Ketamine and its more potent S-enantiomer, esketamine, function as NMDA-receptor antagonists, offering short-term anesthesia and analgesia benefits. These properties make them popular choices for pediatric anesthesia and sedation during procedures outside of the operating room. However, the impact of ketamine on postoperative cognitive dysfunction (POCD) is still a matter of debate. Clinical studies exploring the potential mitigating effects of ketamine on cognitive impairment following cardiac surgery have yielded inconclusive results, potentially due to ketamine's dual anti-inflammatory and pro-inflammatory effects.
Additionally, when ketamine blocks certain brain receptors (NMDA receptors), it promotes the interaction of glutamate with other receptors (AMPA), leading to the release of a protective brain chemical (BDNF). In models of post-surgery depression, esketamine has been effective in reducing microglial activation and improving depression symptoms through similar mechanisms.
Moreover, ketamine can shift the behavior of microglial cells from a pro-inflammatory state (M1) to a more protective state (M2), linked to the suppression of another inflammatory pathway (HMGB1/RAGE axis). This helps enhance ketamine's protective effects on the brain.
Conversely, recent studies suggest that ketamine may also have a pro-inflammatory role linked to microglial activation, but further research is needed to confirm this. For instance, in vitro evidence indicates that ketamine administration can induce M1 polarization in microglia, potentially increasing neural cell death. The extent to which ketamine promotes this M1 phenotype is not yet understood. It is also suggested that the pro-inflammatory effects of ketamine might depend on the dosage and duration of exposure. High doses or prolonged exposure to ketamine can exacerbate neuroinflammation and impair cognitive functions. Furthermore, developmental neurotoxicity, similar to that induced by propofol, can also occur with ketamine, as demonstrated in neonatal rats where clinical doses activated the hippocampal NLRP3 inflammasome.
Ultimately, understanding the dose-, exposure time-, and age-dependent effects of ketamine on microglial activation and further elucidating its pro-inflammatory mechanisms are crucial. This nuanced approach is necessary to harness ketamine’s potential benefits while mitigating its risks.
