NEURONAL METABOLISM 



tinuously flowing from the cell body down the axon, 

 but in such a way that the many chemical events are 

 inextricably bound to the re-establishment of neural 

 function (119). If the neurofibrils are comprised of 

 the microsomal particles, as, apparently, are the 

 cytoplasmic fibrils of other cells (84, 85), the high 

 ATPase and nucleotide metabolism (10) of the 

 microsomes are suggestive of the notion that the 

 neurofibrils are in a constant state of activity (10, 84). 

 Insofar as protein synthesis is also linked to RNA, a 

 microsomal constituent, the problem of enzymatic 

 and structural regeneration is linked to function. 



SUBSTRATES OF THE NEURON 



Although there is little doubt that glucose is the 

 chief substrate of the central nervous system during 

 rest and activity, the problem with regard to pe- 

 ripheral nerve is considerably more complex. Nerve 

 appears to contain the enzyme systems involved in 

 glycolysis and oxidation via the Krebs' cycle, but the 

 evidence to suggest that carbohydrate is the main 

 substrate either during rest or activity is not entirely 

 adequate. Among the noncarbohydrate substrates 

 that are utilized by neural tissues are amino acids 

 (1, 86), fatty acids (1, 11, 15, 42) and nucleic acids 

 constituents (3, 39), although little is known of their 

 relative importance in comparison to carbohydrates. 

 Glutamic acid, for example, is utilized as readily by 

 mitochondria of brain (7, 18) and nerve (6) .is is 

 pyruvate and, furthermore, contributes to more 

 efficient phosphorylation (i.e. with higher I' ( ) 

 ratios) than does pyruvate (9). This amino acid is 

 present in significant amounts in nerve (75) as well as 

 brain; and insofar as it comprises an intimate link 

 between protein and carbohydrate metabolism in 

 addition to being important to function (117), its 

 possible metabolic role deserves more exploration. 



In the case of peripheral nerve it seems indisputable 

 that the metabolism during activity is differenl from 

 that at rest. A specific inhibitor of the Krebs' cycle, 

 methyl fluoracctate, can depress the resting me- 

 tabolism to less than half while leaving unaffected 

 the extra oxygen consumption of tetanization; 

 conversely, sodium azide abolishes the extra oxidation 

 of activity while not affecting resting metabolism 

 (25). With the use of isotopically labeled amino acid 

 and carbohydrates, it has been shown that acetate 

 and glucose metabolism during excitation of pe- 

 ripheral nerve actually fall below the resting level, 

 whereas the metabolism of amino acids, such as 



glutamate, alanine and glycine, increases significantly 

 (86). Certain proteins from frog sciatic nerve, which 

 appear to be proteolipids (unpublished observations), 

 show an actual increase during excitation while 

 decreasing during ether anesthesia. These proteo- 

 lipids contain proportionately large amounts of 

 glutamate, aspartate and alanine, amino acids which, 

 in the free form, decrease during stimulation (un- 

 published observations). Insofar as nucleic acid 

 constituents of nerve, such as cytosine, guanine and 

 adenine, also decrease during stimulation, it appears 

 likely that a liponucleoprotein complex, described by 

 Folch (33), is being degraded during activity, and that 

 the 'proteolipids' are released as a consequence 

 (unpublished observations). 



Although glucose is the chief fuel of the brain, 

 there are conditions under which noncarbohydrate 

 substrates are apparently utilized. The suggestion 

 that neural tissue i-, able to utilize lipids was made by 

 Gerard (42) man\ years ago, but additional evidence 

 was not forthcoming until recently. A perfused 

 preparation of cat brain is able to survive with 

 apparently normal metabolism and functional 

 activity lor at least 2 hr. without glucose or other 

 exogenous substrates (38). In the absence of glucose 

 the brain is able to degrade its own structural com- 

 ponents, such elements a- the 'microsomes 1 and soluble 

 proteins of the Cerebral cortex hilling to 50 per cent 

 of their 1101 in. il value before functional failure of the 

 preparation ( ; 



Until quite recently, attempts to demonstrate fatty 

 acid oxidation in neural tissues have been larger} 

 unsuccessful. Of the numerous and short-chain fatty 

 acids tested, /3-hydroxybutyrate appears to be the 

 only one oxidized by brain or nerve homogenates and 

 mitochondria (9). Fatty acids are usually potent 

 inhibitors of oxidation and phosphorylation (un- 

 published observations). By means of incorporating 

 carboxyl ('."-labeled palmitate into the endogenous 

 lipids, rat-brain homogenates were shown to oxidize 

 lipids in the presence or absence of glucose at a rale 

 comparable to that of liver (til. During glucose-free 

 perfusion of cat brain, considerable amounts of 

 phospholipids were found to disappear from the 

 cerebral cortex, and it was not possible to account 

 for them on the basis of lipids leaving the brain (3). 

 In the light of these positive findings, the repeated 

 failures to demonstratd fatty acid oxidation in prep- 

 arations of neural tissue is puzzling. It is conceivable 

 that the tissue damage occurring in in vitro prep- 

 arations may be sufficient to either release inhibitory 

 factors (perhaps the lipids themselves) or greatly 



