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

Shih Chang Hsueh, Weiming Luo, David Tweedie, Dong Seok Kim, Yu Kyung Kim, Inho Hwang, Jung Eun Gil, Baek Soo Han, Yung Hsiao Chiang, Warren Selman, Barry J. Hoffer, Nigel H. Greig

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)980-1000
Number of pages21
JournalACS Pharmacology and Translational Science
Volume4
Issue number2
DOIs
Publication statusPublished - Apr 9 2021

Keywords

  • cereblon
  • neurodegeneration
  • neuroinflammation
  • thalidomide
  • traumatic brain injury
  • tumor necrosis factor-α

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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