Two routes are available for blood-nerve exchange of material. One pathway, the direct one, is across the endothelium of the endoneurial microvasculature. The other is an indirect route requiring passage of material through a third compartment interposed between the vascular space and the endoneurial extracellular space. This compartment is the epineurial extracellular space that exchanges directly with the vascular compartment through the relatively leaky epineurial capillaries. Evidence from various physiological and morphological studies strongly indicates that blood-nerve exchange occurs predominantly via endoneurial capillaries and that transperineurial exchange is a minor contributor. Hence, the terms BNB permeability and endoneurial capillary permeability are used interchangeably. Strictly speaking, BNB permeability to a given solute is slightly higher than the endoneurial capillary permeability to that same solute, and the difference is due to the minor contribution from the relatively impermeable perineurium.

3.1. Relative Contributions of Perineurium and Microvessels

Theoretically, blood-borne substances can reach the endoneurial extracellular space either by traversing the endoneurial vascular endothelium or by crossing the multilayered perineurium after gaining access to the perineurial extracellular space. Multiple observations, including the following, favor the former pathway as the major route of blood-nerve exchange. The perineurium is impermeable to ionic lanthanum, but the endoneurial capillaries are not (13, 24). Intravascular perfusion with a hyperkalemic solution inactivates peripheral nerve much more rapidly than when it is bathed by the same hyperkalemic solution (26). Histamine increases the permeability of endoneurial capillaries to macromolecular tracers, but is without effect on the perineurium (27, 28). In leprosy, the endoneurial blood vessels become permeable to ferritin, whereas the perineurium remains impermeable to this tracer (29). In the frog sciatic nerve as well as rat tibial and sciatic nerve, where perineurial permeability has been measured independently, the endoneurial capillaries are more permeable (2, 3, 28, 30-32). During the second to sixth week of Wallerian degeneration, while the perineurial permeability increases about fourfold, the permeability-surface area product (PS) of the frog sciatic nerve decreases by more than 60% reflecting the greater sensitivity of PS to permeability of the capillaries than to that of the perineurium (33). PS of the adult rat sciatic nerve perineurium to (125I) albumin was measured to be 1.48 ± 0.28 x 10-7 ml. g-1.s-1 (n=6) (Weerasuriya, unpublished observations), which is about two orders of magnitude less than the corresponding value for the endoneurial vessels (34). All these studies clearly emphasize the much more restrictive diffusion barrier properties of the perineurium.

Before adequate structural evidence was available, physiologists, on the basis of permeability measurements to hydrophilic solutes of various sizes, postulated that the capillary endothelium contained a set of large and a set of small hydrophilic pores (35, 36). The ratio of large to small pores, though variable, seems to be in the range of about 1:30,000 (37, 38). Recent evidence from electron microscopic studies suggest that the small pores are the interendothelial clefts, which have a width of about 20 nm and occupy about 0.4% of the capillary surface area (39). Because of their rarity, the identity of large pores is less certain. Potential candidates are widened intercellular junctions, transendothelial channels formed by the fusion of plasmalemmal invaginations, and fenestrae. Properties of the small and large pore pathways are exhaustively reviewed elsewhere (40-42).

In contrast to epithelial tissue, the perineurial cells do not display an apicobasal polarity. Thus, the major route for transperineurial passage of material is a paracellular pathway, which consists of a number of belts of intercellular tight junctions arranged in series due to the multilayered nature of the perineurium. The relative impermanence of this route is illustrated by the fact that local anesthetics administered for nerve blocks are injected via a needle that penetrates the perineurial sheath. The number of layers in the perineurium decreases in a proximodistal direction with the fine terminals of sensory and motor nerves having only one or

3.2. Two Routes of Transcapillary Permeation

3.3. Route of Transperineurial

Permeation two layers of perineurial cells (18). In comparison to connective tissue ensheathments of the CNS, the perineurium combines the mechanical strength of the dura mater and the impermanence of arachnoid. A recent report of the presence of VE-cadherin in perineurial cells (43) suggests that perineurial permeability is regulated by mechanisms similar to those operating on the vascular endothelial cells of the endoneurium. The presence of tight junction proteins, occludin, and zonula occludens-1 in perineurial and nerve endothelial cells (44) is consistent with similar mechanisms regulating permeability at these sites. Attempts to examine the consequences of perineurial removal are confounded by a compromise of the endoneurial vasculature that receives nutrient branches from transperineurial arteries (45-48). Nevertheless, this remains an important question especially with regard to perineurial regeneration associated with nerve repair.

3.4. Transporters Given the relative impermeability of the perineurium and at the BNB endoneurial capillaries, it is not surprising that blood-nerve exchange of several solutes depends on the presence of specific transporter molecules at the interface. The endoneurial microenvironment, unlike the cerebral microenvironment, does not require a moment-to-moment regulation of nutrients and oxygen. Several transporters designed to meet the metabolic requirements of endoneurial constituents have been described. The earlier radioisotopic demonstration of facilitated transport of D-glucose (49), have been complemented by reports on the presence of GLUT-1 in endothelial cells and perineurial cells (50-52). In keeping with the earlier postulate that the perineurium is a specialized connective tissue, the above studies did not demonstrate an apicobasal polarity of GLUT-1 transporters in perineurial cells. Thus, the role ofperineurial GLUT-1 transporters appears to be the nourishment of perineurial cells.

Concentrations of endoneurial constituents are affected by exchange across the endoneurial capillary interface and the barrier imposed by the inner layers of the perineurium, as well as the metabolic processes of endoneurial cells. Permeability of the two exchange sites are assessed by morphological and physiological methods. Both techniques have their advantages and limitations. Historically, morphological techniques establish the initial broad parameters and then physiological methods provide quantitative measurements of blood-nerve transfer coefficients. The major advantage of morphological techniques is the localization of barriers to the penetrance of markers and the array of tracers of varying molecular weights, charges, and sizes. On the other hand, these methods are limited by the sensitivity of the histological staining techniques. For example, histological methods have not detected blood-nerve transfer of macromolecules, but physiological methods using radiotracers estimate blood-nerve transfer of

3.5. Assessment of Blood-Nerve Exchange of Solutes albumin at about 10-5 cm/s. Thus, physiological methods not only allow a quantification of transfer rates, but also are more sensitive especially to macromolecules and other larger species. Furthermore, transfer rates of amino acids, sugars, and other small molecules can only be studied by physiological radioiso-topic methods. However, physiological techniques do not allow localization of the sites of transfer or transport. Immunostaining techniques and in situ hybridization complement these transport studies by localizing the putative transporters and diffusion sites. Technical details of measurement of blood-nerve transfer rates are described elsewhere (34, 53) as are theoretical foundations and limitations of blood-tissue transfer studies (54).

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