The blood-brain uptake of 3-O-methyl D-glucose may be mainly interstitial over times less than 45 seconds

The equilibrium distribution space of 3-O-methyl-D-glucose (3OMG), a non-metabolizable analog of D-glucose, is around 50 ml/100 g tissue (50%) in most brain areas 1. The 3OMG space is considerably larger than the extracellular space (18%) but much less than the water space (78% in gray matter; 65% in white matter). In the past we 2, 3 and others have assumed that the 3OMG after crossing the blood-brain barrier instantly mixes in a 50% space in brief (e.g., 30 sec) experiments. This assumption was tested by short-term, ramp infusions of 14C-3OMG in Sprague-Dawley (SPD), spontaneously hypertensive (SHR), and Wistar-Kyoto (WKY) rats. Young adult SPD, SHR, and WKY rats were intravenously infused with 14C-3OMG with a schedule that yielded a continuously rising plasma concentration. Blood was continuously sampled, and experiments terminated at 15 sec (n=4/rat strain), 30 sec (n=3), and 45 sec (n=3). Radioactivity was determined in plasma by liquid scintillation counting and in 7 regions of interest (ROIs) by quantitative autoradiography. The ROIs were sensorimotor (SMC) and occipital (OCC) cortex, caudate-putamen (CPU), medial geniculate (MGT), inferior colliculus (IC), genu of the corpus callosum (GCC), and median eminence (ME). The resulting set of multi-time data (n=10) were inserted into a two compartment (plasma and tissue) model, and the influx (Ki) and effective tissue distribution space (eV) for the 15 - 45 sec interval were obtained for each ROI by compartmental analysis. The difference between eV and 0.5 ml/g were considered significant at p<0.05 level. Among the three strains, plasma glucose concentrations were comparable, and the rates of 3OMG influx were lowest for GCC (white matter; Ki 0. 08 ml/g/ml) and highest for the ME (a circumventricular organ with leaky capillaries; Ki = 0.72 - 1.05 ml/g/ml). The differences in Ki for any ROI were not significant among the three strains. In SMC, OCC, CPU, MGT, IC, and GCC of SPD rats, eV (SE of the estimate) ranged from 0.070.02 ml/g (GCC) to 0.180.05 ml/g (IC). In these ROIs, eV was significantly less than 0.5 ml/g and approximated the extracellular space. For these six ROIs, comparable values of eV were found in WKY, and the differences between eV and 0.5 ml/g were significant. For the ME, eV was >0.5 ml/g for SPD (p>0.05) but only 0.280.07 ml/g for WKY (p<0.05). For each of the seven ROIs, eV values in SHR were 2 or more times higher than in either SPD or WKY and not statistically significantly different than 0.5 ml/g. The assumption of rapid mixing of 3OMG in a 50% tissue space was not upheld for gray and white matter of SPD and WKY rats. The distribution of 3OMG was completely and strangely different in SHR, suggesting considerable variations in the glucose transporter systems of neurons and/or glia among the three strains. Grant support: NIH grants HL-35791, NS-21157, and NS-26004.