γ-diketone central neuropathy: quantitative morphometric analysis of axons in rat spinal cord white matter regions and nerve roots

LoPachin, Richard M.; Jortner, Bernard S.; Reid, Maria L.; Das, Soma

doi:10.1016/j.taap.2003.07.005

Cited by 27 publications

(11 citation statements)

References 61 publications

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“…This is consistent with studies on 2,5-HD axonopathy where cytoskelatal reorganization was observed after direct application of 2,5-HD on rat peripheral nerves [28,40]. LoPachin and colleagues have reported that nerve fiber atrophy, not giant axonal swelling, is a primary neuropathic feature of c-diketone neuropathy [20][21][22][23][24]. Their conclusions are based on the studies with aliphatic c-diketone 2,5-HD and, do not rule out an early presence of proximal giant axonal swellings in ventral spinal roots; moreover the conclusions of LoPachin and colleagues are based on sciatic nerves not spinal roots.…”

Section: Discussionsupporting

confidence: 85%

Axonopathy-Inducing 1,2-Diacetylbenzene Forms Adducts with Motor and Cytoskeletal Proteins Required for Axonal Transport

et al. 2007

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The aromatic hydrocarbon 1,2-diacetylbenzene (1,2-DAB) is a protein-reactive gamma-diketone metabolite of the neurotoxic solvent 1,2-diethylbenzene (1,2-DEB). The effect of neurotoxic 1,2-DAB and its non-neurotoxic isomer 1,3-DAB has been studied on motor proteins and cytoskeletal proteins of rat spinal cord (SC). For in vitro studies, SC slices were incubated with 1, 2, 5, 10 mM of DAB isomers for 30 min at 37 degrees C. For in vivo studies, rats received (i.p.) 20 mg/kg/day of 1,2-DAB or 1,3-DAB, or vehicle (2% acetone in saline), 5 days a week for 2 weeks. Spinal cord and sciatic nerve proteins were subjected to Western blotting using monoclonal mouse antibodies to NF-M, kinesin, dynein, and tau. Proteins were quantified and paired mean comparisons performed to assess concentration-dependent changes in native protein bands. In vitro, 1,2-DAB produced a concentration-dependent decrease of motor and cytoskeletal proteins. While dynein and tau appeared similarly affected by 1,2-DAB, kinesin was most affected by the toxicant. In vivo, 1,2-DAB affected motor and cytoskeletal proteins of sciatic nerves and spinal cord differentially. In general, sciatic nerve proteins were much more affected than spinal cord proteins. The results show that motor proteins that drive axonal transport anterogradely (kinesin) and retrogradely (dynein), cytoskeletal protein NF-M, which is slowly transported in the anterograde direction, and microtubule-associated protein, tau, which is involved in axonal transport, are differentially impacted by 1,2-DAB. By contrast, non-neurotoxic isomer 1,3-diacetylbenzene (1,3-DAB), had no adverse effect on neural proteins either in vitro or in vivo. 2D-Differential in gel electrophoresis (2D-DIGE) of sciatic nerves from neurotoxic 1,2-DAB and non-neurotoxic 1,3-DAB treated rats revealed 197 and 304 protein spots, respectively.

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Section: Discussionsupporting

confidence: 85%

Axonopathy-Inducing 1,2-Diacetylbenzene Forms Adducts with Motor and Cytoskeletal Proteins Required for Axonal Transport

et al. 2007

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“…Both the ultramicroscopic and the electrophysiological analysis also confirmed that 1,2 DAB neurotoxicity affects primarily the proximal segments of the motor fibers, thus resembling one of the major clinical and pathological characteristics of ALS (Williamson and Cleveland 2001;Holzbaur 2004;Cleveland and Rothstein 2001;Bruijn and Cleveland 1996). The reports describing the 1,2 DAB neurotoxicity as an animal model of proximal neuropathy are based on clinical and histopathological methods (Kim et al 2001;Tshala-Katumbay et al 2005;Sabri et al 2007;LoPachin et al 2003). In the present study, it is introduced the electrophysiological evaluation as a non-invasive approach that allows for a better follow up and characterization of the animal's condition during the neuropathy induction and recovery.…”

