CHEMICAL ENVIRONMENT OF THE CENTRAL NERVOUS SYSTEM 



l88l 



Water Exchange 



The question of water exchange between plasma 

 and brain has been investigated by Bering (13) and 

 Sweet et al. (145) who have shown that intravenously- 

 injected deuterium-labeled water rapidly enters all 

 areas of the brain and the cerebrospinal fluid, reach- 

 ing equilibrium with the blood in about 20 min. The 

 time required for the cerebrospinal fluid concentra- 

 tion of deuterium to achieve one half its concentration 

 in the blood was 1.5 min. for the cisterna magna, 8 to 

 1 1 min. for the ventricles, and 18 to 26 min. for the 

 lumbar sac. Equilibrium with the grey matter of the 

 cortex occurred within 1 min. Blockage of the cerebro- 

 spinal fluid system did not alter the rate of deuterium 

 diffusion, and it can be concluded that water ex- 

 changes among the vascular and extravascular com- 

 partments of the central nervous system more rapidly 

 than in most tissues, as a result, most probably, of the 

 relatively dense vascularization of the central nervous 

 s\sicm. This free passage of water requires that the 

 intracranial fluids be essentially isotonic at all times 



Exchange of Metabolic Intermediates 



With respect to organic crystalloids, the blood- 

 brain barrier has been invoked to explain awkward 

 discrepancies between in vivo and in vitro result- "I 

 metabolic substrate utilization. Although in the in 

 vivo situation, only glucose, and to a lesser extent 

 glutamic acid, mannose and maltose plus .1 lew other 

 substrates have been found capable of restoring nor- 

 mal electroencephalographic patterns or conscious- 

 ness following insulin shock or hepatectomy hypo- 

 glycemia (108, 1 13), brain brei or slices not only can 

 oxidize the above compounds, but also lactate, 

 a-ketoglutarate, succinate, fumarate, pyruvate and 

 other intermediates (36, 106, 162). The rate of trans- 

 fer of fructose, lactate, glutamate and succinate from 

 blood to brain is much slower than that of glucose, 

 and may be insufficient to support adequate functional 

 metabolism (93, 94). However, it must not be assumed 

 that the ineffectiveness of substrates in vivo to support 

 central nervous system function is a priori evidence 

 that they do not penetrate the blood-brain barrier. 

 It is possible that substances both penetrate and are 

 metabolized, but are somehow not geared to the 

 metabolic machinery necessary for normal function. 

 In this respect, pyruvate does appear to penetrate 

 into brain tissue rapidly where it is converted to lac- 

 tate, but it has been proposed that the rate of forma- 

 tion of this latter compound is insufficient to provide 



adequate metabolic energy to the central nervous 

 system (36). Likewise, succinate in vitro causes a 

 marked increase in oxygen uptake of brain breis and 

 slices, but little or no increase in carbon dioxide 

 production. It is oxidized rapidly through only one 

 step, to fumarate and malate, and further oxidation 

 takes place very slowly (37). Thus, even if succinate 

 penetrated readily into the central nervous tissue 

 from the blood, it is quite unlikely that it could sup- 

 port function effectively. 



Glutamic acid and glutamine together comprise 

 approximately 50 per cent of the a-amino nitrogen of 

 the nonprotein fraction of the brain, and glutamic 

 acid is the only amino acid which has been found to 

 be oxidizablc by this tissue (162). Following intra- 

 venous administration of large amounts of glutamic 

 acid, there was no increase in brain concentration of 

 this substance. However, after intravenous injection of 

 glutamine, singificantly higher brain concentrations 

 of glutamic acid were found in a number of experi- 

 ments (155). From these studies, Waelsch concluded 

 that the blood-brain barrier is normally permeable to 

 glutamine, and this substance 111. i\ therefore furnish 

 the amino group for amino acids such as alanine, 

 aspartic acid and glutamic acid the carbon structure 

 of which is generated through the citric acid cycle in 

 the central nervous system. 1 limwich ,1 al. ( 79) suggest 

 that the impermeability of the blood-brain barrier to 

 glutamic acid is a function of age. They found that 

 free glutamic acid enters the brain easily in rats 24 

 hr. old but does not penetrate readih at older ages. 



Glucose Exchange 



The clinical use of intravenous hypertonic glucose 

 solutions to produce cerebral dehydration presents 

 direct evidence that the entry of sjlucose into the 

 central nervous system is a more complex process 

 than its entry into most tissues. Although the dehydra- 

 tion so produced is short-lived and supplanted by 

 movement of water into the brain as the glucose is 

 taken up by that organ, nevertheless no delay of this 

 sort occurs in the movement of glucose into the inter- 

 stitial space of other tissues. Geiger and others have 

 investigated this blood-brain glucose transport by 

 means of an in situ brain perfusion technique in which 

 the arterial supply and venous drainage of the cat 

 brain are isolated from the general circulation and 

 perfused, via an external circuit, with a 'simplified 

 blood' consisting of washed beef erythrocytes sus- 

 pended in Krebs'-Ringer's solution, containing 7 per 

 cent native bovine serum albumin (49). With this 



