Traumatic brain injury (TBI) contributes to mortality and disability worldwide, with survivors often experiencing severe cognitive, motor, or consciousness impairments (Bernardi et al., 2023). The pathophysiology of TBI is intricate, comprising both primary and secondary injuries (Maralani and Symons, 2023). The mechanical damage at the initial impact site of the brain is typically irreversible, whereas a cascade of complex pathophysiological events leads to secondary injury (Kalra et al., 2022), characterized by processes such as inflammation, oxidative stress, and the release of excitatory neurotransmitters, which present potential targets for intervention. Recent advancements in neuromodulation technology have demonstrated its potential efficacy in treating various neurological disorders, offering a viable approach for managing TBI.

Transcranial pulsed current stimulation (tPCS) is a burgeoning form of non-invasive neuromodulation technology, which delivers pulsed electrical currents at specific amplitudes and frequencies to the cerebral cortex to modulate corticospinal excitability and enhance behavioral outcomes. Analogous to transcranial direct current stimulation (tDCS), tPCS employs anodal stimulation to induce excitability, whereas cathodal stimulation yields inhibitory effects (Pellegrini et al., 2021). Recent investigations have confirmed the effectiveness and safety of tPCS. For instance, anodal stimulation of the primary motor cortex (M1) through tPCS (a-tPCS) enhances functional connectivity between the cortex and thalamus, leading to significant improvements in cognitive function (Sours et al., 2014). A 20-min session of a-tPCS targeting the right M1 has been shown to notably enhance gait and walking velocity in patients with moderate to severe Parkinson's disease, with no reported adverse events during the intervention (Alon et al., 2012). tPCS not only facilitates recovery from cerebral functional deficits by strengthening brain network connections but also improves neurofunction via anti-inflammatory actions and modulation of neuroplasticity. Previous research indicates that tPCS can amplify calcium ion responses in neurons and astrocytes, thereby regulating long-term potentiation and synaptic plasticity (Ma et al., 2019). Additionally, tPCS applied over the primary somatosensory cortex (S1) diminishes microglial M1 polarization and fosters brain-derived neurotrophic factor (BDNF) production by modulating the PI3K/Akt pathway, resulting in anti-inflammatory, antioxidative, and angiogenic effects that contribute to reduces infarct size following middle cerebral artery occlusion (Wang et al., 2021a). Therefore, exploiting these neuroprotective mechanisms of tPCS might furnish a novel avenue for TBI therapeutics.

Accumulating evidence underscores neuroinflammation as a pivotal factor in the secondary injury and neurological deficits following TBI (Jamjoom et al., 2021; Li et al., 2022). Furthermore, the formation and activation of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome are deemed critical steps in the post-TBI neuroinflammatory cascade (Chakraborty et al., 2023). TBI triggers the activation of the NLRP3 inflammasome within neurons and glial cells, leading to the release of IL-1β and IL-18, as well as the cleavage of Gasdermin D (GSDMD), thereby exacerbating neuronal pyroptosis and microglial activation (Hu et al., 2022). The apoptosis-associated speck-like protein containing a CARD, ASC, regulates the formation of NLRP3 inflammasome by recruiting caspase-1 to the NLR protein complex. NEK7, a NIMA-related kinase 7, plays a crucial role in the activation of NLRP3 inflammasome. It forms a disc-shaped structure by binding to NLRP3, thereby promoting the oligomerization of ASC and the assembly and maturation of caspase-1 (Chen et al., 2019). Our team (Ye et al., 2021) and others (Zhao et al., 2021) have discovered that exogenous Orexin-A can mitigate IL-1β and IL-18 induced neuroinflammation and cell apoptosis by inhibiting NF-κB phosphorylation and NLRP3 activation. Based on these findings, we hypothesize that Orexin-A may alleviate TBI-induced neural damage by suppressing the activity of NLRP3.

Orexin-A (OX-A), an excitatory neuropeptide synthesized in the hypothalamus, serves as an essential component in regulating the circadian cycle, energy homeostasis, and food intake through its interaction with the orexin receptor type 1 (OX1R) (Willie et al., 2001). Previous studies have identified an increase in OX1R expression following focal cerebral ischemia, potentially associated with a decrease in OX-A expression (Dohi et al., 2005). Recent investigations have demonstrated that OX-A effectively attenuates neuroinflammation following cardiac arrest and cerebral hemorrhage, contributing to arousal from coma and enhancing neurological function in mice (Li et al., 2020; Modi et al., 2017). However, investigations into the anti-inflammatory and neuroprotective properties of OX-A in the context of TBI remain limited. Prior experiments conducted by our team have revealed that stimulation of the hypothalamus via deep brain stimulation (Dong et al., 2021) and low-intensity focused ultrasound (Huang et al., 2022) can enhance the secretion of OX-A from the lateral hypothalamus, thereby modulating its concentration in the cortex. The potential of tPCS to improve neurological outcomes by elevating OX-A levels in the brains of TBI-affected mice remains to be fully explored.

In this study, we demonstrated that tPCS can mitigate neuroinflammation and cerebral damage in mice with TBI, leading to a notable enhancement of neurological function. Our findings from both in vivo and in vitro experiments suggest that tPCS may facilitate the secretion of OX-A and modulate the OX1R/NLRP3 pathway, thereby exerting a neuroprotective effect.