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PubMedDate not supplied

Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group III report: weight of evidence and quantitative evaluation of developmental neurotoxicity data.

Work Group III discussed the qualitative and quantitative evaluation of developmental neurotoxicity data for risk assessment purposes. The Work Group concurred with the assumption that developmental neurotoxicity may result from as little as a single exposure, dependent on dose and gestational time of exposure. Maternal toxicity, during the pregnancy and/or lactational period, may confound interpretation of effects observed in the offspring, but the majority of the group agreed that if significant effects were observed in a developmental neurotoxicity study, these effects should be presumed relevant to potential risk in humans. Others in the group indicated that these effects should be designated developmental toxicity but not necessarily developmental neurotoxicity. Concurrent toxicity (in the same organism, at the same dose, etc.) was also discussed, with the same concern as with maternal toxicity, i.e., are the results observed from developmental neurotoxicity per se or from other toxicity impacting on and confounding the neurotoxicity test results. A majority of the group regarded any effect observed in a neurotoxicity test as consistent with developmental neurotoxicity. The minority reserved this designation only for neurotoxic results observed at the lowest adverse effect level and in the absence of other developmental toxicity. Discussion on weighting tests in the battery focussed on apical tests which require the most integrated functions with the caveat for confounding effects from other toxicities. Developmental neurotoxicity data were viewed as potentially useful in establishing a reference dose. The interpretation of statistically significant findings was discussed with caveats for Type I errors, consistency, biological plausibility of findings, and the concern that current draft guidelines and test rules require adult toxicity with the risk of confounding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Methodological approach to the evaluation of neurotoxicity data and the classification of neurotoxic chemicals.

This text is the result of the authors' involvement in a working group on criteria for the identification and classification of neurotoxic chemicals. (The work of the group does not necessarily represent the official stand of the affiliated institutes.) A definition of neurotoxicity and criteria for evaluating studies dealing with neurotoxicology are presented. The evaluation is a stepwise process that ends with assigning the chemicals to groups depending on the available evidence for neurotoxicity (ie, neurotoxic, probably neurotoxic, possibly neurotoxic, probably not neurotoxic, or not classifiable). Finally, the description of the potency of neurotoxic chemicals is briefly discussed. The model has been tested by evaluating selected research papers on the following 10 chemicals: manganese, aluminum, tetrahydrofuran, cyclohexanone, dichlorvos, trichloroethylene, formaldehyde, tri-ortho-cresyl phosphate, n-hexane, and vinyl chloride. There was sufficient evidence for classifying five of the ten chemicals (aluminum, manganese, n-hexane, trichloroethylene, tri-ortho-cresyl phosphate) as definitely neurotoxic to humans, and three were considered to be possibly neurotoxic to humans (dichlorvos, tetrahydrofuran, vinyl chloride). Cyclohexanone and formaldehyde were not classifiable according to the model.

Animals↗

PubMed1988

Triphenyl phosphite neurotoxicity in the hen: inhibition of neurotoxic esterase and of prophylaxis by phenylmethylsulfonyl fluoride.

The neuropathic syndrome resulting in the cat and the rat from single or multiple doses of the phosphorous acid ester tiphenyl phosphite (TPP) has been reported to differ from the syndrome caused by numerous phosphoric acid esters, which is known as organophosphorous compound-induced delayed neurotoxicity (OPIDN). Since the hen is used to test compounds for OPIDN, we chose to study the neurotoxicity of single subcutaneous doses of TPP using this animal model. TPP (1000 mg/kg) produced progressive ataxia and paralysis which began to develop 5-10 days after dosing. Similar signs were observed when subcutaneous doses of the OPIDN-causing agents tri-o-cresyl phosphate (TOCP) or diisopropyl phosphorofluoridate (DFP) were administered. The minimum neurotoxic dose of TPP was 500 mg/kg. Prior administration of phenylmethylsulfonyl fluoride (PMSF) prevented the development of a neuropathy induced by DFP, but did not fully protect the hens from TPP or TOCP. PMSF slowed, but did not prevent, the neuropathy caused by TOCP. PMSF reduced the neurotoxicity of 500 mg/kg TPP, but increased the neurotoxicity of 1000 mg/kg TPP. TPP was found to be a very potent inhibitor of neurotoxic esterase (NTE), the putative target site for OPIDN, in vitro, with a ki of about 2.1 x 10(5) M-1 min-1. Equimolar doses of either TPP (1000 mg/kg) and TOCP (1187 mg/kg) caused over 80% inhibition of neurotoxic esterase (NTE) in brain and sciatic nerve. This high level of NTE inhibition persisted for several weeks. This prolonged inhibition probably accounts for the inability of PMSF to block the neurotoxicity of TOCP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5-HT nerve endings in vitro.

