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

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.

Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms

“…IL-6 maintains the balance between cytotoxic and regulatory T-cells. Overproduction of IL-6 inhibits the differentiation of T-cells into regulatory T-cells and thus promotes the inflammatory state and demyelination in mice [57]. In line with this, IL-6 deficient mice are resistant to MS, and administration of IL-6 receptor (IL-6R) antibodies inhibits the myelin degeneration in EAE mice [57].…”

“…We also postulate that aberrant cytokine release into the CSF of SARS-CoV-2 patients may increase the risk of progression into PD by aggravating the neurodegeneration process, considering the fact that PD patients exhibit elevated levels of pro-inflammatory cytokines (including IL-1β, IL-6, TNF-α, and IFN-γ) in CSF. Cytokine storm activates microglia, which are implicated in the pathophysiology of PD [57]. Moreover, the extreme release of cytokines into the CSF mediated by SARS-CoV-2 dysregulates the balance between production, release, and reuptake of neurotransmitters including dopamine, which possibly contributes to the development of PD [25].…”

“…TNF-α is isolated from active areas of neurodegeneration in postmortem MS brains [57]. Overexpression of TNF-α stimulates apoptosis of oligodendrocytes and infiltration of immune cells into the CSF, while intrathecal injection of TNF-α monoclonal antibodies prevents from the development of MS in animal models of experimental autoimmune encephalomyelitis (EAE) [57]. IL-6 maintains the balance between cytotoxic and regulatory T-cells.…”

“…Overproduction of IL-6 inhibits the differentiation of T-cells into regulatory T-cells and thus promotes the inflammatory state and demyelination in mice [57]. In line with this, IL-6 deficient mice are resistant to MS, and administration of IL-6 receptor (IL-6R) antibodies inhibits the myelin degeneration in EAE mice [57]. Moreover, the aberrant release of IL-6 disrupts the blood-brain barrier integrity and facilitates the infiltration of cytotoxic T-cells [57].…”

The Potential for Natural Antioxidant Supplementation in the Early Stages of Neurodegenerative Disorders

“…Recently, a close correlation has been highlighted between inflammation and neurodegenerative diseases. In some cases, in fact, the chronic activation of innate immunity in the central nervous system (CNS) is triggered while, in other cases, peripheral immune cells pass through the BBB, as happens with multiple sclerosis [20].…”