dl- versus meso-3,4-dimethyl-2,5-hexanedione: A morphometric study of the proximo-distal distribution of axonal swellings in the anterior root of the rat

Rosenberg, Carlyn K.; Genter, Mary Beth; Szakál-Quin, Gyöngyi; Anthony, Douglas C.; Graham, Doyle G.

doi:10.1016/0041-008x(87)90297-3

Cited by 20 publications

(5 citation statements)

References 15 publications

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“…Another myelinated fiber lesion that has engendered recent interest is axonal atrophy, a change that had been previously noted in hexacarbon-treated rats (72,73,80,91) and in vitro neuronal preparations (77). Recent studies by Lehning and colleagues (66) demonstrated that subacute intraperitoneal or subchronic oral (drinking water) administration of 2,5-hexanedione led to equivalent clinical hind-limb weakness, despite the difference in the duration of compound dosing.…”

Section: Hexacarbon Neuropathymentioning

confidence: 97%

“…The neurofilamentous aggregates were initially noted at proximal paranodes (the portion of the axon just proximal to the narrowing of the node of Ranvier). In association with these swellings, there was thinning of the overlying myelin sheath, which led to paranodal demyelination ( Figure 5A, B Another myelinated fiber lesion that has engendered recent interest is axonal atrophy, a change that had been previously noted in hexacarbon-treated rats (72,73,80,91) and in vitro neuronal preparations (77). Recent (Figure 5C, D).…”

Section: P-bromophenylacetylureamentioning

confidence: 99%

“…Inset shows reduction of axonal neurofilaments and approximation of microtubules (arrows), X 12,407; inset, X 87,000. (6,7,38,43,91). This is manifested by progressive proximodistal derivatization that promotes neurofilament accumulation and associated distal axonal swellings, initially noted at proximal heminodes, where the narrowing of the nodal constriction impedes the movement of the cross-linked neurofilaments (41,42).…”

Section: P-bromophenylacetylureamentioning

confidence: 99%

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Mechanisms of Toxic Injury in the Peripheral Nervous System: Neuropathologic Considerations

Jortner

2000

Toxicol Pathol

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Section: Hexacarbon Neuropathymentioning

confidence: 97%

Section: P-bromophenylacetylureamentioning

confidence: 99%

Section: P-bromophenylacetylureamentioning

confidence: 99%

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Mechanisms of Toxic Injury in the Peripheral Nervous System: Neuropathologic Considerations

Jortner

2000

Toxicol Pathol

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“…This raised the issues of whether the neurofilament effect is the cause of the degeneration effects, or whether they are different phenomena caused by common molecular mechanisms or whether they are caused by different mechanisms. Several studies have shown that the γ‐diketones that more rapidly cause protein cross‐linking tend to cause more proximal swellings, and are more neurotoxic in terms of functional deficits , suggesting a link between them. However, the features of IDPN axonopathy are not consistent with the conclusion that agents that cause more proximal axonopathies are functionally more neurotoxic.…”

Section: Mechanisms Underlying Toxic Neurofilamentous Axonopathiesmentioning

confidence: 99%

Toxic neurofilamentous axonopathies– accumulation of neurofilaments and axonal degeneration

Llorens

2013

J Intern Med

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A number of neurotoxic chemicals induce accumulation of neurofilaments in axonal swellings that appear at varying distances from the cell body. This pathology is associated with axonal degeneration of different degrees. The clinical manifestation is most commonly that of a mixed motor-sensory peripheral axonopathy with a distoproximal pattern of progression, as in cases of chronic exposure to n-hexane and carbon disulphide. It has been demonstrated that protein adduct formation is a primary molecular mechanism of toxicity in these axonopathies, but how this mechanism leads to neurofilament accumulation and axonal degeneration remains unclear. Furthermore, little is known regarding the mechanisms of neurofilamentous axonopathy caused by 3,3′-iminodipropionitrile, an experimental toxin that induces proximal axon swelling that is strikingly similar to that found in early amyotrophic lateral sclerosis. Here, we review the available data and main hypotheses regarding the toxic axonopathies and compare them with the current knowledge of the biological basis of neurofilament transport. We also review recent studies addressing the question of how these axonopathies may cause axonal degeneration. Understanding the mechanisms underlying the toxic axonopathies may provide insight into the relationship between neurofilament behaviour and axonal degeneration, hopefully enabling the identification of new targets for therapeutic intervention. Because neurofilament abnormalities are a common feature of many neurodegenerative diseases, advances in this area may have a wider impact beyond toxicological significance.

