Table 3.
Preclinical evidence on the role of ibudilast in neurodegenerative diseases.
| Neurodegenerative Disease | Type of Study | Model | Main Findings | Reference |
|---|---|---|---|---|
| Alzheimer’s disease | In vitro | Cultured hippocampal neurons from rats. | -Ibudilast could protect against glutamate-induced neurotoxicity and increase intracellular cAMP levels. -Ibudilast treatment was associated with reduced glutamate induced Ca2+ influx. |
[23] |
| In vivo | Sprague Dawley rats rat models | -Ibudilast could reverse the LPS- and INF-γ-induced inhibition of LTP in the CA1 region of hippocampus. | [44] | |
| In vivo | Amyloid-beta-injected mice mouse models of AD. | -Ibudilast pretreatment could prevent amyloid-beta-induced memory, spatial learning impairment, and neurotoxicity. -Ibudilast could inhibit the production of pro-inflammatory cytokines NF-κB p65 and TNF-α, prevent the activation of the pro-apoptotic protein caspase-3, and suppress the downregulation of the anti-apoptotic protein Bcl-2 in the cortex and hippocampus. |
[34] | |
| In vivo | Fisher transgenic 344-AD rats. | -Long-term ibudilast treatment was associated with lower hippocampal-dependent spatial memory impairment, hippocampal amyloid-beta plaque deposition, tau paired-helical filament burden, and microgliosis. -RNA sequencing of hippocampal samples showed that ibudilast could affect the expression of the TLR, as well as the ubiquitin–proteasome pathways. -Ibudilast could downregulate the activity of IRAK1 by elevating the expression of IRAK3, affecting the levels of TRAF6 and possibly other TLR-related ubiquitin ligase. |
[65] | |
| Parkinson’s disease | In vivo | MPTP mouse models of PD. | -Pretreatment with ibudilast was associated with reduced astroglia activity and increased GDNF in the striatum. -Ibudilast could also suppress the production of pro-inflammatory cytokines, including IL-6, IL-1β and TNF-α. -Ibudilast did not alter the dopaminergic neuronal cell survival and TH levels in the striatum seven days after the acute MPTP insult in this study. |
[66] |
| Amyotrophic Lateral Sclerosis | In vitro | HEK293 and NSC-34 cells. | -Ibudilast treatment could stimulate the clearance of SOD1 and TDP-43 aggregates, via induction of autophagy, increase in autolysosomes, and enhancement of lysosomal biogenesis, through the enhancement of the nuclear translocation of TFEB and the downregulation of the mTORC1. -Ibudilast could prevent TDP-43-induced neurotoxicity. |
[81] |
| Multiple Sclerosis | In vivo | EAE rat models. | -Ibudilast pretreatment could prevent EAE in rats, although it could not alter the clinical course in case it was administered after the onset of the disease. -Ibudilast pretreatment could reduce neuroinflammatory responses in the spinal cord, inhibit MBP-induced T cell proliferation in the lymph nodes, reduce release of IFN-γ from T cells, and decrease secretion of TNF-α from macrophages. |
[93] |
| Wolfram syndrome | In vitro | Rat insulinoma (INS1) cells. | -Knock out of WFS1 resulted in increased resting cytosolic calcium levels, downregulation of calcium signaling, and reduced insulin secretion. -Ibudilast and calpain inhibitor XI could also restore calcium homeostasis, cell viability and insulin secretion. |
[101] |
| Glaucoma | In vivo | Rat models of ocular hypertension. | -Intraocular administration of ibudilast was associated with reduced microglia activation in the retina and optic nerve, resulting in reduced pro-inflammatory cytokines and gliosis, increased survival and restored axonal degeneration, via the upregulation of cAMP/PKA signaling pathway. | [105] |
cAMP: cyclic adenosine monophosphate; LPS: lipopolysaccharide; INF-γ: interferon-gamma; LTP: long-term potentiation; IRAK1: interleukin 1 receptor associated kinase 1; IRAK3: interleukin-1 receptor-associated kinase 3; TNFR: tumor necrosis factor receptor; TNFR- associated factor 6: TRAF6; IL-6: interleukin 6; IL-1β interleukin-1-β; TNF-α: tumor necrosis factor; GDNF: Glial cell line-derived neurotrophic factor; TH: tyrosine hydroxylase; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, TFEB: transcription factor EB; mTORC1: mammalian target of rapamycin complex 1; EAE: experimental autoimmune encephalitis; PKA: protein kinase A.