Physiological changes in the sciatic nerve endoneurium of lead-intoxicated rats: a model of endoneurial homeostasis

The effects of inorganic lead (Pb) on peripheral nerves were studied by measuring the permeability coefficient-surface area product to albumin (PS_A) of the blood-nerve interface (BNI), water and Pb content of endoneurium, and residual endoneurial plasma volume (V_p) of sciatic nerves of adult rats maintained on a 4% Pb diet for 2-12 weeks. Additionally, body weight, haematocrit, and blood Pb levels were also monitored. Within 1 week, both blood and endoneurial Pb levels had increased significantly above background levels and continued to increase up to the 6th week. Thereafter, over the next 6 weeks, the blood Pb levels were relatively stable, while the endoneurial Pb levels decreased sharply to a quarter of their peak values. The wet/dry weight ratio of the endoneurium, an indicator of nerve oedema, increased by about 30% from the 4th to 12th week, reaching a water content of 75% corresponding to a 24% increase of the total fascicular area. PS_A increased only by the 8th week, without an accompanying increase in V_p. This suggests that the increase in PS_A reflects an increase in the permeability of the BNI. Furthermore, the moderate 3-fold increase in PSinA is more consistent with an adaptive response of the BNI to changes in the endoneurial microenvironment rather than a massive breakdown or disruption of the BNI. This is supported by the inconsistent or mild leakage of horseradish peroxidase from endoneurial capillaries observed in Pb-intoxicated rats^5,19. The present study quantitatively confirms the prevalent hypothesis on the pathogenetic mechanism of Pb neuropathy that Pb accumulation in Schwann cells and myelin causes a primary segmental demyelination and nerve oedema, followed by an epiphenomenal increase in BNI permeability. This hypothesis is further elaborated to postulate that the increase in permeability of the BNI is a dynamic, adaptive response to maintain the relative constancy of the milieu interieur of axons and Schwann cells.