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HANDBOOK OK 1M1VM ."i ^ Nil Kol'l IYSIOI.OOY III 



preparation it has been possible to maintain brain 

 functions (normal corneal reflex, pupillary reactions 

 to light, natural respiration, maintenance of systemic 

 arterial pressure and vasomotor responses, normal 

 electrocorticogram, spontaneous blinking; and move- 

 ments of facial structures, and easily elicited cortical 

 electrical responses to stimulation of an extremity) 

 for over 4 hr., under appropriate circumstances. 



The glucose content of the brain was normally 

 found to be 25 to 40 per cent lower than that of the 

 blood, and small variations in blood glucose concen- 

 tration were followed by proportionate changes in the 

 brain, as had been reported previously (62, 90, 119). 

 However, if the blood glucose concentration was 

 elevated considerably beyond the normal ranges of 

 variations, then the brain glucose concentration did 

 not increase proportionately. For example, increasing 

 blood glucose concentration to 800 mg per cent in- 

 creased the brain glucose content to only 300 mg per 

 cent, and subsequent increase in blood glucose to 

 1600 mg per cent produced only negligible further in- 

 creases in the brain. Such an effect is compatible with 

 the concept of a metabolic pump transporting glucose 

 from the plasma into the central nervous system. The 

 finite capacity of such a pump could become limiting 

 it sufficiently high blood glucose concentrations, and 

 further increases in the glucose "reservoir" would not 

 increase the maximum rate of transport across the 

 blood-brain barrier. 



Further evidence for such an active glucose trans- 

 port system resulted from the observation that unless 

 a freshl) isolated liver was included in the perfusion 

 circuit, the brain could be maintained for only brief 

 periods. Without the liver (or liver extract), the glu- 

 cose content of the cerebral cortex progressiv civ 

 diminished in spile of high glucose concentrations in 

 the blood 1 his impairment of glucose uptake by the 



brain in the absence of liver could be prevented by 

 the addition of two nucleosides, uridine and cytidine, 

 to the perfusion blood (51). If glucosamine was 

 added to the perfusion blood at a time when glucose 

 uptake was blocked, this amine was taken up and 

 pin isphorv laled by the brain. 



In the blood-brain barrier glucose transport proc- 

 ess, ii is possible that the sugar is chemically altered 

 in such a was thai ii becomes 'acceptable' to the 

 functional cells oi the central nervous system. The 

 n nils of Wolff & Tschirgi (165) iua\ indicate that 

 the centra] nervous system utilizes glucose onK if this 

 is taken up from the plasma, across the blood-brain 



bi a, and not if introduced via the cerebrospinal 



iliiid In these experiments, the blood-sugar level ol 



anesthetized cats was reduced by insulin until the 

 disappearance ol the palellai reflex Subsequent per- 

 fusion of the spinal subarachnoid space for hours with 

 Ringer's solution containing 100 to 600 mg per cent 

 of glucose, between a lumbar and cisternal tap, failed 

 to restore the reflexes, which were, however, readily 

 restored by intravenous glucose injections. Alteration 

 i it ( 'a ++ or K + concentration in the perfusate produced 

 immediate changes in spinal reflexes, respiration and 

 pupillary size, indicating the availabliliiv of the per- 

 fusate to neural elements. 



On the other hand, the ineffectiveness of intra- 

 thecal glucose for maintaining normal spinal cord 

 function may be simply due to the diffusion distance 

 from the subarachnoid space to the central grey sub- 

 stance. If, as discussed above, no centripetal flow of 

 cerebrospinal fluid occurs into the depths of the spinal 

 cord substance, then it seems quite likely that the rate 

 of delivery of glucose from the spinal subarachnoid 

 space to the neuron perikarya would be insufficient to 

 support normal metabolism. Subarachnoid alterations 

 of Ca ++ or K. + could readily produce changes in motor 

 activity by influencing the superficial fiber tracts or 

 grey matter immediately adjacent to the subarachnoid 

 space. 



Extensive investigations with cell types other than 

 nervous tissue have shown that glucose transport into 

 other living cells does not follow the laws of simple 

 diffusion but apparently involves some active chemical 

 process. Phosphorylation was thought to be part of the 

 transport mechanism in the intestinal absorption oi 

 sugars (68, 107, 152), but recent studies have shown 

 that the process is more complex, apparently involv- 

 ing alteration of the glucose carbon skeleton itself 



(74- 



/.>' 



Considering the effect of cytidine and uridine 



on sugar uptake and oxidation bv the brain, Geiger 

 (49) proposes that the polysaccharide synthesis via 



glucuronic acid and glucosamine mav be involved in 

 the blood-brain glucose transport mechanism. This 

 hypothesis is based on the observation that in peni- 

 cillin-treated staphylococcus aureus, a compound 

 formed by the coupling of uridine, glucosamine and 

 amino acids is accumulating at a high rate 1121, 

 1421. This compound is postulated to be the precursor 

 of the cell wall, inhibited from further conjugation bv 

 the presence of penicillin. As mentioned previously, 

 glucosamine is taken up and phosphorv lated bv the 

 perfused cal brain when glucose is unable lo pene- 

 trate the blood-brain barrier, and the existence of 

 glucos.11 nine-containing mucopolysaccharides in 

 nerves and brain has been reecntlv demonstrated 

 (54). Insulin, postulated to influence importantly the 



