Figure 1.

Effects of ibudilast possibly related to neurodegenerative diseases. Ibudilast can suppress neuroinflammation by inhibiting microglia activation, downregulating the pro-inflammatory cytokines TNF-α, IL-1β and IL-6, upregulating the anti-inflammatory cytokine IL-10 and regulating IRAK1, IRAK3 and TRAF6. Ibudilast can upregulate the neurotrophic factors GDNF, NT-3, NT-4 and NGF and prevent mitochondrial impairment by restoring the mitochondrial membrane potential. It can also affect the autophagy-lysosomal system by regulating mTORC1-TFEB pathway. Ibudilast can also promote TDP-43 and SOD1 aggregates clearance, thereby suppressing abnormal protein aggregation. Ibudilast also affects ubiquitin–proteasome system by regulating TLR-related ubiquitin ligase, and it protects against glutamate-induced neurotoxicity by reducing Ca²⁺ influx. Ibudilast also protects against neuronal apoptosis by downregulating caspase-3 and upregulating bcl-2. Ibudilast may also suppress oxidative stress by reducing the production of ROS. Apart from PDEs inhibition, ibudilast can also inhibit MIF and TLR-4. MIF inhibition and subsequent MIF reduction results in the downregulation of its receptor CD74 and AKT expression. TLR-4 blocking may lead to the reduced production of pro-inflammatory cytokines via pathways that also implicate NF-κΒ, IRAK1 and TRAF6. Although it is not fully elucidated which of the above molecular and cellular effects of ibudilast are mediated through PDE inhibition; the small red circles indicate the specific mechanisms that there is some evidence suggesting to be at least partially induced by the inhibition of PDEs.