N-adamantyl phthalimidine: a new thalidomide-like drug that lacks cereblon binding and mitigates neuronal and synaptic loss, neuroinflammation, and behavioral deficits in traumatic brain injury and LPS challenge

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Title
N-adamantyl phthalimidine: a new thalidomide-like drug that lacks cereblon binding and mitigates neuronal and synaptic loss, neuroinflammation, and behavioral deficits in traumatic brain injury and LPS challenge
Author(s)
S C Hsueh; W Luo; D Tweedie; D S Kim; Y K Kim; I Hwang; J E Gil; Baek Soo Han; Y H Chiang; W Selman; B J Hoffer; N H Greig
Bibliographic Citation
ACS Pharmacology Translational Science, vol. 4, no. 2, pp. 980-1000
Publication Year
2021
Abstract
Neuroinflammation contributes to delayed secondary cell death following traumatic brain injury (TBI), has the potential to chronically exacerbate the initial insult, and represents a therapeutic target that has largely failed to translate into human efficacy. Thalidomide-like drugs have effectively mitigated neuroinflammation across cellular and animal models of TBI and neurodegeneration but are complicated by adverse actions in humans. We hence developed N-adamantyl phthalimidine (NAP) as a new thalidomide-like drug to mitigate inflammation without binding to cereblon, a key target associated with the antiproliferative, antiangiogenic, and teratogenic actions seen in this drug class. We utilized a phenotypic drug discovery approach that employed multiple cellular and animal models and ultimately examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) TBI in mice. NAP mitigated LPS-induced inflammation across cellular and rodent models and reduced oligomeric α-synuclein and amyloid-β mediated inflammation. Following CCI TBI, NAP mitigated neuronal and synaptic loss, neuroinflammation, and behavioral deficits, and is unencumbered by cereblon binding, a key protein underpinning the teratogenic and adverse actions of thalidomide-like drugs in humans. In summary, NAP represents a new class of thalidomide-like drugs with anti-inflammatory actions for promising efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.
Keyword
ThalidomideTraumatic brain injuryNeuroinflammationTumor necrosis factor-αCereblonNeurodegeneration
ISSN
2575-9108
Publisher
ACS
DOI
http://dx.doi.org/10.1021/acsptsci.1c00042
Type
Article
Appears in Collections:
Division of Research on National Challenges > Biodefense Research Center > 1. Journal Articles
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