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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-? (TNF-?), 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-? mRNA, inhibiting TNF-? 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-? in neuroinflammation, as well as appraise current research on the potential of IMiDs as treatments for neurological disorders.

SUBMITTER: Jung YJ

PROVIDER: S-EPMC6904283 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Jung Yoo Jin YJ Tweedie David D Scerba Michael T MT Greig Nigel H NH

Frontiers in cell and developmental biology 20191204

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 ...[more]

PMID: 31867326

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Project description:OBJECTIVE:To determine whether patients randomized to unapproved, disease-modifying interventions in neurodegenerative disease trials have better outcomes than patients randomized to placebo by performing a systematic review and meta-analysis of risk and benefit experienced by patients in randomized placebo-controlled trials testing investigational treatments for Alzheimer disease, Parkinson disease, Huntington disease, or amyotrophic lateral sclerosis (ALS). METHODS:We searched MEDLINE, Embase, and ClinicalTrials.gov for results of randomized trials testing non-Food and Drug Administration-approved, putatively disease-modifying interventions from January 2005 to May 2018. Trial characteristics were double-extracted. Coprimary endpoints were the treatment advantage over placebo on efficacy (standardized mean difference in outcomes) and safety (risk ratios of serious adverse events and withdrawals due to adverse events), calculated with random effects meta-analyses. The study was registered on PROSPERO (CRD42018103798). RESULTS:We included 113 trials (n = 39,875 patients). There was no significant efficacy advantage associated with assignment to putatively disease-modifying interventions compared to placebo for Alzheimer disease (standardized mean difference [SMD] -0.03, 95% confidence interval [CI] -0.07 to 0.01), Parkinson disease (SMD -0.09, 95% CI -0.32 to 0.15), ALS (SMD 0.02, 95% CI -0.25 to 0.30), or Huntington disease (0.02, 95% CI -0.27 to 0.31). Patients with Alzheimer disease assigned to active treatment were at higher risk of experiencing serious adverse events (risk ratio [RR] 1.15, 95% CI 1.04-1.27) and withdrawals due to adverse events (RR 1.44, 95% CI 1.21-1.70). CONCLUSIONS:Assignment to active treatment was not beneficial for any of the indications examined and may have been slightly disadvantageous for patients with Alzheimer disease. Our findings suggest that patients with neurodegenerative diseases are not, on the whole, harmed by assignment to placebo when participating in trials.

Dataset Information

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

Publications

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

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