Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS

Tumor necrosis factor alpha (TNFalpha) is considered to play a critical role in the development of various pathological processes in the central nervous system (CNS), such as neuronal degeneration, demyelination and HIV-related pathology. In order to search for the agents which suppress TNFalpha production in the CNS for future treatment of these pathological conditions, we examined the effects of ibudilast on TNFalpha production by murine microglia and astrocytes. Some actions of ibudilast are reportedly mediated by inhibition of type IV phosphodiesterase (PDE). Type IV PDE inhibitor has been shown to be the most effective for experimental autoimmune inflammatory demyelination. Therefore, we also determined the subtype of PDE inhibited by ibudilast. Ibudilast significantly and selectively suppressed TNFalpha production by microglia in a dose-dependent manner, without affecting their viability. The inhibition assay indicated that ibudilast is a rather selective inhibitor for type III PDE purified from brain, heart and kidney with moderate inhibitory activity against types I, II and IV PDEs from various tissues. Although it required 10 microM or higher concentrations to effectively suppress TNFalpha production in vitro, the combination of ibudilast with other subtypes of PDE inhibitors synergistically suppressed TNFalpha and nitric oxide production by microglia at 1 microM, a similar concentration that could be obtained in vivo at usual therapeutic dose. Thus, ibudilast, when used in a combination with other PDE inhibitors, will be useful for future strategies to treat intractable neurological diseases in which TNFalpha may play a causative role.