Table 1.

Chronological Reports of the Mechanisms Regulating HBOT-Induced Neuroprotection.

Study	Discovery
Jadhav et al., 2009	In surgical brain injury (SBI) mice, HBOT preconditioning ameliorated neurological function and cerebral edema; these neuroprotective effects seemed to be regulated by COX-2 mechanisms, as HBOT attenuated SBI-induced elevation of hypoxia-inducible factor-1alpha and COX-2 activity [170].
Mu et al., 2013	In permanent MCAO animal models, daily HBOT conditioning at 48 h post-surgery diminished infarct volume and improved neurological function, which correlated with elevated CREB protein expression in the hippocampus and peri-infarct area, boosting cell multiplication. Regarding acute pMCAo models, HBOT increased cerebral PP1-γ expression, alleviating CREB phosphorylation and ubiquitination spurred by ischemia. Moreover, HBOT’s regenerative effects against ischemic stroke can be associated with CREB and PP1-γ mechanisms [37].
Lu et al., 2014	In transient MCAO rat models, HBOT spurred an increase in ERK1/2 signaling due to higher levels of ROS, leading to the attenuation of autophagy. When U0126, an inhibitor of the ERK1/2 pathway, was applied, infarct size and autophagy were ameliorated [171].
Xue et al., 2016	MCAO rats subjected to HBOT preconditioning exhibited diminished infarct size, improved neurological behavior, and upregulated Sirt1, Nrf2, HO-1, and SOD1 expression, as well as reduction of MDA. Blocking of Sirt1 or Nrf2 abolished HBOT-induced protective effects, as Nrf2, HO-1, and SOD1 were repressed. Moreover, the protective actions of Sirt1, spurred by HBOT, may consist of the Nrf2/antioxidant defense mechanism [172].
Guo et al., 2016	Following successive HBOT pre-treatment over five days, rats underwent hyperglycemic MCAO. Preconditioning with HBOT significantly ameliorated hemorrhagic transformation induced by the Nod-like receptor protein 3 signaling and reduced infarct size, altogether rehabilitating neurological performance. HBOT’s neuroprotective effects could be linked to the ROS/thioredoxin-interacting protein/Nod-like receptor protein 3 mechanism [126].
Yang et al., 2017	HBOT ameliorated neurological impairment in TBI rats via upregulation of VEGF, VEGFR2, Raf-1, MEK1/2, and ERK1/2, stimulating proliferation of neural stem cells (NSC) and homing of these cells to the lesion site. The examination of HBOT’s protective effects in vitro showed similar results, as HBO drastically amplified NSC proliferation and VEGF/ERK signaling [123].
Hu et al., 2017	In hyperglycemia MCAO rats, exposure to two atmospheres of HBO for an hour immediately after dextrose administration ameliorated depleted ATP and nitcotinamide adenine dinucleotide levels, which in turn elevated silent mating type information regulation 2 homolog 1, alleviating cerebral infarct and neurological dysfunction, along with repressing hemorrhagic transformation [14].
He et al., 2019	Mice models of acute TBI demonstrated escalated levels of apoptotic neurons and caspase-3 activity, along with attenuation of signaling pathways that regulate apoptosis in neurons (e.g., pAkt/Akt, pGSK3β/GSK3β, and β-catenin). By eliminating the TBI-induced alterations in these pathways, HBOT suppressed neuronal apoptosis [173].
Ying et al., 2019	BDNF/TrkB signaling has been shown to influence rehabilitation after SCI. In vivo, SCI rat models were exposed to HBOT, and both dendritic/synaptic deterioration and apoptosis were ameliorated, which could be linked to higher levels of BDNF and TrkB activity. When ANA-12, an inhibitor of the BDNF/TrkB pathway, was administered, HBOT’s neuroprotective effects were reversed, indicating that HBOT’s therapeutic benefits are mediated by BDNF/TrkB signaling [174].
Zhou et al., 2019	Following HBOT, Sprague-Dawley rats with spinal cord injury (SCI) displayed ameliorated motor function and attenuated secondary injuries, such as inflammation and glial scar production. By blocking AKT and NF-kB signaling, HBOT repressed molecules associated with inflammation (iNOS and COX-2) and glial scar generation (GFAP and NG2) [175].