Hyperbaric oxygen therapy promotes neurogenesis: where do we stand?

Abstract

Neurogenesis in adults, initiated by injury to the central nervous system (CNS) presents an autologous repair mechanism. It has been suggested that hyperbaric oxygen therapy (HBOT) enhances neurogenesis which accordingly may improve functional outcome after CNS injury. In this present article we aim to review experimental as well as clinical studies on the subject of HBOT and neurogenesis. We demonstrate hypothetical mechanism of HBOT on cellular transcription factors including hypoxia-inducible factors (HIFs) and cAMP response element binding (CREB). We furthermore reveal the discrepancy between experimental findings and clinical trials in regards of HBOT. Further translational preclinical studies followed by improved clinical trials are needed to elucidate potential benefits of HBOT.

Figure 1

Potential mechanisms of HBOT and HIF-1α. In hypoxia, HIF-1α activates EPO and VEGF to promote neurogenesis. The accumulation of HIF-1α further induces the expression of p53 protein and BNIP3, leading to cell death. HBOT stabilizes HIF-1α, preventing it from overexpression and further, activates the Wnt pathway. Abbreviation: PHDs, prolyl hydroxylase; HIF-1α, hypoxia-inducible factor 1α; EPO, e rythropoietin; VEGF, vascular endothelial growth factor; NGN1, Neurogenin1; TCF, T-cell factor.

Figure 2

Potential mechanisms of HBOT associated CREB activation and degradation: CREB activates its downstream genes when phosphorylated, while PP1 catalyzes the dephosphorylation of CREB. PP1γ is the core subunit of PP1. In hypoxia, PP1γ is repressed, leading to over-phosphorylation of CREB, followed by CREB ubiquitination and degradation by 26s proteasome. HBOT may reverse this process by reactivating PP1γ and blocking CREB degradation. Thus, phosphorylated CREB activates the downstream genes (BDNF, Bcl-2, VGF, et al.) to promote neurogenesis. Abbreviation: PP1γ, protein phosphatase-1; CREB, cAMP response element-binding; Ub, ubiquitin; CRE, cAMP response elements; CBP, CREB binding protein.