The mechanism underlying the serotoninergic neurotoxicity of some amphetamine derivatives, such as p-chloroamphetamine (pCA) and 3,4-methylenedioxymethamphetamine (MDMA), is still debated. Their main acute effect, serotonin (5-HT) release from nerve endings, involves their interaction with 5-HT transporters (SERTs), as substrates. Although this interaction is required for the neurotoxic effects, 5-HT release alone may not be sufficient to induce long-term 5-HT deficits. Some non-neurotoxic compounds, including p-methylthioamphetamine (MTA) and 1-(m-chlorophenyl)piperazine (mCPP), have 5-HT releasing properties in vivo and in brain slices comparable to that of neurotoxic amphetamine derivatives. We measured 5-HT release in superfused rat brain synaptosomes preloaded with [3H]5-HT, a model that distinguishes a releasing effect from reuptake inhibition. MTA and mCPP induced much lower release than pCA and MDMA. The striking difference between our findings in synaptosomes and those obtained in vivo or in brain slices is probably related to a different compartmentalisation of 5-HT in the different experimental models. Studies in synaptosomes, where the vesicular storage of 5-HT is predominant, could therefore bring to light differences between neurotoxic and non-neurotoxic 5-HT releasing agents which cannot be appreciated in other experimental models and might be useful to identify the mechanisms responsible for the neurotoxicity induced by amphetamine derivatives.

Amphetamines↗

PubMed1992

Delayed neurotoxicity of trixylenyl phosphate and a trialkyl/aryl phosphate mixture, and the modulating effect of atropine on tri-o-tolyl phosphate-induced neurotoxicity.

Two hydraulic fluids, Fyrquel EHC (trixylenyl phosphate) and Reofos 65 (trialkyl/aryl phosphate mixture), were examined for effects of organophosphorus-induced delayed neurotoxicity (OPIDN) in hens using the OECD Test Guideline (1984). Furthermore, the influence of atropine and the concentration of tri-o-tolyl phosphate (TOTP) in the oil vehicle on the development of OPIDN were investigated. For Fyrquel EHC a neurotoxic effect was demonstrated with single oral doses of 5, 10 and 15 g/kg. Reofos 65 caused no clinical neurotoxic effect after single oral doses of 5, 10 and 15 g/kg. Redosing at day 22 with Reofos 65 did not result in clinical delayed neurotoxicity, but minor histopathological changes were found in the spinal cord and peripheral nerves. Atropine 10 mg/kg im delayed the onset of OPIDN caused by TOTP 1 g/kg po without affecting the final neurotoxic effect. Dilution of TOTP in large amounts of soybean oil vehicle reduced its neurotoxic effect. In conclusion, the neurotoxic potential of the hydraulic fluids was very low. The effect of atropine and the concentration of the test compound in oil vehicle should be taken into consideration when designing experiments on OPIDN.

Animals↗

PubMed2006

S100B protects LAN-5 neuroblastoma cells against Abeta amyloid-induced neurotoxicity via RAGE engagement at low doses but increases Abeta amyloid neurotoxicity at high doses.

At the concentrations normally found in the brain extracellular space the glial-derived protein, S100B, protects neurons against neurotoxic agents by interacting with the receptor for advanced glycation end products (RAGE). It is known that at relatively high concentrations S100B is neurotoxic causing neuronal death via excessive stimulation of RAGE. S100B is detected within senile plaques in Alzheimer's disease, where its role is unknown. The present study was undertaken to evaluate a putative neuroprotective role of S100B against Abeta amyloid-induced neurotoxicity. We treated LAN-5 neuroblastoma cultures with toxic amounts of Abeta25-35 amyloid peptide. Our results show that at nanomolar concentrations S100B protects cells against Abeta-mediated cytotoxicity, as assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein isothiocyanate nick end-labeling (TUNEL) experiments, by countering the Abeta-mediated decrease in the expression of the anti-apoptotic factor Bcl-2. This effect depends on S100B binding to RAGE because S100B is unable to contrast Abeta-mediated neurotoxicity in neurons overexpressing a signaling-deficient RAGE mutant lacking the cytosolic and transducing domain. Our data suggest that at nanomolar doses S100B counteracts Abeta peptide neurotoxicity in a RAGE-mediated manner. However, at micromolar doses S100B is toxic to LAN-5 cells and its toxicity adds to that of the Abeta peptide, suggesting that additional molecular mechanisms may be involved in the neurotoxic process.

