Kalkman Hans O
Retired Pharmacologist, Gänsbühlgartenweg 7, 4132 Muttenz, Switzerland.
Biomedicines. 2023 Sep 28;11(10):2664. doi: 10.3390/biomedicines11102664.
Ketamine is a racemic mixture composed of two enantiomers, S-ketamine and R-ketamine. In preclinical studies, both enantiomers have exhibited antidepressant effects, but these effects are attributed to distinct pharmacological activities. The S-enantiomer acts as an NMDA-channel blocker and as an opioid μ-receptor agonist, whereas the R-enantiomer binds to σ1-receptors and is believed to act as an agonist. As racemate, ketamine potentially triggers four biochemical pathways involving the AGC-kinases, PKA, Akt (PKB), PKC and RSK that ultimately lead to inhibitory phosphorylation of GSK3β in microglia. In patients with major depressive disorder, S-ketamine administered as a nasal spray has shown clear antidepressant activity. However, when compared to intravenously infused racemic ketamine, the response rate, duration of action and anti-suicidal activity of S-ketamine appear to be less pronounced. The σ1-protein interacts with μ-opioid and TrkB-receptors, whereas in preclinical experiments σ1-agonists reduce μ-receptor desensitization and improve TrkB signal transduction. TrkB activation occurs as a response to NMDA blockade. So, the σ1-activity of R-ketamine may not only enhance two pathways via which S-ketamine produces an antidepressant response, but it furthermore provides an antidepressant activity in its own right. These two factors could explain the apparently superior antidepressant effect observed with racemic ketamine compared to S-ketamine alone.
氯胺酮是一种由两种对映体（S-氯胺酮和R-氯胺酮）组成的外消旋混合物。在临床前研究中，两种对映体均表现出抗抑郁作用，但这些作用归因于不同的药理活性。S-对映体作为N-甲基-D-天冬氨酸（NMDA）通道阻滞剂和阿片μ受体激动剂起作用，而R-对映体与σ1受体结合并被认为起激动剂作用。作为消旋体，氯胺酮可能触发涉及AGC激酶、蛋白激酶A（PKA）、蛋白激酶B（Akt，PKB）、蛋白激酶C（PKC）和核糖体S6激酶（RSK）的四条生化途径，最终导致小胶质细胞中糖原合成酶激酶3β（GSK3β）的抑制性磷酸化。在重度抑郁症患者中，经鼻喷雾给药的S-氯胺酮已显示出明显的抗抑郁活性。然而，与静脉输注的外消旋氯胺酮相比，S-氯胺酮的反应率、作用持续时间和抗自杀活性似乎不那么显著。σ1蛋白与μ阿片受体和酪氨酸激酶受体B（TrkB）相互作用，而在临床前实验中，σ1激动剂可减少μ受体脱敏并改善TrkB信号转导。TrkB激活是对NMDA阻断的反应。因此，R-氯胺酮的σ1活性不仅可能增强S-氯胺酮产生抗抑郁反应的两条途径，而且其本身还具有抗抑郁活性。这两个因素可以解释与单独使用S-氯胺酮相比，外消旋氯胺酮观察到的明显更优的抗抑郁效果。
