METABOLISM OF THE CENTRAL NERVOUS SYSTEM IN VIVO 



.847 



and their rates of utilization or production per 100 

 gm of average brain taken as a whole per minute, 

 derived from studies employing the nitrous oxide 

 technique under more or less physiological conditions. 



It is apparent from table 1 that the ultimate source 

 of energy for the brain under normal conditions is 

 the oxidation of glucose. The only energy-yielding 

 substances shown consistently and repeatedly to be 

 removed from the blood in significant amounts by 

 the brain are oxygen and glucose, and the only 

 product of the cerebral metabolism, other than water, 

 consistently released to the blood is carbon dioxide. 

 The finding of an uptake by the normal brain of glu- 

 tamic acid with a release of glutamine by Adams and 

 his co-workers (1) requires further confirmation, par- 

 ticularly in view of the observation in mice and rats l>\ 

 Schwerin et al. (164) of the inability of glutamic acid to 

 penetrate the blood-brain barrier. At any rate, the up- 

 take of glutamic acid is exactly balanced In the release 

 of glutamine, indicating a combination of glutamati 

 with ammonia, a process requiring rather than liberat- 

 ing energy. The role of this reaction may be simplv 

 the detoxification of ammonia released during cerebral 

 functional activity (25, 141, 14JI. 



Of the other substances studied, no significant 

 utilization or production by the brain of a-ketogluta- 

 ratc or ketone bodies, such as acetoacetatc or 

 /3-hydroxybutyrate, has been observed in normal 

 human subjects and patients in diabetic acidosis 

 (95) or in ketotic animals (ijji ). As for pyruvate and 

 lactate, the results have been inconsistent. In normal 

 human subjects two studies have reported significant 

 arterial-cerebral venous lactate differences, one 

 indicating uptake (198) and the other release (56) 

 by the brain. Kety (95) has found no evidence of 

 lactate or pyruvate utilization or production in 

 normal human subjects, and no pyruvate but definite 

 lactate production in diabetic acidosis. Himwich & 

 Himwich (82) have observed a small but significant 

 production of both lactate and pyruvate in a group 

 of hospital patients. It is likely that there is normally 

 a small production of lactate and pyruvate by the 

 brain, but that the present analytical methods are 

 not sufficiently precise to detect it consistently. 

 During cerebral anoxia, however, the release of 

 lactate has been found in animals to be considerable 

 and easily demonstrated (128). 



Recently Martin and co-workers (124) have 

 demonstrated in rabbits that, although total gluta- 

 thione concentration is unchanged in the blood pass- 

 ing through the brain, 30 per cent of the reduced 

 glutathione is converted to the oxidized form. The 

 arteriovenous differences for both the reduced and 



oxidized forms of glutathione are, therefore, con- 

 siderable on a weight basis, approximately 7.5 mg 

 per cent or two thirds that of glucose; but this oxida- 

 tion accounts for only l ±i of the total oxygen eon- 

 sumption of the brain. Preliminary observations in 

 normal human subjects indicate a similar phenomenon 

 (Mcllwain, personal communication). The signifi- 

 cance of this reaction to cerebral metabolism and 

 function is at present unknown. 



The failure to demonstrate significant arteriovenous 

 differences for other metabolites does not preclude a 

 role for them in the cerebral metabolism. Their 

 rates of utilization or production by the brain may 

 be so small that their arteriovenous differences are 

 rendered insignificant by the normally rapid cerebral 

 blood How. For example, radioactive tracer studies 

 with C' 4 -labeled lysine 11071 have demonstrated 

 its rapid incorporation from the blood into the pro- 

 teins of the mouse brain, despite an insignificant 

 arteriovenous difference. Metabolites ma) be unable 

 (o traverse the blood-brain barrier, but when ad- 

 ministered directly into the spinal fluid, are taken 

 up by tin- brain Thus, S"-methionine has been found 

 (o be incorporated into brain proteins from spinal 

 fluid but not from blood (49). Such substances, 

 although not supplied exogenously by the blood, 

 may be formed endogenously within the brain bv 

 the cerebral metabolism and utilized there to a 

 considerable degree. In vitro studies, for example, 

 have demonstrated the ability of cerebral tissues to 

 metabolize a number of intermediates of the glycolytic 

 and tricarboxylic cycles which do not exchange 

 I >et ween brain and blood (19). 



Normal Metabolic Rate 



From the data on the rate of oxygen consumption 

 of the brain presented in table 1, it is apparent that 

 its energy output is quite substantial, indeed one of 

 the highest of all the organs of the body. Consuming 

 oxygen at an average rate of 3.5 ml per 100 gm per 

 min., a brain of average weight, approximately 

 1,400 gm, accounts for a total oxygen consumption 

 of 49 ml per min. or almost 20 per cent of the total 

 basal body oxygen consumption of the normal young 

 human adult. Kennedy and his associates (87) have 

 found even higher cerebral metabolic rates in child- 

 hood (fig. 1), approximately 40 per cent higher, so 

 that in a 5-year old child, for example, the brain, 

 which at this age has reached close to its mature size, 

 may consume half of the total body oxygen uptake. 



The rapid rate of cerebral oxygen consumption is 

 almost balanced by the carbon dioxide production 



