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.

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.

• Authors: 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
• Journal: ACS pharmacology & translational science (ACS Pharmacol Transl Sci) Vol. 4 Issue 2 Pg. 980-1000 (Apr 09 2021) ISSN: 2575-9108 [Electronic] United States
• PMID: 33860215 (Publication Type: Journal Article)
• Copyright: © 2021 American Chemical Society.