Section: Discussionmentioning

confidence: 59%

Therapeutic Effect of the Combined Use of Growth Hormone Releasing Peptide-6 and Epidermal Growth Factor in an Axonopathy Model

et al. 2010

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Amyotrophic lateral sclerosis (ALS) is a disease of the central nervous system characterized by loss of spinal motor neurons, for which no effective treatment exists. Epidermal growth factor (EGF) and growth hormone releasing peptide-6 (GHRP-6) have been considered as good candidates for the treatment of this disease, due to their well documented effects in eliciting pleiotrophic and cell survival mechanisms. The aim of the present work was to evaluate the separate and combined effects of both peptides in an experimental animal model of ALS, the proximal axonopathy induced by 1,2 diacetylbenzene (1,2 DAB) in mice. The evaluations were conducted by means of behavioral tests (trapeze, tail suspension, gait pattern, and open field) and by recording the complex muscle action potential (CMAP) in three different hind limb segments: proximal S1, medial S2, and distal S3. Intraperitoneal daily administration of 1,2 DAB produced significant reduction in body weight, muscle strength, extensor reflex, spontaneous activity, and changes in gait pattern parameters. In parallel 1,2 DAB produced significant prolongation of onset latency and decrease in amplitude of CMAP and in the integrated complex action potential index. Daily administration of the separate compounds did not accelerate the recovery of the affected parameters, except for the gait pattern. The combined treatment produced significant improvement in behavioral parameters, as well as in electrophysiological recovery, particularly in the proximal segment of CMAP. The latter results confirm the proximal character of 1,2 DAB neuropathy, and suggest that combined therapy with EGF and GHRP-6 might be a good therapeutic strategy for the treatment of ALS.

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“…Other studies however identified axon atrophy as a significant feature of γ-diketone neuropathy [e.g., see 11, 12]. To resolve this apparent conflict, we conducted a series of quantitative morphometric studies to characterize the spatiotemporal expression of axonal swelling, atrophy and degeneration in conventionally fixed central [13, 14] and peripheral [15, 16] nerves of HD-intoxicated rats. Results showed that swollen axons were an exclusive but infrequent product of long-term (307–98 days) HD intoxication at lower daily dose-rates (100–175 mg/kg/d; respectively; Fig.…”

Section: γ-Diketone Neuropathy – Morphometric Analysesmentioning

confidence: 99%

“…These data indicate that regardless of dose-rate, axon atrophy developed in gracile and tibial nerve regions was an early consequence of HD intoxication. In both regions, however, giant neurofilamentous swellings were prevalent only in severely intoxicated animals; i.e., 175 mg/kg/d × 98 days and 400 mg/kg/d × 21 days [4, 13, 16]. …”

Section: Figurementioning

confidence: 99%

Toxic neuropathies: Mechanistic insights based on a chemical perspective

LoPachin

Gavin

2015

Neuroscience Letters

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2,5-Hexanedione (HD) and acrylamide (ACR) are considered to be prototypical among chemical toxicants that cause central-peripheral axonopathies characterized by distal axon swelling and degeneration. Because the demise of distal regions was assumed to be causally related to the onset of neurotoxicity, substantial effort was devoted to deciphering the respective mechanisms. Continued research, however, revealed that expression of the presumed hallmark morphological features was dependent upon the daily rate of toxicant exposure. Indeed, many studies reported that the corresponding axonopathic changes were late developing effects that occurred independent of behavioral and/or functional neurotoxicity. This suggested that the toxic axonopathy classification might be based on epiphenomena related to dose-rate. Therefore, the goal of this mini-review is to discuss how quantitative morphometric analyses and the establishment of dose-dependent relationships helped distinguish primary, mechanistically relevant toxicant effects from non-specific consequences. Perhaps more importantly, we will discuss how knowledge of neurotoxicant chemical nature can guide molecular-level research toward a better, more rational understanding of mechanism. Our discussion will focus on HD, the neurotoxic γ-diketone metabolite of the industrial solvents n-hexane and methyl-n-butyl ketone. Early investigations suggested that HD caused giant neurofilamentous axonal swellings and eventual degeneration in CNS and PNS. However, as our review will point out, this interpretation underwent several iterations as the understanding of γ-diketone chemistry improved and more quantitative experimental approaches were implemented. The chemical concepts and design strategies discussed in this mini-review are broadly applicable to the mechanistic studies of other chemicals (e.g., n-propyl bromine, methyl methacrylate) that cause toxic neuropathies.

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γ-diketone central neuropathy: quantitative morphometric analysis of axons in rat spinal cord white matter regions and nerve roots

Cited by 27 publications

References 61 publications

Axonopathy-Inducing 1,2-Diacetylbenzene Forms Adducts with Motor and Cytoskeletal Proteins Required for Axonal Transport

Axonopathy-Inducing 1,2-Diacetylbenzene Forms Adducts with Motor and Cytoskeletal Proteins Required for Axonal Transport

Therapeutic Effect of the Combined Use of Growth Hormone Releasing Peptide-6 and Epidermal Growth Factor in an Axonopathy Model

Toxic neuropathies: Mechanistic insights based on a chemical perspective

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