METABOLISM OF THE CENTRAL NERVOUS SYSTEM IN VIVO 



1859 



asparagine or ATP (185, 186, 188), and clinical 

 trials of L-glutamine and L-asparagine in epilepsy 

 have been reported to result in some degree of control 

 of clinical seizures (185, 186). Pyridoxine deficiency 

 and pyridoxine antagonists have been found to cause 

 epileptiform seizures in man (171, 172, 186) and 

 animals (186). This finding may be of major sig- 

 nificance in view of the recently uncovered role of 

 this vitamin in the form of pyridoxal-5 '-phosphate 

 as a coenzyme in the transamination and decarboxyla- 

 tion reactions of some of the amino acids of obvious 

 importance in the metabolism of the central nervous 

 system (186). Indeed, the suggestive findings that 

 7-aminobutyric acid, the product of the decarboxyla- 

 tion of glutamate, a pyridoxal-5'-phosphate dependent 

 reaction peculiar to the nervous system (4, 1411-149, 

 191, 197), may be a chemical mediator of functional 

 inhibition in the central nervous system (10, 32, 71) 

 leads to intriguing possibilities not only concerning 

 the chemical abnormalities in epileptiform seizures 

 but also regarding the fundamental chemical mecha- 

 nisms underlying the normal functions of the Central 

 nervous system. 



MISCELLANEOUS DISORDERS. A number of other states 

 of disordered function of the central nervous system 

 have been studied, some with and others without 

 gross evidence of deranged metabolism. In table 3 

 are included a few of those which have been observed 

 in human patients and found to be associated with 

 alterations in the cerebral metabolic rate. Since no 

 serious impairment in cerebral blood flow or nutrient 

 .supply has been found in these conditions, the func- 

 tional and metabolic disturbances have been con- 

 sidered to be the results of unknown intracellular 

 defects. Thus, there have been found to be con- 

 comitant reductions in mental function and cerebral 

 metabolic rate in acute alcoholic intoxication (8), 

 in delirium tremens (9), in barbiturate intoxication 

 (39), in neurosyphilis when dementia paralytica is 

 present (74, 138), and in organic dementia of various 

 types (115). Freyhan and his associates (48) found a 

 low cerebral oxygen consumption in senile psychosis, 

 both with and without cerebral arteriosclerosis, but 

 others have reported similarly low values in elderly 

 nonpsychotic subjects (37, 169). In schizophrenia, a 

 disease of obvious qualitative though not necessarily 

 quantitative changes in mental function, there is no 

 clear evidence of any alteration in cerebral metabo- 

 lism. Gordan and co-workers (63) have reported 

 reduced values for cerebral oxygen consumption in 

 cases of greater than 4 years duration, but these 



findings are in disagreement with the results of other 

 studies (103, 178). In multiple sclerosis in which the 

 functional defect is more neurological than psycho- 

 logical, no alteration in cerebral metabolic rate has 

 been observed (1, 156). However, during exacerba- 

 tions of the disease, the brain was found by Adams 

 and co-workers ( 1 ) to take up glutaminc and release 

 glutamate in equivalent amounts, a pattern opposite 

 to that observed in the normal state. The administra- 

 tion of succinate occasionally reversed the pattern 

 toward normal without any significant change in 

 metabolic rate. Since it is the amidation of glutamate 

 by ammonia to form glutamine which is apparentlv 

 involved in this abnormal pattern, these workers 

 ( 1 ) suggest that inadequate detoxification of ammonia 

 in the central nervous system may play a role in the 

 pathogenesis of multiple sclerosis. 



EFFECTS OF HORMONES AND DRUGS ON IN VIVO 

 MI.IVHuIiSM m| IMF. MNIRVI NERVOUS SYSTEM 



Hormones and H I hugs 



THYROID HORMONE. The accelerativ e effect which the 

 thyroid hormone has been found to have on the 

 metabolic processes oi almost all bod) tissues dors not 

 seem to occur in the brain. In human adults suffering 

 from hyperthyroidism, no alteration in cerebral 

 oxygen consumption has been observed despite 

 marked increases in the total body metabolic rale 

 (153, 165, 179 I In- picture in hypothyroidism is 

 less clear. In adult hypothyroid patients one study 

 found a reduction in cerebral metabolic rate (159); 

 another found no difference from normal during the 

 disease and no change following effective thyroid 

 medication (165). In juvenile hypothyroidism, for 

 example cretinism, Himwich and co-workers (79) 

 found bv means of cerebral arteriovenous oxygen 

 differences and the thermoelectric flow recorder 

 qualitative evidence of an increase in cerebral meta- 

 bolic rate following thyroid administration. In studies 

 in rats Fazekas and his co-workers (40 1 found in 

 artificially induced hyperthyroidism that the cortical 

 oxygen consumption rose more rapidly from its 

 postnatal low level to the normal adult level. Once the 

 level of the mature state was attained, there was no 

 difference in the cortical oxygen consumptions of the 

 hyperthyroid and normal rats. No differences from 

 normal were observed in hypothyroidism. From 

 all this evidence, it appears that the thyroid hormone 

 exerts its effect on the brain chiefly during its period 

 of growth and development. Once maturation has 



