Given the relative impermeability of the BNI, it is not surprising that exchange of several solutes depends on the presence of specific pumps, transporters, enzymes and receptors designed to meet the metabolic, ionic and other requirements of nerve [for review see
5]. The endoneurial microenvironment, unlike the cerebral microenvironment, does not require a moment-to-moment regulation of nutrients and oxygen. The earlier radioisotopic demonstration of facilitated transport of
d-glucose [
137], have been complemented by reports on the presence of GLUT-1 in both endothelial cells and perineurial cells [
32,
33,
79]. 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, suggesting that the role of perineurial GLUT-1 transporters is the nourishment of these ensheathing cells. In nerve, Na
+, K
+-ATPase is present in both luminal and abluminal plasma membranes of endothelial cells as well as the innermost perineurial cells [
113,
125], with no apparent polarity at either site, which is in contrast to the predominately abluminal expression in brain endothelial cells [
12] and implies that maintenance of the ionic microenvironment of nerve is less critical than that in brain [
5]. Alkaline phosphatase, which is found on both the luminal and abluminal surfaces of brain endothelial cells, is absent from perineurial cells but is found on endoneurial endothelial cells, where it transports phosphate ions and esters, and hydrolyzes phosphorylated metabolites [
83,
176]. The L-type amino acid transporter (LAT-1), which preferentially transport neutral amino acids, the creatine transporter, which moves the creatine necessary for storage of high-energy phosphate groups, as well as the monocarboxylate acid transporter (MCT-1), which transports monocarboxylates such as lactate, have been demonstrated in nerve and brain endothelia in vitro and/or in vivo [
57,
104,
148]. More recently, LAT-1, creatine transporter and MCT-1 were detected in primary endoneurial endothelial cell cultures [
204]. The transferrin receptor (OX-26 antigen), which the transports ferric ions required as co-factors supporting oxidative and other metabolism, is present in only trace amounts in endothelial cells and perineurium [
111]. An important efflux transporter of toxins and xenobiotics, p-gp or multidrug resistance gene 1a, has also been demonstrated in the BNI [
147]. While expression of GLUT-1, alkaline phosphatase, and OX-26 antigen in the brain endothelia is astrocyte-dependent, it is unclear what factors regulate expression of these and other key molecules in the BNI, although Schwann cell signaling via desert hedgehog has recently been implicated in the development of the perineurium [
113] and more recently in the induction and maintenance of the BNI [
154]. Moreover, recent in vitro experiments suggest that pericytes modify BNI function and junctional molecules through secretion of a variety of soluble factors [
156].