Certain neurotoxic chemicals, including acrylamide and 2,5-hexanedione, are known to produce a disease state referred to as a neurofilamentous axonopathy and/or central peripheral distal axonopathy. Besides the nervous system selective action of these chemicals, numerous studies have suggested selective vulnerability of specific neuron types or neuronal components. This selectivity data is valuable in providing insights into potential mechanisms of action. Comparison of neural components particularly sensitive to the toxins with differences in their structure, function and chemistry can identify subcellular mechanisms which are the key toxic site of action. Currently available data on this topic is confusing due to the lack of a systematic analysis of selective vulnerability. Some morphological data suggests the largest diameter axons are selectively vulnerable to ACR and HD. However, other morphological and physiological data contradict this conclusion and suggest another form of selectivity. It has become apparent that neurons, or their components, which are capable of sustained discharge (i.e. non-adaptable) are affected prior to their adaptable counterparts in acrylamide neuropathy. The purpose of the studies outlined in this proposal is to systematically compare the sensitivity of different sized axons and axons with differing levels of adaptation to acrylamide and 2,5-hexanedione.
The specific aims will be carried out by studying the functional changes caused by these toxins in sensory and motor systems which either have different diameter axons or differing levels of adaptation. This will include electrophysiological studies to determine the time course and severity of involvement of various nociceptors, muscle spindles and motor unit types to ACR and HD. Furthermore, axoplasmic transport changes caused by these toxins will be examined in axons of varied diameter and in different motor unit types (and adaptation levels). The total result will be the determination of whether or not a selective vulnerability of neurons to these toxins occurs and, if so, is it based upon axonal diameter or upon the functional ability to maintain discharge? In addition, if the selectivity is different with these agents it would be highly suggestive of different modes of action of acrylamide and 2,5-hexanedione.
