Browsing by Subject "TAK1"

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    Pharmacological Inhibition of TAK1 as a Therapeutic Target to Reduce Inflammation and Pain
    (2020) Scarneo, Scott

    Chronic pain is a prevalent health concern, affecting up to 100 million people in the US alone, yet treatment options remain limited. The origins of pain have been tightly linked to inflammation and in specific tumor necrosis factor (TNF) a pro-inflammatory cytokine, has been identified as a key driver of pain and inflammation. TNF can bind to its TNFR1 receptor located on the terminals of primary afferent nociceptors to directly increase their activity. In addition, TNF can stimulate pro-inflammatory cytokine production and immune cell activation. Patients with chronic pain exhibit increased levels of TNF, with higher levels in those with greater pain. TNF antibodies (eg, Remicade, Humira and Cimzia) are currently available for the treatment of inflammatory pain conditions such as rheumatoid arthritis. However, 40% of patients fail to respond to TNF antibodies, leading for the need to develop novel small molecule TNF inhibitors. TGFβ-activated kinase (TAK1) inhibition has been previously shown to potently reduce TNF signaling. Takinib, a potent inhibitor of TAK1 represents a novel method of regulating TNF production and pro-inflammatory signaling. Here, I show that TAK1 inhibition prevents inflammatory, neuropathic and functional pain by modulating immune responses and nociceptor activity. Overall, our findings support the therapeutic potential of a TAK1 inhibitor as a novel therapeutic to reduce inflammation and chronic pain.

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    ItemOpen Access
    Transforming growth factor-β-activated kinase 1 (TAK1) mediates chronic pain and cytokine production in mouse models of inflammatory, neuropathic, and primary pain.
    (The journal of pain, 2023-04) Scarneo, Scott; Zhang, Xin; Wang, Yaomin; Camacho-Domenech, Jose; Ricano, Jennifer; Hughes, Philip; Haystead, Tim; Nackley, Andrea G
    The origin of chronic pain is linked to inflammation, characterized by increased levels of pro-inflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of pro-inflammatory cytokine signaling that has been well characterized in the context of cancer and autoimmune disorders, yet its role in chronic pain is less clear. Here, we evaluated the ability of our TAK1 small molecule inhibitor, takinib, to attenuate pain and inflammation in pre-clinical models of inflammatory, neuropathic, and primary pain. Inflammatory, neuropathic, and primary pain was modeled using intraplantar complete Freund's adjuvant (CFA), chronic constriction injury (CCI), and systemic delivery of the COMT inhibitor OR486, respectively. Behavioral responses evoked by mechanical and thermal stimuli were evaluated in separate groups of mice receiving takinib or vehicle prior to pain induction (baseline) and over 12 days following CFA injection, 4 weeks following CCI surgery, and 6 hours following OR486 delivery. Hindpaw edema was also measured prior to and 3 days following CFA injection. Upon termination of behavioral experiments, dorsal root ganglia (DRG) were collected to measure cytokines. We also evaluated the ability of takinib to modulate nociceptor activity via in vitro calcium imaging of neurons isolated from the dorsal root ganglia of Gcamp3 mice. In all three models, TAK1 inhibition significantly reduced hypersensitivity to mechanical and thermal stimuli and expression of pro-inflammatory cytokines in DRG. Furthermore, TAK1 inhibition significantly reduced the activity of tumor necrosis factor (TNF)-primed/capsaicin-evoked DRG nociceptive neurons. Overall, our results support the therapeutic potential of TAK1 as a novel drug target for the treatment of chronic pain syndromes with different etiologies. PERSPECTIVE: This article reports the therapeutic potential of TAK1 inhibitors for the treatment of chronic pain. This new treatment has the potential to provide a greater therapeutic offering to physicians and patients suffering from chronic pain as well as reduce the dependency on opioid based pain treatments.