CHEMICAL ENVIRONMENT OF THE CENTRAL NERVOUS SYSTEM 



1873 



review that the results of vital dye studies could not 

 be explained without hypothesizing three distinct 

 barriers: the blood-brain barrier coextensive with the 

 cerebral vasculature, the blood-cerebrospinal fluid 

 barrier located presumably in the choroid plexuses, 

 and the cerebrospinal fluid-brain barrier which has 

 been mentioned earlier in this chapter (fig. 4). Despite 

 the evidence for assuming considerable similarity 

 between cerebrospinal fluid and central nervous sys- 

 tem interstitial fluid, various reasons have been 

 marshalled to differentiate functionally between the 

 blood-brain and the blood-cerebrospinal fluid 

 barriers. After intravenous administration, some 

 drugs have been shown to exert their pharmacologic 

 action on the central nervous system before they 

 reach detectable concentrations in the cerebrospinal 

 fluid. This does not necessarily imply a uniquely 

 different mechanism involved in these two barriers, 

 since the observation can be explained by assuming 

 that the local perincuronal concentration of the drug 

 achieves pharmacological levels by passage from 

 adjacent capillaries before sufficient material to be 

 detected has entered the large cerebrospinal fluid 

 reservoir. However, it does imply that the drug need 

 not pass into the cerebrospinal fluid before reaching 

 the neuronal milieu. 



Of greater significance in suggesting a difference 

 between the blood-brain barrier mechanism and 

 blood-cerebrospinal fluid mechanism is the statement 

 by Friedmann & Elkeles (45) that the barriers react 

 differently to the electric charge of various vital dyes. 

 According to these authors, the blood-cerebrospinal 

 fluid barrier is more permeable to acidic (negatively 

 charged) dyes, whereas the blood-brain barrier is 

 more permeable to basic (positively charged) dyes. 

 In general, conclusions from vital dye studies con- 

 cerning the blood-extravascular barriers of the central 

 nervous system are tenuous at best. Even if plasma 

 levels of the dyes are carefully controlled and equated 

 on a molar basis, still it is virtually impossible to con- 

 clude from visual inspection alone that more or less 

 dye has penetrated to the intercellular fluid of the 

 central nervous system simply because the tissue is 

 grossly or microscopically more or less colored than 

 with equimolar blood concentrations of other dyes. 

 The final coloration will depend not only on the 

 amount of dye present in the interstitial fluid, but 

 upon the color intensity of the dye, upon the oxida- 

 tion-reduction reactions which markedly affect the 

 color of many dyes, upon methods of sample prepara- 

 tion for observation, and upon the penetration and 

 accumulation of the dye within the intracellular 

 compartment. 



It has been suggested (146, p. 34) that the incon- 

 trovertible observation that, generally speaking, 

 intravenous basic dyes do stain the central nervous 

 system more readily than acidic ones may result from 

 the greater propensity for plasma protein conjugation, 

 at blood pH, by the acidic dyes, as shown by Bennhold 

 some years ago (12). Thus the measure of blood- 

 brain barrier impermeability with an acidic dye, 

 such as trypan blue, may be largely a measure of 

 blood-brain barrier impermeability to plasma proteins 

 with which the dye is strongly associated. 



The concept that the blood-cerebrospinal fluid 

 barrier has significantly different permeability char- 

 acteristics than the blood-brain barrier for meta- 

 bolically significant solutes has been recently 

 supported by Bakay (9). This author believes that, 

 following intravenous injection of P 3 - as inorganic 

 phosphate, the bulk of the isotope arriving at the 

 cerebral cortex uses the cerebrospinal fluid as inter- 

 mediary. He bases this opinion on radioautographs 

 of sectioned cat brains made shortly after intravenous 

 injection of 1'-', which show that the pattern of ap- 

 pearance of the isotope is identical with that in a 

 brain injected intracisternally. The diffusion in both 

 ( ases spreads from the surfaces in contact with the 

 cerebrospinal fluid centripetally into the tissue. 

 Following intravenous administration, the high initial 

 concentration of P 3 - in the periventricular Livers, as 

 compared with oilier areas, suggests to Bakay that a 

 large portion of the plasma phosphate enters the 

 cerebrospinal fluid through the choroid plexus. He 

 concludes ; 



"A dualistic theory could serve as a working hy- 

 pothesis to explain the diffusion of phosphates from 

 the blood into the central nervous system. During 

 the initial phase of absorption P* 2 enters the brain via 

 the cerebrospinal fluid after it has passed the blood- 

 cerebrospinal fluid barrier. This phase is characterized 

 by a large concentration of the tracer in the surface 

 areas and a decline in activity of the cerebrospinal 

 fluid. The pattern of diffusion is the same whether the 

 tracer has been injected intravenously or intracis- 

 ternally. The latter phase of absorption shows a slow 

 and gradual increase of P 32 concentration in the 

 entire brain, presumably due to a direct passage of 

 the tracer through the blood-brain barrier by trans- 

 capillary exchange" (9). 



Herlin (71) agrees with this general conclusion but 

 emphasizes the slowness of movement of subarachnoid 

 radioactive orthophosphate into the deeper regions 

 of the central nervous system. He interprets the results 

 of Bakay & Lindberg (10) and Lindberg & Ernster 

 (105), who showed that 40 per cent of the P 32 in the 



