Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence
Neurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer’s disease, Parkinson’s disease, amyolotrophic lateral sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegene...
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MDPI AG
2022-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/23/8448 |
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| author | Efthalia Angelopoulou Efstratios-Stylianos Pyrgelis Christina Piperi |
| author_facet | Efthalia Angelopoulou Efstratios-Stylianos Pyrgelis Christina Piperi |
| author_sort | Efthalia Angelopoulou |
| collection | DOAJ |
| description | Neurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer’s disease, Parkinson’s disease, amyolotrophic lateral sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegenerative diseases. Despite their diversity, these diseases share some common pathophysiological mechanisms: the abnormal aggregation of disease-related misfolded proteins, autophagosome–lysosome pathway dysregulation, impaired ubiquitin–proteasome system, oxidative damage, mitochondrial dysfunction and excessive neuroinflammation. There is still no effective drug that could halt the progression of neurodegenerative diseases, and the current treatments are mainly symptomatic. In this regard, the development of novel multi-target pharmaceutical approaches presents an attractive therapeutic strategy. Ibudilast, an anti-inflammatory drug firstly developed as an asthma treatment, is a cyclic nucleotide phosphodiesterases (PDEs) inhibitor, which mainly acts by increasing the amount of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), while downregulating the pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4). The preclinical evidence shows that ibudilast may act neuroprotectively in neurodegenerative diseases, by suppressing neuroinflammation, inhibiting apoptosis, regulating the mitochondrial function and by affecting the ubiquitin–proteasome and autophagosome–lysosome pathways, as well as by attenuating oxidative stress. The clinical trials in ALS and progressive MS also show some promising results. Herein, we aim to provide an update on the emerging preclinical and clinical evidence on the therapeutic potential of ibudilast in these disorders, discuss the potential challenges and suggest the future directions. |
| first_indexed | 2024-03-09T17:39:43Z |
| format | Article |
| id | doaj.art-7c0774892d8c4275be9e5415d45996f3 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T17:39:43Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-7c0774892d8c4275be9e5415d45996f32023-11-24T11:42:25ZengMDPI AGMolecules1420-30492022-12-012723844810.3390/molecules27238448Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical EvidenceEfthalia Angelopoulou0Efstratios-Stylianos Pyrgelis1Christina Piperi21st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, 11528 Athens, Greece1st Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, 11528 Athens, GreeceDepartment of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, GreeceNeurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer’s disease, Parkinson’s disease, amyolotrophic lateral sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegenerative diseases. Despite their diversity, these diseases share some common pathophysiological mechanisms: the abnormal aggregation of disease-related misfolded proteins, autophagosome–lysosome pathway dysregulation, impaired ubiquitin–proteasome system, oxidative damage, mitochondrial dysfunction and excessive neuroinflammation. There is still no effective drug that could halt the progression of neurodegenerative diseases, and the current treatments are mainly symptomatic. In this regard, the development of novel multi-target pharmaceutical approaches presents an attractive therapeutic strategy. Ibudilast, an anti-inflammatory drug firstly developed as an asthma treatment, is a cyclic nucleotide phosphodiesterases (PDEs) inhibitor, which mainly acts by increasing the amount of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), while downregulating the pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4). The preclinical evidence shows that ibudilast may act neuroprotectively in neurodegenerative diseases, by suppressing neuroinflammation, inhibiting apoptosis, regulating the mitochondrial function and by affecting the ubiquitin–proteasome and autophagosome–lysosome pathways, as well as by attenuating oxidative stress. The clinical trials in ALS and progressive MS also show some promising results. Herein, we aim to provide an update on the emerging preclinical and clinical evidence on the therapeutic potential of ibudilast in these disorders, discuss the potential challenges and suggest the future directions.https://www.mdpi.com/1420-3049/27/23/8448ibudilastPDE inhibitorneurodegenerationmicrogliaautophagylysosomes |
| spellingShingle | Efthalia Angelopoulou Efstratios-Stylianos Pyrgelis Christina Piperi Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence Molecules ibudilast PDE inhibitor neurodegeneration microglia autophagy lysosomes |
| title | Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence |
| title_full | Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence |
| title_fullStr | Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence |
| title_full_unstemmed | Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence |
| title_short | Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence |
| title_sort | emerging potential of the phosphodiesterase pde inhibitor ibudilast for neurodegenerative diseases an update on preclinical and clinical evidence |
| topic | ibudilast PDE inhibitor neurodegeneration microglia autophagy lysosomes |
| url | https://www.mdpi.com/1420-3049/27/23/8448 |
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