TY - JOUR
T1 - N-Adamantyl Phthalimidine
T2 - 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
AU - Hsueh, Shih Chang
AU - Luo, Weiming
AU - Tweedie, David
AU - Kim, Dong Seok
AU - Kim, Yu Kyung
AU - Hwang, Inho
AU - Gil, Jung Eun
AU - Han, Baek Soo
AU - Chiang, Yung Hsiao
AU - Selman, Warren
AU - Hoffer, Barry J.
AU - Greig, Nigel H.
N1 - Funding Information:
This research was supported in part by the following: (i) The Intramural Research Program, National Institute on Aging, National Institutes of Health, United States; (ii) Grants from (a) the Ministry of Science and Technology, Taiwan (MOST 104-2923-B-038-001-MY3 and MOST 108-2321-B-038-008), (b) DP2-107-21121-01-N-05, Taipei Medical University, Taipei, Taiwan, and (c) National Institutes of Health R56 AG057028; and (iii) The Duane and Joyce Collins Neurosurgery Fund, Department of Neurological Surgery, Case Western Reserve University, Cleveland, OH.
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/4/9
Y1 - 2021/4/9
N2 - 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.
AB - 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.
KW - cereblon
KW - neurodegeneration
KW - neuroinflammation
KW - thalidomide
KW - traumatic brain injury
KW - tumor necrosis factor-α
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U2 - 10.1021/acsptsci.1c00042
DO - 10.1021/acsptsci.1c00042
M3 - Article
AN - SCOPUS:85104027420
SN - 2575-9108
VL - 4
SP - 980
EP - 1000
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 2
ER -