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“…In either case, it appears to be well accepted that 2,5-HD induces modification of the primary amine side chains of critical lysine residues of NF or related cytoskeletal proteins (3) to form pyrroles (4)(5)(6)(7)(8)(9)(10)(11). Evidence that pyrrole formation is associated with neurotoxicity is that 2,5-HD analogues that form pyrroles more rapidly are more neurotoxic (5,10,(12)(13)(14)(15)(16). However, at least as far as the axonal swellings are observed, there is disagreement as to whether pyrrole formation and the associated alteration of noncovalent interactions of NF within the NF-microtubule meshwork is sufficient to cause neurofilament accumulation (6,7,9,16), or whether autoxidation of the pyrroles to reactive intermediates and subsequent protein-protein crosslinking is an obligatory event (4,17,18).…”

Section: Introductionmentioning

confidence: 99%

Novel 2,5-Hexanedione Analogues. Substituent-Induced Control of the Protein Cross-Linking Potential and Oxidation Susceptibility of the Resulting Primary Amine-Derived Pyrroles

Singh

Gopal

et al. 2001

Chem. Res. Toxicol.

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The neurotoxic gamma-diketone, 2,5-hexanedione (2,5-HD), induces neurofilamentous swellings at prenodal sites in proximal axons as a consequence of pyrrolation of lysine epsilon-amino groups on neurofilament proteins. However, there is disagreement as to whether pyrrole formation and the associated alteration of noncovalent interactions is sufficient to cause neurofilament accumulation, or whether pyrrole autoxidation and subsequent protein-protein cross-linking is an obligatory event. To investigate gamma-diketones that might form pyrroles inert to autoxidative-induced cross-linking, we synthesized 1,1,1-trifluoro-2,5-hexanedione, 3-(trifluoromethyl)-2,5-hexanedione (3-TFMHD), and two 3-(dialkylaminocarbonyl)-2,5-diketones and assessed their rates of pyrrole formation with amines, the oxidation susceptibility of the resulting pyrroles, and the protein cross-linking potential in vitro, relative to those of 3-methyl-2,5-hexanedione. 1,1,1-Trifluoro-2,5-hexanedione does not form pyrroles, but the three 2,5-HD analogues with an electron-withdrawing 3-substituent all rapidly formed pyrroles that were inert to autoxidation. Although 3-TMFHD nonetheless still induced cross-linking of ribonuclease A, by a nonoxidative mechanism independent of the pyrrole, the two 3-(dialkylaminocarbonyl)-2,5-diketones did not exhibit any protein cross-linking. As these two gamma-diketones possess aqueous-organic partitioning properties similar to those of 2,5-HD, they should serve as useful mechanistic probes in further studies.

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dl- versus meso-3,4-dimethyl-2,5-hexanedione: A morphometric study of the proximo-distal distribution of axonal swellings in the anterior root of the rat

Cited by 20 publications

References 15 publications

Mechanisms of Toxic Injury in the Peripheral Nervous System: Neuropathologic Considerations

Mechanisms of Toxic Injury in the Peripheral Nervous System: Neuropathologic Considerations

Toxic neurofilamentous axonopathies– accumulation of neurofilaments and axonal degeneration

Novel 2,5-Hexanedione Analogues. Substituent-Induced Control of the Protein Cross-Linking Potential and Oxidation Susceptibility of the Resulting Primary Amine-Derived Pyrroles

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