gamma-Diketone peripheral neuropathy - I. Quantitative morphometric analyses of axonal atrophy and swelling

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.