Ibudilast, a Pharmacologic Phosphodiesterase Inhibitor, Prevents Human Immunodeficiency Virus-1 Tat-Mediated Activation of Microglial Cells

Abstract

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorders (HAND) occur, in part, due to the inflammatory response to viral proteins, such as the HIV-1 transactivator of transcription (Tat), in the central nervous system (CNS). Given the need for novel adjunctive therapies for HAND, we hypothesized that ibudilast would inhibit Tat-induced excess production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα) in microglial cells. Ibudilast is a non-selective cyclic AMP phosphodiesterase inhibitor that has recently shown promise as a treatment for neuropathic pain via its ability to attenuate glial cell activation. Accordingly, here we demonstrate that pre-treatment of both human and mouse microglial cells with increasing doses of ibudilast inhibited Tat-induced synthesis of TNFα by microglial cells in a manner dependent on serine/threonine protein phosphatase activity. Ibudilast had no effect on Tat-induced p38 MAP kinase activation, and blockade of adenosine A2A receptor activation did not reverse ibudilast's inhibition of Tat-induced TNFα production. Interestingly, ibudilast reduced Tat-mediated transcription of TNFα, via modulation of nuclear factor-kappa B (NF-κB) signaling, as shown by transcriptional activity of NF-κB and analysis of inhibitor of kappa B alpha (IκBα) stability. Together, our findings shed light on the mechanism of ibudilast's inhibition of Tat-induced TNFα production in microglial cells and may implicate ibudilast as a potential novel adjunctive therapy for the management of HAND.

Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine

“…3E,F). Our data agrees with previously published data by others showing an inhibition of inflammatory responses and an increase in anti-inflammatory responses by AV411 [42–45]. …”

“…It has been reported that AV411 can disrupt transcriptional activity of NF-ĸB and the stability of IκBα [42]. In an effort to explain how AV411 diminished MIF and TNF-α induced release by Tat ± morphine treatment, degradation of IκBα and nuclear translocation of NF-κB were determined by western blotting analysis (data not shown), and tracked by immunofluorescence labeling (Fig.…”

“…Furthermore, cART does not directly target the inflammatory cascades thought to contribute to HIV encephalitis and HAND [42]. In fact, recent evidence indicates that the sustained production of Tat protein contributes to chronic immune activation seen in HIV-1-infected individuals maintained on cART [48], and provided partial justification for our use of Tat in the present study.…”

Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) produced by chronic methamphetamine intake in rats

“…Studies have shown the potential of this drug in reducing neuroinflammation in a number of neurological conditions such as relapsing-remitting multiple sclerosis (Barkhof et al, 2010), Tat-induced neurotoxicity (Kiebala and Maggirwar, 2011), potentiation of opioid analgesia (Hutchinson et al, 2009), and attenuation of methamphetamine-taking and relapse in animal models (Beardsley et al, 2010;Snider et al, 2013). At present, it is unknown how ibudilast impacts the synapse-a key structure involved in neurotransmission and neuroplasticity.…”

Role of phosphodiesterase-4 in alcohol-induced organ injury.

“…Detailed analysis of cell populations expressing PDE4B2 after endotoxin injection revealed that microglia, astrocytes and endothelial cells showed the highest expression of PDE4B2 [195]. Notably, PDE4 specific inhibitor Rolipram has been demonstrated to significantly attenuate microglial activation in response to various stimuli, including endotoxin in several studies [191,[204][205][206][207]. These studies indicate a critical role of PDE4B in glial cell activation.…”