Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson’s Disease

Casu, Maria Antonietta; Mocci, Ignazia; Isola, Raffaella; Pisanu, Augusta; Boi, Laura; Mulas, Giovanna; Greig, Nigel H.; Setzu, Maria Dolores; Carta, Anna R.

doi:10.3389/fnagi.2020.00031

Cited by 14 publications

(20 citation statements)

References 87 publications

(113 reference statements)

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“…Pomalidomide has been investigated for use in neurological conditions such as Parkinson’s disease. It can improve age-related neurological impairment/motor disability 76 and can reduce ischemic brain injury in an in vivo study 77 .…”

Section: Resultsmentioning

confidence: 99%

Prediction of severe adverse events, modes of action and drug treatments for COVID-19’s complications

Astore

Zhou

Jacob

et al. 2021

Sci Rep

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Following SARS-CoV-2 infection, some COVID-19 patients experience severe host driven adverse events. To treat these complications, their underlying etiology and drug treatments must be identified. Thus, a novel AI methodology MOATAI-VIR, which predicts disease-protein-pathway relationships and repurposed FDA-approved drugs to treat COVID-19’s clinical manifestations was developed. SARS-CoV-2 interacting human proteins and GWAS identified respiratory failure genes provide the input from which the mode-of-action (MOA) proteins/pathways of the resulting disease comorbidities are predicted. These comorbidities are then mapped to their clinical manifestations. To assess each manifestation’s molecular basis, their prioritized shared proteins were subject to global pathway analysis. Next, the molecular features associated with hallmark COVID-19 phenotypes, e.g. unusual neurological symptoms, cytokine storms, and blood clots were explored. In practice, 24/26 of the major clinical manifestations are successfully predicted. Three major uncharacterized manifestation categories including neoplasms are also found. The prevalence of neoplasms suggests that SARS-CoV-2 might be an oncovirus due to shared molecular mechanisms between oncogenesis and viral replication. Then, repurposed FDA-approved drugs that might treat COVID-19’s clinical manifestations are predicted by virtual ligand screening of the most frequent comorbid protein targets. These drugs might help treat both COVID-19’s severe adverse events and lesser ones such as loss of taste/smell.

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Section: Resultsmentioning

confidence: 99%

Prediction of severe adverse events, modes of action and drug treatments for COVID-19’s complications

Astore

Zhou

Jacob

et al. 2021

Sci Rep

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“…Moreover, thalidomide remains a treatment choice for erythema nodosum leprosum (ENL), an inflammatory complication of leprosy, which was first described in Sheskin (1965) and FDA approved in 1998 ( Melchert and List, 2007 ; Asatsuma-Okumura et al, 2020 ). Preclinical studies of FDA approved IMiDs, as well as novel IMiDs such as 3,6′-dithiopomalidomide (3,6′-DP) and adamantyl thalidomide derivatives, support repurposing of IMiDs as therapeutics for neurological diseases with inflammatory components, such as AD, PD, stroke, traumatic brain injury and multiple sclerosis ( Russo et al, 2012 ; He et al, 2013 ; Yoon et al, 2013 ; Eitan et al, 2015 ; Wang et al, 2016 ; Boi et al, 2019 ; Casu et al, 2020 ; Lin et al, 2020 ; Hsueh et al, 2021 ; Figure 2 ). Compared with classical immunosuppressants and TNF-α-targeting drugs such as Etanercept and Infliximab, the pharmacokinetic features of IMiDs offer several advantages that make them more suitable for treating chronic neurological disorders.…”

Section: Immunomodulatory Imide Drugs (Imids)mentioning

confidence: 99%

“…Interestingly, IMiDs decreased the α-Syn-induced inflammatory response also in non-motor regions of the brain such as the hippocampus, an area involved in cognitive deficits of PD, supporting a role of neuroinflammation in these non-motor symptoms ( Valera et al, 2015 ; Williams-Gray et al, 2016 ). A recent study demonstrated the pomalidomide efficacy in a drosophila LRRK2 WD40 mutant PD model, with LRRK2 being a common genetic cause of PD ( Casu et al, 2020 ; Dues and Moore, 2020 ). These flies develop motor impairment and gradually lose dopaminergic neurons with age ( Casu et al, 2020 ).…”

Section: Imids and Neurodegenerative Disorders: Preclinical And Clinical Evidencementioning

confidence: 99%

“…A recent study demonstrated the pomalidomide efficacy in a drosophila LRRK2 WD40 mutant PD model, with LRRK2 being a common genetic cause of PD ( Casu et al, 2020 ; Dues and Moore, 2020 ). These flies develop motor impairment and gradually lose dopaminergic neurons with age ( Casu et al, 2020 ). Dietary administration of pomalidomide prevented age-dependent motor impairment and neuronal loss in motor-related dopaminergic clusters ( Casu et al, 2020 ).…”

Section: Imids and Neurodegenerative Disorders: Preclinical And Clinical Evidencementioning

confidence: 99%

“…These flies develop motor impairment and gradually lose dopaminergic neurons with age ( Casu et al, 2020 ). Dietary administration of pomalidomide prevented age-dependent motor impairment and neuronal loss in motor-related dopaminergic clusters ( Casu et al, 2020 ). The pomalidomide derivative 3,6′-DP has also been shown to reduce cell loss in primary dopaminergic neuron cultures exposed to α-Syn oligomers ( Lin et al, 2020 ).…”

Section: Imids and Neurodegenerative Disorders: Preclinical And Clinical Evidencementioning

confidence: 99%

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

et al. 2021

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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.

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

et al. 2022

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Marketed drugs for Parkinson’s disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40–45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients.

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Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson’s Disease

Cited by 14 publications

References 87 publications

Prediction of severe adverse events, modes of action and drug treatments for COVID-19’s complications

Prediction of severe adverse events, modes of action and drug treatments for COVID-19’s complications

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

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

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