METABOLISM OF THE CENTRAL NERVOUS SYSTEM IN VIVO 



I8 5 I 



Walker (125) found that glutamate, aminoacetate 

 and paraminobenzoic acid would occasionally restore 

 conscious behavior in man during insulin coma but 

 that they also caused an elevation in blood glucose 

 level. Succinate was found to do neither. Weil- 

 Malherbe (195) has occasionally found glutamate, 

 arginine, glycine and succinic acid to produce 

 arousal from insulin coma, but this effectiveness was 

 believed to result from an increased blood glucose 

 concentration secondary to the elevation in blood 

 epinephrine level caused by these substances. 



It is clear that few substances other than glucose 

 can reverse the effects of hypoglycemia in man, and 

 in those cases it is likely that they do so by increasing 

 the blood glucose concentration. On the other hand, 

 the failure of a substance to restore normal functions 

 during hypoglycemia mav be the result of inadequate 

 dosage or an inability to penetrate the blood-brain 

 barrier. It does not prove its inability to substitute 

 for glucose once it is in the tissues in adequate amounts. 

 However, as regards the functioning of the nervous 

 system of the intact animal, which is dependent on 

 substrates supplied only by the blood, no adequate 

 substitute for glucose has been found, and il must, 

 therefore, be considered essential for normal physi- 

 ological behavior of the central nervous system. 



Miscellaneous Substances of Importance in Metabolism 

 of the Central Nervous System 



Recent developments have led to an increased 

 interest in the many substances other than glucose 

 and oxygen that must be of vital importance in the 

 metabolic functions of the central nervous svstem. 

 Oxygen and glucose are concerned only with the 

 production of available energy, but there are in- 

 numerable substances and processes involved in 

 the transfer and utilization of this energy. Studies 

 involving the chemical analysis of brain tissue ob- 

 tained from animals exposed to various experimental 

 conditions indicate, for example, that phosphates and 

 nucleotides play the same role in the transfer of 

 energy within the brain as in other tissues (129). 

 During periods of reduced cerebral activity, such as 

 sleep or narcosis, energy-rich phosphate compounds 

 accumulate (141), and during increased activity, 

 such as convulsions, they are depleted and inorganic 

 phosphate is increased (141). Nitrogen-containing 

 compounds have also been implicated in the meta- 

 bolic processes associated with activity of the central 

 nervous system. During increased nervous activity 

 there is an increase of nonprotein nitrogen and 



ammonia within the brain (52, 194). It is likely that 

 the reactions involving the reductive animation of 

 ketoglutarate to form glutamate and the amidation 

 of glutamate to form glutamine are of fundamental 

 importance in the ammonia metabolism of the 

 brain ( 14, 194). 



Recently, 7-aminobutyric acid, formed by the 

 decarboxylation of glutamate by an enzyme more 

 concentrated in the central nervous system than in 

 other tissues (4, 146-148, 197), has been suspected of 

 being a chemical mediator of central inhibition (10, 

 32, 71). Since pyridoxal-j'-phosphate is an essential 

 coenzyme in this reaction, a major role for pyridoxinc 

 in the metabolism and function of the central nervous 

 svstem is evident (148, 149, 191). Indeed, the produc- 

 tion of convulsive stales l>\ pyridoxine deficiency or 

 antagonists has ahead) suggested such a role (186). 



In studies in the perfused cat brain, Geitjer and 

 his associates have found that the v erv ability of the 

 brain to maintain both aerobic utilization of glucose 

 and function is dependent upon the availability of the 

 two pyrimidine nucleosides, cvtidinc and uridine 

 (54). In their absence, impermeabilitv to glucose and 

 depletion of brain galactoside and phospholipid 

 contents developed. Uridine alone restored the 

 galactoside contents and cvtidinc the phospholipid 

 contents to the normal level. Both were needed for 

 the restoration of normal carbohv xirate metabolism 

 and function. 



It is evident then that there is a vast array of 

 metabolic processes not directly related to the aerobic 

 utilization of glucose but vitallv concerned with the 

 functional activity of the tissues. However, many of 

 these reactions require energy and are thus dependent 

 on the oxidation of sjlucose for this energy. Similarly, 

 the abilitv of the central nervous svstem to provide 

 energy by the oxidation of glucose is in turn de- 

 pendent on the maintenance of the integrity of these 

 other metabolic processes 



PHYSIOLOGICAL INTERRELATIONSHIPS OF METABOLISVI 

 OF THE CENTRAL NERVOUS SYSTEM 



There have been no convincins; studies to date to 

 indicate any qualitative changes in the nature of the 

 metabolism of the central nervous system with chang- 

 ing physiological states. Any changes, such as they 

 are, have been mainly in rate and even then, com- 

 pared with other organs, the metabolic rate of the 

 central nervous system, at least the brain as a whole, 

 appears to vary so little as to suggest that it possesses 



