Background and Aims: Brain derived neurotrophic factor (BDNF) is a key protein involved in neurogenesis, influencing the regulation, growth and survival of neurons, learning and memory (Chen et al., 2013). Its systemic concentration has been shown to rise in response to acute hypoxia (Hubold et al., 2009) though to what extent the human brain contributes remains to be established. Thus, in the present study, we measured the jugular venous to radial arterial concentration difference (JV-RADIFF) to document, for the first time, the trans-cerebral exchange kinetics of BDNF during hypoxia. We also chose to measure nitrite (NO2-) exchange since cellular evidence suggests that BDNF formation may be regulated by nitric oxide (NO) (Xiong et al., 2009). Methods: Ten healthy males were examined in normoxia and following 12h passive exposure to poikilocapnic normobaric hypoxia (~13% O2). Blood samples were obtained simultaneously from the RA and internal JV. Plasma was assayed for NO2- using ozone-based chemiluminescence and platelet-poor BDNF via enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN, USA). Global cerebral blood flow (CBF) was determined in the desaturation mode using inhaled nitrous oxide (5%) as the tracer (Kety and Schmidt, 1945). Cerebral plasma flow (CPF) was calculated as CBF x (1-haematocrit) and trans-cerebral exchange calculated as CPF x JV-RADIFF. Following confirmation of distribution normality using Shapiro-Wilk W tests JV-RADIFF data were analysed with a two factor repeated measures ANOVA and post-hoc Bonferroni-corrected paired samples t-tests. Exchange data were analysed using a paired samples t-test expressed as mean ± standard deviation (SD).Results: Hypoxia was associated with a decrease in arterial oxygen content (8.5 ± 0.4 to 7.1 ± 0.4 mmol/L, P < 0.05) whereas no changes were observed in CPF (51± 9 to 57 ± 7 mL/100g/min, P > 0.05) or platelet count (190 ± 51 vs. 177 ± 76 x 109/L, P > 0.05). A net cerebral output of BDNF (169 ± 300 pg/min/g) and uptake of NO2- (-126 ± 94 nmol/min/g) was apparent at baseline during normoxia. Hypoxia was shown to suppress (P < 0.05 vs. normoxia) both BDNF output (25± 94 pg/min/g) and NO2- uptake (-16 ± 47 nmol/min/g) due to a reduction in JV outflow and RA inflow respectively. Conclusions: The present findings fail to confirm the systemic rise in BDNF previously observed during hypoxia (Hubold et al., 2009) and further exclude the human brain as a contributory source. To the contrary, the cerebral output of BDNF was shown to decrease during hypoxia and the concomitant reduction in NO2- uptake suggests that its cerebral formation may be regulated by NO consumption.