Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders.

Yoo Jin Jung,Nigel H Greig,Michael T Scerba,Anna R Carta,David Tweedie,Augusta Pisanu,Dong Seok Kim,Maria Francesca Palmas

doi:10.3389/fnins.2021.656921

Abstract

Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.

Highlights

Chronic neuroinflammation is a common feature across numerous neurological disorders, including neurodegenerative diseases, myelin disorders, and several psychiatric disorders (Goldsmith et al, 2016; Han et al, 2019; Jung et al, 2019; Yuan et al, 2019)
Supporting preclinical results, a recent retrospective study has reported that glitazone use was associated with a significantly lower incidence of Parkinson’s disease (PD) in diabetic patients (Brakedal et al, 2017), the single clinical trial testing pioglitazone on PD progression failed to report any improvement in disease symptoms (NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators, 2015)
An increasing number of studies have suggested that modulating inflammation through physical exercise or anti-inflammatory medications is beneficial for preventing Alzheimer disease (AD) pathology or mitigating AD symptoms, such as cognitive dysfunction, in various preclinical models of AD (Frankola et al, 2011; Gabbita et al, 2012; Russo et al, 2012; Tweedie et al, 2012; Decourt et al, 2016)

Summary

Introduction

Chronic neuroinflammation is a common feature across numerous neurological disorders, including neurodegenerative diseases, myelin disorders, and several psychiatric disorders (Goldsmith et al, 2016; Han et al, 2019; Jung et al, 2019; Yuan et al, 2019). A good example of this is the recently developed adamantyl thalidomide compound, N-adamantyl phthalimidine (NAP), shown to mitigate LPS-induced elevations in proinflammatory cytokines in cellular and animal models and provide anti-inflammatory effects in models of TBI without binding to CRBN (Hsueh et al, 2021).

Results

Conclusion