Targeting neuroinflammation: The role of 3-monothiopomalidomide (3-MP) in neurodegenerative disorders

Authors

• P Parekh
• SC Hush
• B Batsaikhan
• D Tweedie
• C Patel
• N Vargesson
• BJ Hoffer
• DS Kim
• NH Greig

Abstract

Traumatic Brain Injury (TBI) is a major risk factor for neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), with neuroinflammation playing a critical role in secondary cell death that can worsen the initial injury. Although targeting neuroinflammation holds therapeutic promise, clinical trials have often fallen short. Thalidomide-like immunomodulatory imide drugs (IMiDs) have shown potential in reducing neuroinflammation in TBI and neurodegenerative diseases, mainly by suppressing TNF-α, a key activator of microglial cells. However, the therapeutic application of these IMiDs is often limited by adverse effects, caused by their interaction with cereblon, a key protein in the E3 ubiquitin ligase complex, leading to the degradation of specific endogenous neosubstrates (including those involved in embryo development). To address these issues, we developed 3-Mono-thiopomalidomide (3-MP), a novel IMiD inspired by thalidomide, designed to curb inflammation without triggering adverse effects associated with traditional IMiDs (e.g., teratogenicity). Through a phenotypic drug discovery approach and testing in various animal models, we optimized and validated 3-MP’s efficacy and safety. Our findings demonstrate that 3-MP enters brain (brain/plasma ratio ~0.45), ameliorates proinflammatory cytokine/chemokine levels in plasma and cortex of rats challenged with systemic lipopolysaccharide (LPS: a classic inflammatory model). Further, we performed immunohistochemical, biochemical, and behavioral evaluations in a controlled cortical impact (CCI) mouse model of moderate TBI. 3-MP alleviated behavioral impairments, reduced activation of astrocytes and microglia, and restored glial cell morphology. In summary, 3-MP represents a promising new IMiD with potent anti-inflammatory effects, offering potential for treating TBI and possibly other neurodegenerative diseases.

Scientific Focus Area: Neuroscience

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