Esketamine is neuroprotective against traumatic brain injury through its modulation of autophagy and oxidative stress via AMPK/mTOR-dependent TFEB nuclear translocation

Traumatic brain injury (TBI) is caused by trauma to the head, often leading to a variety of functional disorders (Capizzi et al., 2020). According to recent statistics, the number of individuals suffering from TBI exceeds 60 million each year, with 5 million cases progressing to severe TBI (Dewan et al., 2018; Iaccarino et al., 2018). TBI consists of two phases: primary- and secondary injury. Following primary injury, a complex cascade of secondary injury mechanisms are initiated that include oxidative stress, apoptosis, autophagy and a loss of neuronal cells (Capizzi et al., 2020; Cornelius et al., 2013; McGinn and Povlishock, 2016). Those findings indicate that suppressing these responses can enhance functional recovery.

Autophagy is involved in several neuroprotective processes following TBI (Zeng et al., 2020). TFEB is a master regulator of lysosomal biogenesis, the nuclear translocation of which is a key regulator of autophagy (David, 2011). Accumulating evidence suggests that activated TFEB is neuroprotective through its role in autophagy (Liu et al., 2019; Wang et al., 2020a, Wang et al., 2020b; Zhuang et al., 2020). However, the association between TFEB and autophagy during TBI remain undefined. In terms of TFEB activity, it is principally regulated by mTORC1 (Vega-Rubin-de-Celis et al., 2017). Prior study has shown that the activation of AMPK and mTOR suppression induce the nuclear translocation of TFEB (Young et al., 2016). Nrf2 is a transcription factor that participates in the modulation of oxidative stress and is considered a target of TFEB (Li et al., 2021). Hence, the activation of autophagy and subsequent regulation of oxidative stress via TFEB represent a potential therapeutic strategy for TBI.

(S)-ketamine, termed esketamine, is approved by the FDA for treatment-resistant depression (Smith-Apeldoorn et al., 2019). Recent clinical studies also highlight esketamine has been shown to promote neuronal activation (Höflich et al., 2017) and neuroplasticity in the hippocampus (Höflich et al., 2021). In aspect of action mechanism of esketamine, it has further found to improve postoperative cognitive ability through modulation of the STING/TBK1 pathway (Li et al., 2022). In TBI, the neuroprotection effects of esketamine remain poorly defined.

Here, we investigated the neuroprotection mechanism(s) of esketamine against TBI. Our data show that esketamine modulates autophagy and oxidative stress via AMPK/mTOR-dependent TFEB nuclear translocation.

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