Potentiation in the neurotoxic induction of experimental chronic neurodegenerative disorders: N-butyl benzenesulfonamide and aluminum chloride.
Repeated monthly intracisternal inoculations of N-butyl benzenesulfonamide induced a chronic, slowly progressive myelopathy in young adult New Zealand white rabbits that was manifested by hyperreflexia, spasticity, hypertonia, gait impairment and altered tonic immobility responses. The neuropathological features consisted of scattered neuroaxonal spheroids, fusiform distention of the intramedullary portions of the spinal cord ventral roots and, as defined by microtubule-associated protein-2 (MAP 2) immunoreactivity, an initial distention and subsequent loss of dendritic processes in neurons of the nucleus motoris lateralis with the perikaryon of these cells remaining intact. A similar chronic progressive myelopathy was induced by repeated low dose intracisternal inoculations of aluminum chloride in New Zealand white rabbits. However, the neuropathological changes were more extensive and consisted of dendritic, axonal and perikaryal inclusions of phosphorylated and nonphosphorylated neurofilament localized to spinal motor neurons in the nucleus motoris medialis, substantia grisea intermedia and select brainstem nuclei with only minimal involvement of the nucleus motoris lateralis. The co-administration of these two neurotoxins over the course of 8 months induced striking behavioral changes as well as a fulminant myelopathy. This was accompanied by a loss of neuronal perikarya in the nucleus motoris accompanied by a loss of neuronal perikarya in the nucleus motoris lateralis and topographically extensive neocortical neurofilamentous degeneration. These features suggest that potentiation occurs when the two toxins are co-administered, a view supported by an estimation of the co-neurotoxicity coefficient (CNC greater than 1). Our results have implications for understanding human neurodegenerative disorders in which potentiation of insults may occur, producing a clinical and neuropathological disease state not expected from either agent alone.
Strong
M J
MJ
Department of Clinical Neurological Sciences, University Hospital, London, Ontario, Canada.
Garruto
R M
RM
D000535:Aluminum / Q000008:administration & dosage / Q000633:toxicity*; D000077410:Aluminum Chloride; D017607:Aluminum Compounds; D000818:Animals; D002712:Chlorides / Q000008:administration & dosage / Q000633:toxicity*; D002908:Chronic Disease; D004357:Drug Synergism; D005260:Female; D007150:Immunohistochemistry; D009410:Nerve Degeneration / Q000187:drug effects*; D009422:Nervous System Diseases / Q000139:chemically induced*; D011817:Rabbits; D013449:Sulfonamides / Q000008:administration & dosage / Q000633:toxicity*; D000096926:Benzenesulfonamides
D000535:Aluminum; D000077410:Aluminum Chloride; D017607:Aluminum Compounds; D002712:Chlorides; D013449:Sulfonamides; C065565:N-butylbenzenesulfonamide; D000096926:Benzenesulfonamides