Intracerebral hemorrhage (ICH) is the predominant form of hemorrhage and frequently leads to severe motor deficits (Jiang et al., 2019). The disruption of the corticospinal tracts (CST), responsible for transmitting cortical commands directly to the spinal cord, is a central pathological feature linked with persistent functional disabilities following ICH (Jiang et al., 2019). Clinically, patients with preserved CST integrity have shown better motor outcomes compared to those with disrupted CST after putaminal hemorrhage. Thus, the CST integrity may serve as a predictive marker for long-term motor outcomes following stroke (Zhang et al., 2024; Koyama et al., 2018).

To promote functional recovery after ICH, a lot of attention has been paid to foster regenerative growth of injured CST axons across the lesion site (Volbers et al., 2021). To this end, several important regulators such as mTOR/PTEN, STAT3/SOCS3, KLFs, and Sox11 (Liu et al., 2017) have been identified to promote CST axonal regrowth. In addition to this, previous studies revealed that maintaining microtubule stability at the early stage after ICH could inhibit CST degeneration and significantly promote locomotor recovery (Yang et al., 2018). Considering the inherently poor regrowth ability of CST axons (Kim et al., 2023), it might be more translational to identify effective treatment that alleviates CST axon degeneration after ICH.

Previous studies have indicated that immediate mechanical trauma to the hemorrhage is exacerbated by tissue swelling and inflammation in the surrounding area (Xiao et al., 2023), which occurs shortly after ICH (Wilkinson et al., 2018). Our previous study revealed significant axonal degeneration in CST axons around the hematoma within 24 h post ICH, attributable to axonal mitochondrial impairment (Yang et al., 2022). Additionally, the role of reactive oxygen species (ROS), primarily generated by mitochondria, in contributing to axonal degeneration is well-established (Qu et al., 2016). Thus, preventing axonal mitochondrial injury at early stage post ICH will protect the integrity of CST.

Current therapeutic strategies for ICH include medical and surgical approaches (Hemphill 3rd et al., 2015). Randomized controlled trials (RCTs) investigating surgical interventions for ICH have not confirmed significant benefits (Mendelow et al., 2013; Mendelow et al., 2005). Likewise, although neuroprotective medications have shown promise in laboratory settings, clinical trials have not yet replicated these successful outcomes (Chamorro et al., 2021). Therapeutic hypothermia (HT) has gained recognition as a promising neuroprotective treatment due to its multifaceted beneficial effects on the brain (Rewell et al., 2017; Mifsud et al., 2014). Mechanistic research suggests that HT primarily exerts its neuroprotective effects by modulating inflammation and cell death processes (Liddle et al., 2022; Kim et al., 2022), delaying microglia proliferation (Liu et al., 2018). Furthermore, HT has been found to mitigate glutamate accumulation and subsequent excitotoxicity caused by calcium influx (Yenari and Han, 2012), reduce intracellular acidosis levels, and suppress the formation of oxygen free radicals (Sosunov et al., 2022). In light of this, previous clinical studies has indicated that HT improved motor-function scores after perinatal asphyxia (Azzopardi et al., 2014) and National Institutes of Health Stroke Scale (NIHSS) which include motor function after acute brain injury (Wang et al., 2024; Su et al., 2015).

However, whether HT plays a direct role in reducing mitochondria dysfunction and, more importantly, maintaining the CST integrity post IHC remains largely unknown. In the current study, we aimed to investigate the impact of HT on CST axonal degeneration within 24 h following ICH. To achieve this, we employed chemogenetic activation of excitatory neurons in the bilateral preoptic area (POA) to induce HT. Our findings represented that HT exerted a beneficial effect on preventing axonal degeneration and preserving integrity of CST after ICH through inhibiting mitochondrial impairment.