INTRACRANIAL AND INTRAOCULAR FLUIDS 



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nervous tissue. Although the blood-brain barrier has 

 been the theme of many hundreds of papers, it has 

 been only recently that anything of a quantitative 

 nature has been published on it. Wallace & Brodie 

 (230) provided the answer to our problem, so far as 

 the bromide, iodide and thiocyanate ions are con- 

 cerned, by showing that when these ions were injected 

 into the blood, they came into equilibrium with the 

 extracellular space of the nervous tissue at approxi- 

 mately the same rate as with the cerebrospinal fluid. 

 A more comprehensive study (58) extended to sub- 

 stances of varying lipoid solubility showed that with 

 lipoid-insoluble substances, for example the isotope 

 Na 24 , the picture described by Wallace & Brodie was 

 correct, Na' J1 coming into equilibrium with the extra- 

 cellular space of the nervous tissue at the same rate as 

 with the cerebrospinal fluid. With lipoid-soluble sub- 

 stances, on the other hand, the nervous tissue came 

 into much more rapid equilibrium so that at any- 

 given moment during the process of equilibration 

 with the plasma, the cerebrospinal fluid lagged behind 

 badly. Hence the concentration of the lipoid-soluble 

 substance in the tissue adjoining the cerebrospinal 

 fluid was always such as to favor diffusion from the 

 tissue into the fluid, either in the ventricle or in the 

 subarachnoid space. Water exchanges very rapidly 

 between blood and cerebrospinal fluid (21 91 and, as 

 with the lipoid-soluble substances, its rate of equili- 

 bration between plasma and nervous tissue is verj 

 much more rapid than between plasma and cerebro- 

 spinal fluid (31). In general, then, we max say that 

 when a substance is injected into the blood, it passes 

 into the nervous tissue directly across the blood-brain 

 barrier; it passes into the cerebrospinal fluid by way of 

 the choroid plexuses and possibly from the vessels of 

 the pia. During the approach to equilibrium, i.e. the 

 equalization of concentrations between plasma and 

 fluids, the concentrations in the extracellular fluid of 

 the nervous tissue and in the cerebrospinal fluid will 

 not always be the same. If the substance is a rapid pen- 

 etrator, like ethyl alcohol, the concentration in the 

 nervous tissue will be higher than in the cerebrospinal 

 fluid, and the latter will be assisted in its approach to 

 equilibrium by diffusion from the nervous tissue. With 

 ions, and probably with a number of lipoid-insoluble 

 nonelectrolytes, it would seem that the concentrations 

 remain sufficiently close so that significant movement 

 of material from one system to the other does not 

 occur. With certain other substances, it may well be 

 that the concentration in the nervous tissue lags be- 

 hind that in the cerebrospinal fluid so that the latter 

 may be said to be the source of some of the material 



reaching the nervous tissue from the blood. 10 This 

 would appear to be true of inorganic phosphate; if 

 this ion, 'tagged' with P 32 , is injected into the blood, 

 its penetration into the cerebrospinal fluid and the 

 nervous tissue is slow (13, 39, 116, 185). When the 

 inorganic phosphate is introduced directlv into the 

 subarachnoid space, it is rapidly taken up by the nerv- 

 ous tissue (14, 195) where it is incorporated into or- 

 ganic complexes. Consequently, when inorganic phos- 

 phate is injected into the blood, because the phosphate 

 passing across the blood-brain barrier is rapidly incor- 

 porated into complexes by the nervous tissue, the con- 

 centration in the extracellular fluid of this tissue may 

 be expected to be always lower than in the cerebro- 

 spinal fluid so that diffusion of phosphate from the 

 cerebrospinal to the extracellular fluid will occur. In 

 other words, in this case the cerebrospinal fluid acts as 

 a transporting medium for inorganic phosphate from 

 blood to nervous tissue, augmenting the amounts that 

 pass directly across the blood-brain barrier. 



It must be borne clearly in mind that these conclu- 

 sions, derived from kinetic studies of the blood-cere- 

 brospinal fluid and the blood-brain barriers, tell us 

 little as to the possibilities of tin- flow of fluid from one 

 compartment to the other. Thus the literature con- 

 tains mam references to a subsidiary source of the 

 cerebrospinal fluid derived from the nervous tissue, 

 but the circumstance th.it a substance diffuses from 

 the nervous tissue to the cerebrospinal fluid during 

 the approach to equilibrium with the plasma does not 

 mean that there is necessarily, or even probably, a 

 flow of fluid in this direction. All that the experiments 

 show is that gradients of concentration may exist, and 

 from this circumstance it follows that diffusion will 

 occur down these gradients. 



Blood-Brain Barrier 



As revealed by the simultaneous measurements of 

 penetration into the cerebrospinal fluid and nervous 

 tissue described above, this barrier has qualitatively 

 the same characteristics as the blood-cerebrospinal 

 fluid and blood-aqueous humor barriers, the factor of 

 lipoid solubility being dominant in determining ease 

 of escape from blood to nervous tissue. Where lipoid- 

 insoluble molecules and ions are concerned, quite 

 large differences in rates of penetration into the nerv- 

 ous tissue are observed, as with the other barriers. 

 In certain regions of the nervous system, however, the 



10 Stern & Gautier (212-214) considered that the cerebro- 

 spinal fluid was the sole source of material passing from blood to 

 the central nervous tissue. 



