EXPERIMENTAL-MODEL OF MOTOR-NEURON DISEASE - ORAL ALUMINUM NEUROTOXICITY

To evaluate the pathogenetic role of environmental factors, especially metal intoxication, in amyotrophic lateral sclerosis (ALS), we conduc ted neuropathological and morphometrical studies of chronic oral alumi num (Al) neurotoxicity using young Japanese white rabbits fed a Ca- an d Mg-deficient diet supplemented with Al-citrate for 7 to 19 months. S pheroids and globules, which were seen as axonal swellings packed with interwoven, small bundles of 10-nm neurofilaments, chromatolytic neur ons, and degenerated neurons with satellite gliosis, were observed in the anterior horn of the spinal cord of rabbits treated with Al-citrat e. Spheroids and globules were immunohistochemically stained with SMI 31, a monoclonal antibody for phosphorylated neurofilament heavy and m edium epitopes. Compared to controls, the number of spheroids and glob ules was significantly increased in rabbits fed a Ca/Mg-deficient diet with and without chronic Al administration, and the number of large n eurons (> 20 mu m in shortest diameter) in the fifth cervical spinal c ord was decreased in rabbits fed a Ca/Mg-deficient diet with chronic A l administration. These changes in the present chronic Al intoxication model were more marked than those observed in our previous subacute s tudy in which rabbits were intoxicated with Al for 1 month. Degenerate d terminal buttons with accumulated neurofilaments were also observed in the spinal anterior horn of the chronic Al-treated rabbits. Chromat olytic change of motor neurons and axonal swellings (spheroids) in the spinal anterior horn are considered to be early changes in ALS, and t he present findings in rabbits resemble these early changes. We specul ate that Al, orally administered to rabbits, accumulates in the spinal cord and affects the processing or transport mechanisms of neurofilam ents, the regulatory system of phosphorylation-dephosphorylation of cy toskeletal proteins, and the integrity of membrane function, or that i t interacts with the phosphates of nucleic acids, leading to the devel opment of neurofilamentous abnormality, chromatolytic and other degene rative changes in the anterior horn of the spinal cord. We consider or al Al intoxication, combined with a Ca/Mg deficiency, a reasonable exp erimental model to investigate the pathogenesis of ALS.