Amyloid beta-Peptides↗

PubMed1985

Characterization of [3H]di-isopropyl phosphorofluoridate-binding proteins in hen brain. Rates of phosphorylation and sensitivity to neurotoxic and non-neurotoxic organophosphorus compounds.

The experiments described in this paper were designed to isolate [3H]di-isopropyl phosphorofluoridate-binding proteins by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis for the purpose of characterizing and identifying potential initiation sites for organophosphorus-compound-induced delayed neurotoxicity. The major Paraoxon-insensitive Mipafox-sensitive binding protein (Mr 160 000) was found to be identical with one previously identified as neurotoxic esterase, an enzyme that has been proposed to be the target site for organophosphorus-compound-induced delayed neurotoxicity. However, two other binding proteins with suitable binding characteristics were also found in smaller amounts, one of which has not been detected previously. Di-isopropyl phosphorofluoridate was found to phosphorylate all three of these proteins at rates similar to the rate at which neurotoxic esterase is inhibited by di-isopropyl phosphorofluoridate. Varying the concentration of di-isopropyl phosphorofluoridate or the time of incubation produced similar increases in binding to each of the labelled proteins. This suggests that the reaction rates of di-isopropyl phosphorofluoridate with proteins may be described by first-order kinetics, and the concentration of the Michael is complex formed during binding is minimal for all the phosphorylated proteins. The recovery of the binding activity in the 160 000-Mr band was found to be similar to the recovery of neurotoxic esterase activity, lending further support to the contention that this band is identical with neurotoxic esterase.

Animals↗

PubMed1985

Experimental study on the enhancement of the neurotoxicity of methyl n-butyl ketone by non-neurotoxic aliphatic monoketones.

The neurotoxicity of methyl n-butyl ketone is known to be enhanced by combination with methyl ethyl ketone. This study was conducted to clarify the potentiating effect of aliphatic monoketones on the neurotoxicity of methyl n-butyl ketone. Rats were subcutaneously injected in the back with 4 mmol/kg/day of methyl ethyl ketone, methyl n-propyl ketone, methyl n-amyl ketone, or methyl n-hexyl ketone mixed with an equimolar dose of methyl n-butyl ketone five days a week for 20 weeks. The maximum motor fibre conduction velocity and the distal latency were measured every two weeks in the tail nerves of the treated animals and controls. All the monoketones tested enhanced the neurotoxicity of methyl n-butyl ketone. Of the compounds tested, methyl n-hexyl ketone, which had the longest carbon chain, enhanced the neurotoxicity of methyl n-butyl ketone most strongly. These results suggest that the length of the carbon chain of the aliphatic monoketones combined with methyl n-butyl ketone was related to the enhancement of the neurotoxicity of the neurotoxic compound.

Animals↗

PubMed2001

Inhibitors of Na(+)/H(+) and Na(+)/Ca(2+) exchange potentiate methamphetamine-induced dopamine neurotoxicity: possible role of ionic dysregulation in methamphetamine neurotoxicity.

