Hyperbaric oxygen therapy (HBOT) refers to the medical use of oxygen at levels higher than atmospheric pressure. The potential applications of HBOT following ischemic stroke have been investigated in various animal models and clinical trials [1–5]. Previous studies utilizing experimental models of ischemic stroke demonstrated that HBOT improved neurological functions , reduced infarct size [3, 4], decreased hemorrhagic transformation , and promoted neurogenesis [6–9]. It has also been suggested that these effects are achieved through a variety of mechanisms, including reduction of oxidative and metabolic stress, amelioration of brain edema, suppression of inflammation and apoptosis, as well as stabilization of the blood brain barrier, by activation of cellular transcription factors . A major effect of HBOT is the elevation of oxygen partial pressure within the blood and therefore the restoration of oxygen supply to the penumbra after ischemic stroke .
Recent evidence revealed that HBOT modulates the synthesis and degradation of several hormones. Edstrom and his colleagues investigated the effect of HBOT on endocrine organs and found that hyperbaric oxygen evoked adrenal hypertrophy, reduced thymus weight but increased thyroid weight . Animal experiments further demonstrated that serum levels of adrenal epinephrine and norepinephrine increased in spontaneously hypertensive rats that received HBOT (2 ATA, 90 min) . The serum concentration of cortisol, as well as the concentration of glucocorticoid receptors in the rat’s lung were reduced following HBOT (3 ATA, 5 hrs) . In clinical studies, HBOT (2.0 ATA, 10 days) increased serum levels of estrogen and estrogen receptors in infertile patients , and decreased erythropoietin (EPO) concentrations in healthy subjects (2.5 ATA, 90 min) . HBOT (2.5ATA, 1 hr X 10 sessions) improved the metabolic control and reduced insulin requirements in patients with type 2 diabetes mellitus (T2DM) after stem cell transplantation . However, short-term HBOT (2.5 ATA, 90 min X 3 days) did not alter levels of circulating insulin, insulin-like growth factor (IGF), leptin, interleukin-8 (IL-8) or nitric oxide (NO) in patients with T2DM . Furthermore, single HBOT (2.5 ATA, 1 hr) failed to induce a generalized hormonal stress reaction in 8 divers, who showed normal serum concentrations of epinephrine, norepinephrine, antidiuretic hormone (ADH), atrial natriuretic peptide (ANP) and renin after the HBOT session . In summary, while it has been suggested that HBOT interrelates with endogenous hormone pathways, long-term HBOT, rather than single or short-term based therapies, affected the hormone balance to a greater extend. So far, there is no research related to hormone profiles induced by HBOT in ischemia patients or animal models. Thus, it is not clear whether HBOT can ameliorate ischemic brain injury by modulating the serum levels of specific hormones.
Among all hormones modulated with HBOT, leptin is a promising candidate for the treatment of ischemic stroke . Leptin, a 16 kDa peptide produced and released by adipocytes, acts via its receptors in the hypothalamus to decrease appetite and increase energy expenditure [21, 22]. The secretion of leptin from adipocytes is regulated by multiple factors, including body weight, food intake, insulin and hypoxia . Exogenous administration of leptin, attenuated neuronal hypoxic injury in both in vivo [24, 25] and in vitro [20, 26] studies. Endogenous leptin expression as well as mRNA levels were found increased in the peri-infarct brain tissue up to 24 hrs after permanent middle cerebral artery occlusion (pMCAo) in mice . In oxygen-breathing mice, serum leptin was increased six to seven fold by hyperoxia and leptin mRNA was elevated within the adipose tissue . To date, no studies have investigated the relationship between HBOT and endogenous leptin in ischemic stroke models. In this present study, we hypothesized that multiple and long term HBOT can exert neuroprotection by increasing the serum level of leptin in pMCAo rats.