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

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.

Keywords: IMiDs®; neurodegenarative diseases; neuroinflammation; neuropsychaitric disorders; pomalidomide; thalidomide.

FIGURE 1

Immunomodulatory imide drugs interactions with cereblon (CRBN) and TNF-α mRNA. IMiDs destabilize the 3′-untranslated region (3′-UTR) of TNF-α mRNA, inhibiting TNF-α protein synthesis and inhibiting inflammatory pathways (Moreira, 1993; Zhu et al., 2003). The glutarimide moiety of the thalidomide backbone catalyzes E3 ubiquitin ligase complex formation, targeting proteins for proteolysis (Chamberlain et al., 2014; Fischer et al., 2014; Petzold et al., 2016; Steinebach et al., 2018).

FIGURE 2

Chemical structures of IMiDs: (A) Thalidomide comprises of conjoined phthalimide and glutarimide moieties – with a chiral center. (B) Clinically approved (lenalidomide, pomalidomide and apremilast) and experimental IMiDs: IMiDs can be structurally altered to enhance function, increase bioavailability, and reduce adverse side effects (Zhu et al., 2003; Luo et al., 2011, 2018). For instance, the CNS MPO Score of thionated Pomalidomide, 3,6′-Dithiopomalidomide (3,6′-DP), is 5.5, making it higher than that of Pomalidomide, which has a score of 4.8; CNS MPO Scores predict drug BBB permeability calculated by Chemicalize using BBB penetration factors such as molecular weight and topological polar surface area (see Table 1).

FIGURE 3

The potential role of inflammation in MDD. The relationships between inflammation and depression are still unclear, but there are two main mechanisms through which inflammation can contribute to depression: chronic stress or systemic inflammation can lead to microglial activation, which can lead to the production of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IFN-γ. This leads to the propagation of inflammatory pathways, which can (1) activate the hypothalamic–pituitary adrenal (HPA) axis to produce cortisol and cause an imbalance in serotonin, norepinephrine, and epinephrine; (2) increase in the production of indoleamine-2,3-dioxygenase (IDO), resulting in serotonin depletion and increased quinolinic acid and contributing to cell death (Kopschina Feltes et al., 2017). It is likely that both pathways could underlie MDD progression and neurotransmitter imbalances that lead to various comorbid symptoms such as mood, behavioral, or cognitive impairments such as sleep, concentration, and cognition (Mössner et al., 1998; Donegan et al., 2014; Watkins et al., 2014).