Thompson Institute, University of the Sunshine Coast, Queensland, Australia..
Thompson Institute, University of the Sunshine Coast, Queensland, Australia.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jul 13;101:109921. doi: 10.1016/j.pnpbp.2020.109921. Epub 2020 Mar 10.
Anorexia nervosa (AN) is a severe, biological brain disorder with significant medical risks and a tenacious development over time. Unfortunately, few treatments show efficacy in people with AN although numerous therapies including pharmacological have been explored. Zinc deficiency has been implicated in AN and zinc is important in a large range of processes in the brain. In particular, it is an allosteric modulator of NMDA receptors - the maintenance of zinc levels within a normal, narrow range is essential for glutamatergic functioning. Chronic zinc deficiency increases neuronal stores of calcium and reduces direct modulation of NMDA receptors which collectively lead to overactivation and upregulation of NMDA receptors. This may facilitate pathologically high levels of glutamate, calcium influx and subsequent excitotoxicity, which can disrupt synaptogenesis and synaptic plasticity. While studies of zinc supplementation in AN have shown some promise, the efficacy of this treatment is limited. This may be due to AN illness chronicity and the significant changes already made, as well as a reduced potency of zinc to inhibit NMDA receptors in a pathological state. Thus, we propose that the safe (at low doses) yet more potent NMDA receptor antagonist, ketamine, may act to normalise a perturbed glutamatergic system and increase synaptogenesis in the short term. This 'kickstart' via ketamine could then allow zinc supplementation and other forms of treatment to enhance recovery in AN.
神经性厌食症（AN）是一种严重的、生物学上的大脑紊乱，存在重大的医疗风险，且随着时间的推移会顽强发展。不幸的是，尽管已经探索了包括药理学治疗在内的许多疗法，但很少有治疗方法对 AN 患者有效。锌缺乏与 AN 有关，而锌在大脑的许多过程中都很重要。特别是，它是 NMDA 受体的别构调节剂——维持锌水平在正常、狭窄的范围内对于谷氨酸能功能至关重要。慢性锌缺乏会增加神经元内的钙储存，并减少 NMDA 受体的直接调节，这两者共同导致 NMDA 受体过度激活和上调。这可能促进病理性高水平谷氨酸、钙内流和随后的兴奋性毒性，从而破坏突触发生和突触可塑性。虽然锌补充治疗 AN 的研究显示出一些希望，但这种治疗的疗效有限。这可能是由于 AN 疾病的慢性和已经发生的重大变化，以及锌在病理性状态下抑制 NMDA 受体的效力降低。因此，我们提出，安全（低剂量）但更有效的 NMDA 受体拮抗剂氯胺酮可能会在短期内作用于正常化受扰的谷氨酸能系统并增加突触发生。通过氯胺酮的这种“启动”可以使锌补充剂和其他形式的治疗增强 AN 的恢复。
