The Emerging Translational Potential of MNK Inhibitors for the Treatment of Chronic Pain.
The Emerging Translational Potential of MNK Inhibitors for the Treatment of Chronic Pain.
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MNK 抑制剂治疗慢性疼痛的新兴转化潜力。
DOI：
10.1016/j.neuroscience.2023.02.009
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发表时间：
2023
期刊：
影响因子：
3.3
通讯作者：
Khanna,Rajesh
中科院分区：
文献类型：
--
作者：
Nelson,TylerS;Khanna,Rajesh
2019年，估计20.4%（5000万）的美国成年人患有慢性疼痛，7.4%（1960万）的美国成年人患有经常限制生活或工作活动的高影响慢性疼痛（Zelaya et al.，2020年）。不幸的是，缺乏有效，安全和非成瘾性的治疗方法来管理这种“慢性疼痛流行病”，迫切需要新的治疗方法。几十年的临床前研究涉及三种促分裂原活化蛋白激酶（MAPK）酶在初级感觉传入和脊髓背角两者中的疼痛敏化的诱导和维持：细胞外信号调节激酶（ERK）、p38和c-Jun N-末端激酶（JNK）（Obata和Noguchi，2004; Ma和Quirion，2005; Ji等人，2009; Mai等人，2020年）。MAPK在通过将细胞外刺激转导为细胞内翻译后和转录修饰来调节神经可塑性中是关键的（托马斯和Huganir，2004）（图1）。值得注意的是，可以抑制MAPK信号传导，特别是ERK信号传导的活化的疗法可以有效治疗慢性疼痛（Ji等人，2009). MAP激酶相互作用激酶（MNK 1和MNK 2）在ERK和p38 MAPK的下游被激活（Waskiewicz等人，1997年）。MNK使真核起始因子4 E（eIF 4 E）磷酸化，eIF 4 E是参与伤害性敏化的mRNA翻译的关键调节因子（Uttam等人，2018年）（图1）。有趣的是，MNKs-eIF 4 E信号传导对感觉神经元可塑性的贡献在无脊椎动物和脊椎动物中是进化保守的（Mihail et al.，2019），发现于年轻和老年哺乳动物（Mody et al.，2020），并且是无数疼痛样表型所必需的（Jeevakumar等人，2020; Mody等人，2020; Shiers等人，2020; Lackovic等人，2022年）。因此，MNK的药理学操作是用于逆转在MAPK信号传导下游的慢性疼痛状态中驱动神经元过度兴奋性的翻译调节剂的有希望的治疗靶标（Yousuf等人，2021年）（图1）。
In 2019, an estimated 20.4%(50.0 million) of US adults had chronic pain, and 7.4% of US adults (19.6 million) had high-impact chronic pain that frequently limited life or work activities (Zelaya et al., 2020). Unfortunately, effective, safe, and non-addictive treatments for the management of this “chronic pain epidemic” are absent, and novel therapeutics are desperately needed. Several decades of preclinical research implicate three mitogen activated protein kinase (MAPK) enzymes in the induction and maintenance of pain sensitization in both primary sensory afferents and the spinal cord dorsal horn: extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK)(Obata and Noguchi, 2004; Ma and Quirion, 2005; Ji et al., 2009; Mai et al., 2020). MAPKs are critical in regulating neural plasticity via the transduction of extracellular stimuli into intracellular post-translational and transcriptional modifications (Thomas and Huganir, 2004)(Fig. 1). Notably, therapies that can inhibit the activation of MAPK signaling, in particular ERK signaling, may be effective for the treatment of chronic pain (Ji et al., 2009).MAP kinase-interacting kinases (MNK1 and MNK2) are activated downstream of both ERK and p38 MAPKs (Waskiewicz et al., 1997). The MNKs phosphorylate eukaryotic initiation factor 4 E (eIF4E), which is a key regulator of the translation of mRNAs involved in nociceptive sensitization (Uttam et al., 2018)(Fig. 1). Intriguingly, the contribution of MNKs-eIF4E signaling to sensory neuron plasticity is evolutionarily conserved across invertebrates and vertebrates (Mihail et al., 2019), found in both young and aged mammals (Mody et al., 2020), and necessary for a myriad of pain-like phenotypes (Jeevakumar et al., 2020; Mody et al., 2020; Shiers et al., 2020; Lackovic et al., 2022). Thus, pharmacological manipulation of MNKs is a promising therapeutic target for reversing translational regulators driving neuronal hyperexcitability in chronic pain states downstream of MAPK signaling (Yousuf et al., 2021)(Fig. 1).