Ej. Lehning et al., gamma-Diketone peripheral neuropathy - I. Quantitative morphometric analyses of axonal atrophy and swelling, TOX APPL PH, 165(2), 2000, pp. 127-140
Quantitative morphometric analysis was used to characterize expression of m
yelinated axon swelling and atrophy in rat peripheral nerve during 2,5-hexa
nedione (HD) intoxication. HD was administered by gavage according to diffe
rent daily dosing regiments (100, 175, 250, or 400 mg/kg/day) and four prox
imodistal nerve regions (5th lumbar spinal nerve, proximal and distal sciat
ic nerve, and tibial nerve) were examined morphometrically. Morphometric de
terminations were made at four behavioral endpoints (unaffected, slight, mo
derate, and severe toxicity) and were correlated to electrophysiologic meas
urements of peripheral nerve function. Results show that, for all HD dose r
ates, onsets of behavioral neurotoxicity and nerve dysfunction were general
ly related to development of abundant axon atrophy. The proximodistal manif
estation of atrophy was dependent upon the dosing rate; i.e., the atrophy r
esponse produced by subacute intoxication with higher daily dosing rates (2
50 and 400 mg/kg/day) was restricted to distal nerve regions whereas subchr
onic induction with lower dosing rates (100 and 175 mg/kg/day) produced abu
ndant fiber atrophy in all proximodistal areas. In contrast to atrophy, axo
nal swellings constituted an inconsistent minor morphologic response, the e
xpression of which was dependent upon subchronic dosing rates (100-250 mg/k
g/day). Subacute HD administration (400 mg/kg/day) produced significant cha
nges in neurobehavior and nerve electrophysiologic parameters in the absenc
e of peripheral axon swelling. Thus, conditional expression of swellings su
ggests they are an epiphenomenon related to low-dose induction rates. Fiber
atrophy, however, was numerically dominant, correlated with nerve dysfunct
ion, and occurred at all dosing levels. These characteristics suggest atrop
hy is a neurotoxicologically significant feature of gamma-diketone peripher
al neuropathy. (C) 2000 Academic Press.