of
potential mechanisms underlying pathophysiology, focusing on the impact of TLR4/TLR2 blockade on
demyelination and remyelination, neuronal cell death, and neuroinflammation. These studies provide a
thorough investigation of the role of TLR4/TLR2 in major MS-relevant symptoms of EAE.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('LINDA WATKINS', 18)}}的其他基金
Enduring enhancement of neuropathic pain by early post-trauma morphine
创伤后早期吗啡持久增强神经性疼痛
- 批准号:
9906887 - 财政年份:2018
- 资助金额:
$ 33.68万 - 项目类别:
Enduring enhancement of neuropathic pain by early post-trauma morphine
创伤后早期吗啡持久增强神经性疼痛
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10393512 - 财政年份:2018
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$ 33.68万 - 项目类别:
Targeting neuropathic pain prevention: Modulating the neuroimmunology of peripheral nerve injury
以预防神经病理性疼痛为目标:调节周围神经损伤的神经免疫学
- 批准号:
10062833 - 财政年份:2016
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$ 33.68万 - 项目类别:
Spinal adenosine modulator: enduring anti-inflammatory action in neuropathic pain
脊髓腺苷调节剂:对神经性疼痛具有持久的抗炎作用
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7805660 - 财政年份:2009
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$ 33.68万 - 项目类别:
Spinal adenosine modulator: enduring anti-inflammatory action in neuropathic pain
脊髓腺苷调节剂:对神经性疼痛具有持久的抗炎作用
- 批准号:
7937819 - 财政年份:2009
- 资助金额:
$ 33.68万 - 项目类别:
Models and mechanisms for the transition of acute-to-chronic orofacial pain
急性至慢性口面部疼痛转变的模型和机制
- 批准号:
7936108 - 财政年份:2009
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$ 33.68万 - 项目类别:
Models and mechanisms for the transition of acute-to-chronic orofacial pain
急性至慢性口面部疼痛转变的模型和机制
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7805658 - 财政年份:2009
- 资助金额:
$ 33.68万 - 项目类别:
Optoid Analgesics: Modulation of Trigeminal & Spinal Glial Activation
Optoid 镇痛药:三叉神经的调节
- 批准号:
7840785 - 财政年份:2009
- 资助金额:
$ 33.68万 - 项目类别:
Immune and Gilia Regulation of Pain & Analgesic Actions
免疫和吉利亚疼痛调节
- 批准号:
8284453 - 财政年份:2008
- 资助金额:
$ 33.68万 - 项目类别:
Exploring the Potential of Glia for Regulating Clinically Relevant Opiod Actions
探索神经胶质细胞调节临床相关阿片类药物作用的潜力
- 批准号:
8267435 - 财政年份:2008
- 资助金额:
$ 33.68万 - 项目类别:
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