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.

3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury

“…Indeed, in some cases, anti-inflammatory treatments may be detrimental [ 30 , 31 ]. In this light, the IMiD drug class was chosen consequent to its known action to lower TNF-α generation and proinflammatory cytokine levels [ 32 ], as a new anti-inflammatory strategy to mitigate TBI.…”

“…This prompted a recently initiated lenalidomide Alzheimer’s disease clinical trial (MCLENA-1) [ 44 ], as lenalidomide is a more potent second-generation analog against TNF-α within the IMiD drug class [ 45 ]. Additionally, there is well-documented teratogenic sequela with this drug class that, although not potentially relevant for Alzheimer’s patients due to their age, may be relevant for TBI subjects, thereby motivating the search for new compounds that are less encumbered by prohibitive adverse actions [ 32 , 41 , 46 ]. Replacing the oxygen of select carbonyl groups with sulfur within thalidomide, particularly in the 3 and 6′ positions ( Figure 1 ), augments the TNF-α-lowering action [ 47 ].…”

Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease

“…Despite massive preclinical and clinical effort, marketed drugs for the treatment of PD remain symptomatic in their efficacy and appear ineffective in stopping or slowing disease progression. An increasing knowledge of PD neuropathology together with the wide availability of drugs with regulatory-approved safety data, endorses drug-repurposing as an appealing strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications [1][2][3][4]. In this quest, drugs targeting components of the inflammatory response represent an attractive diseasemodifying strategy, and several clinically available immunosuppressive and immunomodulatory drugs have been tested for their neuroprotective activity in preclinical models of PD [5].…”

“…An attractive class of drugs in this context are the immunomodulatory imide drugs (IMiDs), such as thalidomide and its analogs, that have shown beneficial effects on neurodegeneration in preclinical models of PD [1,16,17]. Compared to drugs with immunosuppressive activity, whose clinical translation is often hampered by toxicological and pharmacokinetic limitations, IMiDs offer several advantageous features that make them more suitable for treating chronic neurological disorders.…”

Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy

“…Worthy of note is that Crbn -null mice are viable and do not present major malformations ( Rajadhyaksha et al, 2012 ; Lee et al, 2013 ); however, memory and learning deficits are apparent in these animals ( Bavley et al, 2018 ). Because of Cereblon binding and the outstanding immunomodulatory capacity of thalidomide, the drug has been implicated in the treatment of neurodegenerative and neuropsychiatric disorders; however, thalidomide neuroimmunomodulatory mechanisms do not appear to be Cereblon-dependent and probably occur through TNFa mRNA degradation ( Jung et al, 2021 ).…”