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Review
. 2019 Dec 4:7:313.
doi: 10.3389/fcell.2019.00313. eCollection 2019.

Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments

Yoo Jin Jung  1 , David Tweedie  1 , Michael T Scerba  1 , Nigel H Greig  1
Affiliations
Review

Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments

Yoo Jin Jung et al. Front Cell Dev Biol. .

Abstract

Neuroinflammation is initiated when glial cells, mainly microglia, are activated by threats to the neural environment, such as pathogen infiltration or neuronal injury. Although neuroinflammation serves to combat these threats and reinstate brain homeostasis, chronic inflammation can result in excessive cytokine production and cell death if the cause of inflammation remains. Overexpression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine with a central role in microglial activation, has been associated with neuronal excitotoxicity, synapse loss, and propagation of the inflammatory state. Thalidomide and its derivatives, termed immunomodulatory imide drugs (IMiDs), are a class of drugs that target the 3'-untranslated region (3'-UTR) of TNF-α mRNA, inhibiting TNF-α production. Due to their multi-potent effects, several IMiDs, including thalidomide, lenalidomide, and pomalidomide, have been repurposed as drug treatments for diseases such as multiple myeloma and psoriatic arthritis. Preclinical studies of currently marketed IMiDs, as well as novel IMiDs such as 3,6'-dithiothalidomide and adamantyl thalidomide derivatives, support the development of IMiDs as therapeutics for neurological disease. IMiDs have a competitive edge compared to similar anti-inflammatory drugs due to their blood-brain barrier permeability and high bioavailability, with the potential to alleviate symptoms of neurodegenerative disease and slow disease progression. In this review, we evaluate the role of neuroinflammation in neurodegenerative diseases, focusing specifically on the role of TNF-α in neuroinflammation, as well as appraise current research on the potential of IMiDs as treatments for neurological disorders.

Keywords: apremilast; immunomodulatory imide drugs (IMiDs); lenalidomide; neurodegeneration; neuroinflammation; pomalidomide; thalidomide; tumor necrosis factor-α (TNF-α).

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Figures

FIGURE 1
FIGURE 1
Effects of TNF-α in the CNS. Inflammatory stimuli such as Aβ, α-synuclein or oxidative stress can cause neuronal death and glial cell activation, which leads to the release of inflammatory cytokines such as TNF-α. In severe cases, peripheral macrophages can infiltrate the compromised blood-brain barrier to propagate an immune response in the CNS. TNF-α activates two types of receptors- TNFR1 and TNFR2. These function differentially, with TNFR1 promoting apoptosis and activating NF-κB, which leads to proinflammatory cytokine production and glial activation, which leads to neuroinflammation and neuronal death. More glial cell activation occurs in response to this pathway, feeding the positive feedback loop of increased neuroinflammation leading to increased cell death and vice versa. On the other hand, TNFR2 activation appears largely to be neuroprotective, stimulating neurogenesis and promoting cell survival and growth (Chen and Palmer, 2013; Longhi et al., 2013).
FIGURE 2
FIGURE 2
(A–C) History of thalidomide and IMiDs. (A) Thalidomide discovery, market withdrawal, and repurposing (Sheskin, 1965; Lenz, 1988; Vargesson, 2015). (B) FDA approval of IMiDs (Aragon-Ching et al., 2007; FDA and CDER, 2014; Fala, 2015; Ríos-Tamayo et al., 2017). (C) Preclinical studies using IMiDs (Sampaio et al., 1991; Corral et al., 1996; Zhu et al., 2003; Baratz et al., 2015; Wang et al., 2016b; Decourt et al., 2017; Liu T. et al., 2017; Rubenstein et al., 2018).
FIGURE 3
FIGURE 3
Thalidomide mechanism of action and pleiotropic effects: Following introduction of cell stressors such as inflammatory cytokines or pathogens, the NF-kB transcription factor is activated, leading to increased transcription and translation of TNF-α. Thalidomide binds to the 3′-UTR of TNF-α mRNA, leading to mRNA destabilization and inhibiting TNF-α cytokine production. Thalidomide has anti-angiogenic (D’Amato et al., 1994; Zeldis et al., 2011) and anti-proliferative (Arrieta et al., 2002; Zeldis et al., 2011; Mendy et al., 2012) properties, inhibiting tumor growth, and making it a promising candidate for cancer treatment. Thalidomide also possesses anti-inflammatory (Sampaio et al., 1991; Zeldis et al., 2011; Farfán et al., 2015) properties, which have the potential to be used in inhibiting inflammation contributing to neurological disease. Thalidomide has differential roles in the periphery versus the CNS, activating anti-apoptotic (Baratz et al., 2015; Farfán et al., 2015; Tsai et al., 2018) pathways in neurons and pro-apoptotic (Mitsiades et al., 2002; Gockel et al., 2014) in monocytes.
FIGURE 4
FIGURE 4
Protein degradation mechanism of Thalidomide via cereblon-binding: Thalidomide is composed of glutarimide and phthalimide moieties, which interact differentially with various targets. The glutarimide ring binds cereblon to create an E3 ubiquitin ligase complex (Mendy et al., 2012), while phthalimide targets non-cereblon proteins (Noguchi et al., 2004). The formation of an E3 ubiquitin ligase complex leads to protein degradation (Winter et al., 2015; An and Fu, 2018), which underlies the ability of IMiDs to treat multiple myeloma (Krönke et al., 2014) and potentially other diseases in which protein aggregation or malfunction play a role. The exact mechanism of TNF-α inhibition by IMiDs is yet to be elucidated, but is likely to be a combination of effects of both glutarimide and phthalimide moieties (Schett et al., 2010; Millrine and Kishimoto, 2017; Chelucci et al., 2019). CRBN, Cereblon; DDB1, DNA damage-binding protein 1; CUL4, Cullin-4; ROC1, Regulator of Cullins-1.
FIGURE 5
FIGURE 5
Chemical structures of thalidomide and its analogs.
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References

    1. Agrawal P. (2015). Advantages and challenges in drug re-profiling. J. Pharmacovigil. 2 2–3. 10.4172/2329-6887.S2-e002 - DOI
    1. Akizuki M., Yamashita H., Uemura K., Maruyama H., Kawakami H., Ito H., et al. (2013). Optineurin suppression causes neuronal cell death via NF-kB pathway. J. Neurochem. 126 699–704. 10.1111/jnc.12326 - DOI - PubMed
    1. Al Saieg N., Luzar M. J. (2006). Etanercept induced multiple sclerosis and transverse myelitis. J Rheumatol. 33 1202–1204. - PubMed
    1. Alzheimer’s Association, (2019). 2019 ALZHEIMER’S DISEASE FACTS AND FIGURES Includes a Special Report on Alzheimer’s Detection in the Primary Care Setting: Connecting Patients and Physicians. Available at: https://alz.org/media/Documents/alzheimers-facts-and-figures-2019-r.pdf (accessed July 9, 2019).
    1. An S., Fu L. (2018). Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs. EBioMedicine 36 553–562. 10.1016/j.ebiom.2018.09.005 - DOI - PMC - PubMed

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