TY - JOUR
T1 - A new murine model of giant proximal axonopathy
AU - Tshala-Katumbay, D. D.
AU - Palmer, V. S.
AU - Kayton, R. J.
AU - Sabri, M. I.
AU - Spencer, P. S.
N1 - Funding Information:
Fig. 5 Electron micrograph of an intraspinal swollen axon containing densely packed maloriented 10-nm neurofilaments. Tissues were excised from a mouse treated with 30 mg/kg 1,2-DAB 5 days/ week for 43 days. Epoxy resin-embedded tissues were stained with 2% uranyl acetate followed by 1% lead citrate Fig. 6 Distal sciatic nerve of a mouse treated with 35 mg/kg 1,2-DAB 5 days/week for 23 days. Electron micrograph shows central aggregation of axonal microtubules and mitochondria (arrowheads) in a myelinated fiber. Epoxy resin-embedded tissues were stained with 2% uranyl acetate followed by 1% lead citrate Acknowledgements These studies were supported by PHS grants P42ES10338, U19ES11384, the Oregon Worker Benefit Fund, and a grant from the International Brain Research Organization to D.D. Tshala-Katumbay. The technical expertise of Dan Austin is greatly appreciated.
PY - 2005/4
Y1 - 2005/4
N2 - The aromatic γ-diketone 1,2-diacetylbenzene (1,2-DAB), the putative active metabolite of the organic solvent 1,2-diethylbenzene, forms blue-colored polymeric protein adducts and induces the formation of amyotrophic lateral sclerosis (ALS)-like giant, intraspinal neurofilamentous axonal swellings in Sprague Dawley rats. The pathogenetic mechanism of this neuropathy has yet to be understood. We assessed whether these pathological changes are also seen in the C57BL/6 mouse, the animal of choice for toxicogenomic studies. Mice were treated intraperitoneally with 30, 35, 50, or 70 mg/kg 1,2-DAB or its inactive isomer 1,3-DAB per day (or on alternate days) for up to 43 days. Animals treated with 30 or 35 mg/kg per day 1,2-DAB, but not with 1,3-DAB, developed muscle spasms and progressive weakness, most prominently in hind limbs. Light microscopy revealed swollen axons in spinal anterior horns and proximal ventral roots, and to a lesser extent in dorsal root ganglia of 1,2-DAB-treated animals. Ultrastructural examination of swollen axons revealed clumps of maloriented 10-nm neurofilaments. Sciatic nerves showed clustering of axonal microtubules and other organelles. These findings are qualitatively comparable to those reported in rats treated with 1,2-DAB and represent a suitable phenotype with which to explore molecular mechanisms of proximal, giant neurofilamentous axonopathy using proteomic and genomic technologies.
AB - The aromatic γ-diketone 1,2-diacetylbenzene (1,2-DAB), the putative active metabolite of the organic solvent 1,2-diethylbenzene, forms blue-colored polymeric protein adducts and induces the formation of amyotrophic lateral sclerosis (ALS)-like giant, intraspinal neurofilamentous axonal swellings in Sprague Dawley rats. The pathogenetic mechanism of this neuropathy has yet to be understood. We assessed whether these pathological changes are also seen in the C57BL/6 mouse, the animal of choice for toxicogenomic studies. Mice were treated intraperitoneally with 30, 35, 50, or 70 mg/kg 1,2-DAB or its inactive isomer 1,3-DAB per day (or on alternate days) for up to 43 days. Animals treated with 30 or 35 mg/kg per day 1,2-DAB, but not with 1,3-DAB, developed muscle spasms and progressive weakness, most prominently in hind limbs. Light microscopy revealed swollen axons in spinal anterior horns and proximal ventral roots, and to a lesser extent in dorsal root ganglia of 1,2-DAB-treated animals. Ultrastructural examination of swollen axons revealed clumps of maloriented 10-nm neurofilaments. Sciatic nerves showed clustering of axonal microtubules and other organelles. These findings are qualitatively comparable to those reported in rats treated with 1,2-DAB and represent a suitable phenotype with which to explore molecular mechanisms of proximal, giant neurofilamentous axonopathy using proteomic and genomic technologies.
KW - 1,2-Diacetylbenzene
KW - Axonal swellings
KW - Clustered microtubules
KW - Maloriented neurofilaments
KW - γ-Diketone neuropathy
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U2 - 10.1007/s00401-005-0982-z
DO - 10.1007/s00401-005-0982-z
M3 - Article
C2 - 15759132
AN - SCOPUS:18344379941
SN - 0001-6322
VL - 109
SP - 405
EP - 410
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -