Reversal of peripheral nerve injury-induced neuropathic pain and cognitive dysfunction via genetic and tomivosertib targeting of MNK

Abstract

Neuropathic pain caused by nerve injury presents with severe spontaneous pain and a variety of comorbidities, including deficits in higher executive functions. None of these clinical problems are adequately treated with current analgesics. Targeting of the mitogen-activated protein kinase-interacting kinase (MNK1/2) and its phosphorylation target, the mRNA cap binding protein eIF4E, attenuates many types of nociceptive plasticity induced by inflammatory mediators and chemotherapeutic drugs but inhibiting this pathway does not alter nerve injury-induced mechanical allodynia. We used genetic manipulations and pharmacology to inhibit MNK-eIF4E activity in animals with spared nerve injury, a model of peripheral nerve injury (PNI)-induced neuropathic pain. We assessed the presence of spontaneous pain using conditioned place preference. We also tested performance in a medial prefrontal cortex (mPFC)-dependent rule-shifting task. WT neuropathic animals showed signs of spontaneous pain and were significantly impaired in the rule-shifting task while genetic and pharmacological inhibition of the MNK-eIF4E signaling axis protected against and reversed spontaneous pain and PNI-mediated cognitive impairment. Additionally, pharmacological and genetic inhibition of MNK-eIF4E signaling completely blocked and reversed maladaptive shortening in the length of axon initial segments (AIS) in the mPFC of PNI mice. Surprisingly, these striking positive outcomes on neuropathic pain occurred in the absence of any effect on mechanical allodynia, a standard test for neuropathic pain efficacy. Our results illustrate new testing paradigms for determining preclinical neuropathic pain efficacy and point to the MNK inhibitor tomivosertib (eFT508) as an important drug candidate for neuropathic pain treatment.

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

“…Activation of MNK-eIF4E signaling by type I IFNs has been observed in other cell types where it has been linked to increased immune surveillance (Joshi et al, 2009). Multiple previous studies have demonstrated that activation of MNK-eIF4E-mediated translation events are causative in the production of chronic pain states, including neuropathic pain (Moy et al, 2017; Megat et al, 2019; Shiers et al, 2019). Since both viral infections and prolonged production of type I IFNs can cause neuropathic pain, it is possible that type I IFN receptor signaling to MNK-eIF4E may be a key pathway for production of these types of neuropathies.…”

“…A key pathway linking initial nociceptor activation to nociceptor hypersensitivity and potentially the development of chronic pain is engagement of translation regulation signaling (Obara and Hunt, 2014; Khoutorsky and Price, 2018; de la Pena et al, 2019). Importantly, eIF2α phosphorylation, mTORC1 activation and MNK-eIF4E signaling can all lead to persistent sensitization of nociceptors and all of these pathways have been linked to neuropathic pain disorders (Inceoglu et al, 2015; Khoutorsky et al, 2016; Moy et al, 2017; Megat et al, 2019; Shiers et al, 2019)…”

Behavioral, Biochemical and Electrophysiological Changes in Spared Nerve Injury Model of Neuropathic Pain

“…Deficits in spatial memory were also found in SNI mice on day 14 [37,75] and 30 [36] from surgery. Impairment in cognitive flexibility was also detected in mice in the attentional rule-shifting task 21 days after SNI surgery [76]. Curiously, no impairment in spatial working memory was found in the Morris water maze 3 to 21 days after SNI in mice by Karl et al [77].…”

A pharmacological interactome between COVID-19 patient samples and human sensory neurons reveals potential drivers of neurogenic pulmonary dysfunction

“…A target identified from that paper was the RNA binding protein, eIF4E, the phosphorylation of which has been implicated in coronavirus replication (Banerjee et al, 2002;Mizutani et al, 2004) and the suppression of anti-viral responses (Herdy et al, 2012). Previous work suggests that eIF4E phosphorylation by MNK, a druggable target identified by Gordon et al (2020), plays a key role in regulating the excitability of nociceptors (Moy et al, 2017;Megat et al, 2019;Shiers et al, 2020) and also regulates the translation of many cytokines and chemokines (Furic et al, 2010;Herdy et al, 2012;Amorim et al, 2018). Based on this, we intersected differentially expressed BALF ligand and receptor genes in COVID-19 samples with mRNAs known to be regulated by eIF4E phosphorylation from previous studies (Furic et al, 2010;Aguilar-Valles et al, 2018;Amorim et al, 2018).…”