From Poison to Promise: The Evolution of Tetrodotoxin and Its Potential as a Therapeutic

Abstract

Tetrodotoxin (TTX) is a potent neurotoxin that was first identified in pufferfish but has since been isolated from an array of taxa that host TTX-producing bacteria. However, determining its origin, ecosystem roles, and biomedical applications has challenged researchers for decades. Recognized as a poison and for its lethal effects on humans when ingested, TTX is primarily a powerful sodium channel inhibitor that targets voltage-gated sodium channels, including six of the nine mammalian isoforms. Although lethal doses for humans range from 1.5–2.0 mg TTX (blood level 9 ng/mL), when it is administered at levels far below LD50, TTX exhibits therapeutic properties, especially to treat cancer-related pain, neuropathic pain, and visceral pain. Furthermore, TTX can potentially treat a variety of medical ailments, including heroin and cocaine withdrawal symptoms, spinal cord injuries, brain trauma, and some kinds of tumors. Here, we (i) describe the perplexing evolution and ecology of tetrodotoxin, (ii) review its mechanisms and modes of action, and (iii) offer an overview of the numerous ways it may be applied as a therapeutic. There is much to be explored in these three areas, and we offer ideas for future research that combine evolutionary biology with therapeutics. The TTX system holds great promise as a therapeutic and understanding the origin and chemical ecology of TTX as a poison will only improve its general benefit to humanity.

Metaplasticity: a key to visual recovery from amblyopia in adulthood?

“…Support for this hypothesis came from parallel studies in mouse and cat [63,64 ▪▪ ]. Tetrodotoxin (TTX), a voltage-gated sodium channel blocker, eliminates action potentials in exposed neurons [65 ▪ ]. Intravitreal injection of TTX abolishes visually driven activity and the pupillary light reflex for 17–36 h [66].…”

“…TTX is a potent neurotoxin that can be lethal in humans, but it is well tolerated at low concentrations [65 ▪ ]. Clinical applications for TTX under active study include treatment of cancer-related pain, neuropathic pain, and visceral pain [65 ▪ ,70]. Despite its use and demonstrated safety in other clinical contexts, the proposition of direct translation of TTX-mediated retinal silencing presents several challenges [63,64 ▪▪ ,67].…”

Toxin on the Tip of the Tongue：Tetrodotoxin

“…VGCS存在于整个神经系统和肌肉中，在执行许多基本生理功能中起到重要的作用，这使得TTX 作为一种特异性钠离子通道阻滞剂有望成为万能的治疗药剂。 当以远低于其LD 50 的水平给药时， TTX 表现出特殊的治疗特性，目前已被证明在几种不同的疼痛模型中起到镇痛作用，包括神经性疼痛、 胃肠道和内脏疼痛、癌症相关慢性疼痛等 [15] 。 钠离子通道在从伤害感受器到中枢神经的疼痛传导中占据着重要的作用，TTX展现出镇痛活性 主要是基于其对特性钠离子通道的高度选择性阻断，通过抑制动作电位的启动和传导来阻断神经传 递，因此在治疗神经性疼痛上具有广泛的应用前景。 神经性疼痛是由躯体感觉系统的疾病或损伤引起的，包括周围神经系统和中枢神经系统。在神 经受损后，伤害感受神经元异常的自发放电造成了感受通路中的动作电位和放电频率异常，从而引 起自发性疼痛。在啮齿类动物模型的研究中，TTX治疗神经性疼痛获得了良好的前景。在对小鼠热 痛觉损伤的研究中，发现相比于其他阿片类药物使用时造成的成瘾、镇静和呼吸抑制等有害副作用， 没有出现运动不协调、运动缺陷、呼吸窘迫等现象 [16] ，后续有望进一步在临床上得到验证。 此外，对TTX减轻癌症相关疼痛的能力进行了研究。随着癌症后期的发展，癌症本身、化疗等 治疗方法以及相关并发症都会造成疼痛加剧。TTX作为镇痛剂已经在癌症患者身上得到具有临床意 义的验证，虽然会有如口腔感觉消退和异常的轻微副作用 [17] ，但相比于阿片类易造成成瘾和具有遗 传毒性的药物更适用于长期缓解疼痛。此外，TTX对抑制肿瘤细胞的转移和侵略体现出了一定的作 用，在对结肠直肠癌细胞系的体外研究中发现TTX对两种癌细胞系都有着明显的抑制作用 [18] ，TTX 具有的抗癌活性可用于开发潜在的抗肿瘤药物。 除了缓解疼痛，TTX还在治疗海洛因和可卡因戒断症状上显示出令人欣慰的效果。 海洛因戒断综合征和复发是成功治疗海洛因成瘾的主要问题。即使在长期戒断之后，与毒品相 关的环境因素或暴露于压力源也会促使吸毒者在康复过程中复吸。因此，需要长期防止毒瘾复发。 目前，阿片类药物常在受控的方式下治疗戒断症状，但阿片类药物的成瘾性使其不能长期使用。在 2009年进行了一项涉及45人的双盲、安慰剂对照研究，发现单次肌肉注射10 μg TTX可显著降低暗示 性海洛因成瘾者的焦虑和渴望，而对血压或心率没有显著影响 [19] 。但目前对TTX缓解戒断症状的机 制尚不了解，其他潜在的副作用仍待进一步研究。…”

An Updated Review of Tetrodotoxin and Its Peculiarities

“…TTX is both water soluble and heat stable, therefore not being destroyed by heat processing; on the contrary, it rather increases its toxic effect, whereas there is no known antidote for TTX to date [3,4]. Despite its recognized poisonous, or sometimes lethal effects when ingested by humans at high doses (lethal doses range from 1.5-2.0 mg TTX, equal to blood level 9 ng/mL), when administered at much lower levels, TTX exhibits therapeutic properties, so far mainly targeted to treating cancer-related, neuropathic and/or visceral pain [5].…”