Although the neurotoxic potential of methamphetamine (METH) is well established, underlying mechanisms have yet to be identified. In the present study, we sought to determine whether ionic dysregulation was a feature of METH neurotoxicity. In particular, we reasoned that if METH impairs the function of Na(+)/H(+) and/or Na(+)/Ca(2+) antiporters by compromising the inward Na(+) gradient [via prolonged DA transporter (DAT) activation and Na(+)/K(+) ATPase inhibition], then amiloride (AMIL) and other inhibitors of Na(+)/H(+) and/or Na(+)/Ca(2+) exchange would potentiate METH neurotoxicity. To test this hypothesis, mice were treated with METH alone or in combination with AMIL or one of its analogs; 1 week later, the animals were killed for studies of dopamine (DA) neuronal integrity. AMIL markedly potentiated the toxic effect of METH on DA neurons. Potentiation was not caused by increased core temperature, enhanced DAT activity or higher METH brain levels. The DAT inhibitor, WIN-35,428, protected completely against METH-induced DA neurotoxicity in AMIL pretreated animals, suggesting that the potentiating effects of AMIL require a METH/DAT interaction. Findings with METH and AMIL were extended to six other AMIL analogs (MIA, EIPA, DIMA, BENZ, BEP, DiCBNZ), another species (rats), and neuronal type (5-HT neurons). These results support the notion that ionic dysregulation may play a role in METH neurotoxicity.

Amiloride↗

PubMed2000

Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage.

Methamphetamine (METH) is a neurotoxic psychostimulant that produces catecholaminergic brain damage by producing oxidative stress and free radical generation. The role of oxygen and nitrogen radicals is well documented as a cause of METH-induced neurotoxic damage. In this study, we have obtained evidence that METH-induced neurotoxicity is the resultant of interaction between oxygen and nitrogen radicals, and it is mediated by the production of peroxynitrite. We have also assessed the effects of inhibitors of neuronal nitric oxide synthase (nNOS) as well as scavenger of nitric oxide and a peroxynitrite decomposition catalyst. Significant protective effects were observed with the inhibitor of nNOS, 7-nitroindazole (7-NI), as well as by the selective peroxynitrite scavenger or decomposition catalyst, 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5-sulfonatophenyl)porphyrinato iron III (FeTPPS). However, the use of a nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), did not provide any significant protection against METH-induced hyperthermia or peroxynitrite generation and the resulting dopaminergic neurotoxicity. In particular, treatment with FeTPPS completely prevented METH-induced hyperthermia, peroxynitrite production, and METH-induced dopaminergic depletion. Together, these data demonstrate that METH-induced dopaminergic neurotoxicity is mediated by the generation of peroxynitrite, which can be selectively protected by nNOS inhibitors or peroxynitrite scavenger or decomposition catalysts.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

beta-amyloid induces caspase-dependent early neurotoxic change in PC12 cells: correlation with H2O2 neurotoxicity.

We examined neurotoxic effects of Abeta(25-35), an active fragment of beta-amyloid (Abeta), and compared the effect with H2O2 neurotoxicity in PC12 cells. Abeta(25-35) induced the loss of mitochondria function as detected using a tetrazolium salt (WST-1) reduction assay and decreased the number of cells adhering to collagen type 1-coated plates. Abeta(25-35) did not induce cell death, as detected by Hoechst 33342/propidium iodide staining. The caspase tetrapeptide inhibitor z-IETD-fluoromethylketone (FMK) and z-LEHD-FMK inhibited the attenuation of WST-1 reduction induced by Abeta(25-35) and H2O2, while the caspase-3 inhibitor z-DEVD-FMK afforded protection only against H2O2 neurotoxicity. Caspase-3 protease activity was increased by treatment of H2O2 but not Abeta(25-35). Thus, Abeta(25-35) induces early neurotoxic events by activating caspases other than caspase-3. H2O2 -induced oxidative stress may not be implicated in Abeta-induced neurotoxic pathways.

Amyloid beta-Peptides↗

PubMed1970

Organophosphorus and other inhibitors of brain 'neurotoxic esterase' and the development of delayed neurotoxicity in hens.

1. The delayed neurotoxic effects of some organophosphorus compounds are associated with phosphorylation of the active site of a nervous-tissue enzyme capable of hydrolysing phenyl phenylacetate. 2. Neurotoxic organophosphorus compounds and some carbamates and sulphonyl fluorides progressively inhibit the enzyme, attaching a substituent covalently at the active site. 3. Prolonged inhibition of the enzyme by phenyl N-benzyl-N-methylcarbamate or phenylmethane-sulphonyl fluoride does not lead to neurotoxic effects. 4. Prior inhibition of the enzyme by carbamates or sulphonyl fluorides in vivo prevents the neurotoxic effects of several organophosphorus compounds. 5. After dosage of hens with protective compounds, protection lasts until about 70% of the enzyme site again becomes available for phosphorylation. 6. Reaction of all the inhibitors at the active site of the enzyme leads to the same inhibitory effect with respect to hydrolysis of phenyl phenylacetate but does not in all cases lead to delayed neurotoxicity. It is concluded that the nature of the group substituted at the enzyme active site determines the toxic response.

