Counteracting Neuronal Alterations in Space and on Earth - Novel Hydroxynorketamine Derivatives are Potent Agents to Enhance Synaptic Plasticity in vitro

Abstract

Space conditions impact neurons and synaptic activity. Thus, the development of neuroprotective agents is necessary for future missions. Loss of synaptic plasticity in the brain has been linked to cognitive deficits, thus providing a promising target for therapeutic interventions. Ketamine, a drug applied in treatment-resistant depression, rapidly induces synaptic plasticity via a BDNF-dependent mechanism. Ketamine features substantial side-effects due to its NMDA receptor interaction. Its most relevant metabolite, hydroxynorketamine (HNK), has been attributed a stimulating effect on synaptic plasticity, while its weak affinity to NMDA receptors leads to a mitigation of the psychotropic side effects. Aiming to utilize this enhancing effect of HNK on synaptic plasticity for astronauts and patients on Earth, novel HNK derivatives were synthesized. These derivatives are investigated for their use as preventative agents or neuro-stimulants while omitting psychotropic side-effects.