6th Edition of Neurology World Conference 2026

Abstract

Excessive microglial-driven neuroinflammation contributes to numerous neurological disorders and represents an attractive therapeutic target. Immunomodulatory imide drugs (IMiDs) suppress inflammation but are limited by toxicity and teratogenicity, largely due to cereblon-mediated degradation of developmental neosubstrates such as SALL4. In pursuit of safer IMiDs, we synthesized 3-monothiopomalidomide (3-MP) that binds cereblon and alters its neosubstrate preference away from SALL4. We evaluated the cellular toxicity, anti-oxidative, and anti-inflammatory effects of 3-MP vs. the clinically approved IMiD Pomalidomide in lipopolysaccharide (LPS)-challenged rodent macrophages (RAW 264.7) and microglial (IMG) cells, as well as in human monocytes (THP1), differentiated macrophages (THP1), and peripheral blood mononuclear cells (PBMCs). Well-tolerated 3-MP doses inhibited production of nitrite and pro-inflammatory cytokines. This anti-inflammation was replicated in a LPS-challenged mouse model (expressing mouse or human cereblon). 3-MP was hence evaluated in an acute neurodegenerative animal model known to involve neuroinflammation: traumatic brain injury (TBI) in mice. 3-MP administration post-TBI mitigated markers of neuroinflammation and behavioral impairment evaluated at 14 days. Teratogenicity was not evident in the preliminary evaluation of 3-MP in chicken embryos. To investigate underlying mechanisms of the novel compound, we are performing bulk RNA-seq and proteomics analysis on LPS-challenged or non-challenged, 3-MP treated or non-treated THP1 monocytes. We predict that 3MP inhibits LPS-induced inflammatory responses through cereblon-dependent and -independent mechanisms in human cells. These studies indicate that suppressing excessive inflammation provides a treatment strategy in TBI and potentially other neurodegenerative disorders involving excessive inflammation and identify 3-MP as a new lead IMiD drug candidate for further development