Animals↗

PubMed2003

Human immunodeficiency virus type 1 gp120 and ethanol coexposure in rat organotypic brain slice cultures: Curtailment of gp120-induced neurotoxicity and neurotoxic mediators by moderate but not high ethanol concentrations.

Human immunodeficiency virus type 1 (HIV-1) envelope protein gp120, implicated with other retroviral proteins in acquired immunodeficiency syndrome (AIDS)-related dementia, causes neuronal degeneration by inciting cascades of neurotoxic mediators from glia. It also may facilitate neuronal glutamate (N-methyl-D-aspartate, NMDA) receptor-mediated excitotoxicity by interacting at the glycine coagonist site. The authors reported that preconditioning rat organotypic hippocampal-cortical slice cultures subchronically with ethanol at concentrations occurring during moderate drinking (20 to 30 mM) prevented gp120's induction of neurotoxic mediators and intracellular calcium, as well as neuronal death. The authors now find that the acute copresence of ethanol in moderate as opposed to high concentrations similarly blocks the retroviral protein's neurotoxic effects in brain slice cultures, assessed with lactate dehydrogenase (LDH) release and propidium iodide (PI) labeling. As with ethanol preconditioning, neuroprotection against gp120 by moderate ethanol coexposure appears secondary to abrogation of the retroviral protein's early induction of arachidonic acid (AA), glutamate, and superoxide (but not nitric oxide) elevations/release. Additionally, experiments indicate that 30 mM ethanol is sufficient to inhibit the NMDA receptor, particularly in the presence of added glycine, thus hindering potential direct neuronal stimulation by gp120. However, in contrast to moderate ethanol, 100 mM ethanol, a concentration tolerated only in chronic alcoholics, potentiates gp120-dependent neurotoxicity (PI labeling) in the hippocampal CA1 region, augments LDH release, and fails to curtail gp120's actions on AA, glutamate, and superoxide-but does suppress nitric oxide induction. The results indicate dominant roles for AA, superoxide, and glutamate-mediated oxidative stress in gp120's neurotoxic mechanism, but perhaps a less important role for NMDA receptor stimulation, which would be constrained at both ethanol concentrations employed. We suggest that ethanol's concentration-dependent, two-edged sword behavior could alter the development of dementia in HIV-1-infected individuals during social consumption or abuse. Further studies are needed to elucidate the differing apparently glial effects of the two concentrations of ethanol.

Animals↗

PubMedDate not supplied

Assay of chicken brain neurotoxic esterase activity using leptophosoxon as the selective neurotoxic inhibitor.

Hen brain microsomal preparation has phenyl valerate-hydrolyzing activity associated with neurotoxic esterase activity. Part of that activity is due to paraoxon-insensitive esterases and a sub-part of this is sensitive to neurotoxic organophosphates, i.e., mipafox and leptophosoxon. This neurotoxic agent sensitive esterase activity is referred to as neurotoxic esterase (NTE). Because of the commercial unavailability and high toxicity of mipafox, which is usually used as the selective inhibitor for assaying NTE, leptophosoxon was used as an alternative to mipafox. Results indicated that the NTE fraction of hen brain microsomal PV-hydrolyzing activity is the same target for either mipafox or leptophosoxon. The inhibitory effect of leptophosoxon against that fraction was much higher than that of mipafox. The availability of leptophos/leptophosoxon makes this assay very useful for screening organophosphorus esters for neurotoxic effects.

Animals↗

PubMed1993

Neurotoxicity of human amylin in rat primary hippocampal cultures: similarity to Alzheimer's disease amyloid-beta neurotoxicity.

Amylin, a 37-amino-acid amyloidogenic peptide, bears biophysical similarities to the amyloid-beta peptide (A beta) deposited in Alzheimer's disease. Using embryonic rat hippocampal cultures we tested whether amylin induces neurotoxicity similar to that previously observed with A beta(1-40). Treatment with human amylin(1-37) resulted in prominent toxicity as assessed by phase-contrast microscopy and quantification of lactate dehydrogenase in the medium. Amylin-induced neurotoxicity was morphologically similar to that induced by A beta(1-40). In contrast, the nonamyloidogenic rat amylin showed negligible neurotoxicity despite having 95% sequence similarity to human amylin. Only full-length human amylin was toxic; various amylin peptide fragments including amino acid residues 20-29 were nontoxic at similar concentrations. These studies suggest that unrelated amyloidogenic peptides like human amylin and A beta can adopt a similar neurotoxic conformation in vitro. Similar conformation-dependent neurotoxicity may drive the prominent neurite degeneration around compacted but not diffuse deposits of A beta in Alzheimer's disease.

Amino Acid Sequence↗

PubMed1989

Toxic neurofilamentous axonopathies and fast anterograde axonal transport. II. The effects of single doses of neurotoxic and non-neurotoxic diketones and beta, beta'-iminodipropionitrile (IDPN) on the rate and capacity of transport.

The site and mode of action of neurotoxic chemicals producing neurofilamentous axonopathies has been speculated to be the axonal transport system. The current study determined the effects of neurotoxic and non-neurotoxic gamma-diketones as well as beta, beta'-iminodipropionitrile (IDPN) upon both the rate and quantity of protein transported in the fast anterograde component of the rat sciatic nerve. 2,5-Hexanedione (2,5-HD), given as 4, 6 and 8 mmoles/kg single ip injections reduced the rate of transport by 18.4-24.7% but more significantly reduced the quantity of protein transported 50-63%. 3,4-Dimethyl-2,5-HD (3,4-DMHD) at single doses of 0.25, 0.50 and 1.0 mmoles/kg similarly reduced the rate and capacity of protein transport. The toxicants did not alter the uptake of leucine and synthesis of protein during the three hour time frame used to measure transport. Although high doses of IDPN reduced the rate of anterograde transport, this toxicant, as well as the non-neurotoxic diketones studied, had no effect upon the quantity of protein transported. Therefore, neurotoxic gamma-diketones which produce distal nerve degeneration had a common effect in decreasing the quantity of protein delivered to the nerve after just a single exposure.

Animals↗

PubMedDate not supplied

Comparison of the behavioral effects of neurotoxic and systemically toxic agents: how discriminatory are behavioral tests of neurotoxicity?

The behavioral effects of carbon tetrachloride-produced impairment of liver function, insulin-produced reduction of plasma glucose levels, and the reduction of food and water intake have been evaluated. Considerable similarity was found among the behavioral effects of systemically toxic agents, three neurotoxicants (triethyltin, acrylamide, and 2,5-hexanedione), and the neuroleptic drug haloperidol. Measure of motor strength differentiated neurotoxic from non-neurotoxic compounds, while measures of motor activity were equally sensitive to neurotoxic, systemically toxic, and non-neurotoxic agents. These findings demonstrate the importance of assessing systemic toxicity before drawing conclusions about the neurotoxicity of a behaviorally active compound.

Animals↗

PubMed1986

Structural basis of gamma-diketone neurotoxicity: non-neurotoxicity of 3,3-dimethyl-2,5-hexanedione, a gamma-diketone incapable of pyrrole formation.

The chronic exposure to gamma-diketones results in the formation of giant neurofilament (NF)-containing axonal enlargements, followed by axonal degeneration in peripheral axons. Based on the specific ability of gamma-diketones to react with primary amino groups to form pyrroles, and the observation of such reaction with NF protein in vitro and with other proteins in vivo, it has been proposed that pyrrole formation at primary amino groups of NF protein is responsible for the neurotoxicity of gamma-diketones. We have tested this hypothesis through an investigation of the neurotoxicity in rats of 3,3-dimethyl-2,5-hexanedione (3,3-DMHD), a gamma-diketone which is incapable of forming pyrroles. 3,3-DMHD was found to produce only a slight alteration of axonal caliber and no clinical neurotoxicity after up to 12 weeks of administration, at a dose over 20 times that for which its isomer 3,4-dimethyl-2,5-hexanedione (3,4-DMHD) produced massive focal NF-containing axonal enlargements and complete paralysis in 4 weeks. These results support the view that the pyrrole-forming capability of gamma-diketones is the initial molecular event in the pathogenesis of gamma-diketone neurotoxicity.

Animals↗