Studies on drug-induced neuropathies. III. Motor nerve deficit in cats with experimental acrylamide neuropathy

doi:10.1016/0014-2999(76)90313-7

European Journal of Pharmacology

Volume 35, Issue 1, January 1976, Pages 177-184

https://doi.org/10.1016/0014-2999(76)90313-7 Get rights and content

Abstract

To assess motor nerve and motor nerve terminal function in acrylamide neuropathy, cats were given i.m. injections of acrylamide (15 mg/kg) daily for 10 days to induce a peripheral neuropathy. Tests of function were performed on the day of the 10th injection (day 0) and 7, 21 and 35 days thereafter. In untreated animals tetanic conditioning evoked stimulus-bound repitition (SBR) in 85% of soleus α-motoneurones. Following administration of acrylamide, the percent of axons elaborating SBR were: day 0–79%, day 7–71%, day 21–31%, day 35–22%. The response of soleus muscle to SBR is normally a post-tetanic potentiation (PTP) of contractile tension which is proportional to the tetanic conditioninf frequency; during the development of the neuropathy, PTP in response to all tetanic frequencies progressively declined, concomitant with and as a result of the declining incidence of SBR. These data indicate that initial functional alterations in motor nerves during acrylamide neuropathy occurs at the level of the nerve terminal, preceding alterations in conduction velocities in the axons. However, the motor nerve deficit is not adequate, in either time to onset or severity, to account for the clinical manifestations of the neuropathy. The possible contribution to clinical signs of the neuropathy made by lesions to other peripheral nerves is discussed.

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Cited by (25)

The changing view of acrylamide neurotoxicity
2004, NeuroToxicology
Acrylamide (ACR) is a water-soluble, vinyl monomer that has multiple chemical and industrial applications: e.g., waste water management, ore processing. In addition, ACR is used extensively in molecular laboratories for gel chromatography and is present in certain foods that have been prepared at very high temperatures. Extensive studies in rodents and other laboratory animals have provided evidence that exposure to monomeric ACR causes cellular damage in both the nervous and reproductive systems, and produces tumors in certain hormonally responsive tissues. Whereas human epidemiological studies have demonstrated a significantly elevated incidence of neurotoxicity in occupationally exposed populations, such research has not, to date, revealed a corresponding increase in cancer risk. Since the announcement by a Swedish research group in April 2002 [J. Ag. Food Chem. 50 (2002) 4998] regarding the presence of ACR in potato and grain-based foods, there has been a renewed interest in the toxic actions of this chemical. Therefore, in this review, we consider the different toxic effects of ACR. The neurotoxic actions of ACR will be the focal point since neurotoxicity is a consequence of both human and laboratory animal exposure and since this area of investigation has received considerable attention over the past 30 years. As will be discussed, a growing body of evidence now indicates that the nerve terminal is a primary site of ACR action and that inhibition of corresponding membrane-fusion processes impairs neurotransmitter release and promotes eventual degeneration. The electrophilic nature of ACR suggests that this neurotoxicant adducts nucleophilic sulfhydryl groups on certain proteins that are critically involved in membrane fusion. Adduction of thiol groups also might be common to the reproductive and carcinogenic effects of ACR. A final goal of this review is to identify data gaps that retard a comprehensive understanding of ACR pathophysiological processes.
Nerve terminals as the primary site of acrylamide action: A hypothesis
2002, NeuroToxicology
Acrylamide (ACR) is considered to be prototypical among chemicals that cause a central–peripheral distal axonopathy. Multifocal neurofilamentous swellings and eventual degeneration of distal axon regions in the CNS and PNS have been traditionally considered the hallmark morphological features of this axonopathy. However, ACR has also been shown to produce early nerve terminal degeneration of somatosensory, somatomotor and autonomic nerve fibers under a variety of dosing conditions. Recent research from our laboratory has demonstrated that terminal degeneration precedes axonopathy during low-dose subchronic induction of neurotoxicity and occurs in the absence of axonopathy during higher-dose subacute intoxication. This relationship suggests that nerve terminal degeneration, and not axonopathy, is the primary or most important pathophysiologic lesion produced by ACR.
In this hypothesis paper, we review evidence suggesting that nerve terminal degeneration is the hallmark lesion of ACR neurotoxicity, and we propose that this effect is mediated by the direct actions of ACR at nerve terminal sites. ACR is an electrophile and, therefore, sulfhydryl groups on presynaptic proteins represent rational molecular targets. Several presynaptic thiol-containing proteins (e.g. SNAP-25, NSF) are critically involved in formation of SNARE (soluble N-ethylmaleimide (NEM)-sensitive fusion protein receptor) complexes that mediate membrane fusion processes such as exocytosis and turnover of plasmalemmal proteins and other constituents. We hypothesize that ACR adduction of SNARE proteins disrupts assembly of fusion core complexes and thereby interferes with neurotransmission and presynaptic membrane turnover. General retardation of membrane turnover and accumulation of unincorporated materials could result in nerve terminal swelling and degeneration. A similar mechanism involving the long-term consequences of defective SNARE-based turnover of Na⁺/K⁺-ATPase and other axolemmal constituents might explain subchronic induction of axon degeneration. The ACR literature occupies a prominent position in neurotoxicology and has significantly influenced development of mechanistic hypotheses and classification schemes for neurotoxicants. Our proposal suggests a reevaluation of current classification schemes and mechanistic hypotheses that regard ACR axonopathy as a primary lesion.
Paradoxical changes in spinal cord reflexes following the acute administration of acrylamide
1986, Toxicology Letters
Acrylamide (ACR) produces a central-peripheral distal axonopathy when administered chronically. This is characterized functionally by decreases in the monosynaptic reflex (MSR) and dorsal root potential (DRP) and alterations in the characteristics of the dorsal root reflex (DRR). Acute administration of ACR inhibits the oxidative enzyme complex NADH-tetrazolium reductase and slows retrograde axoplasmic transport. This study was carried out to determine if the spinal cord reflexes are also affected following acute administration of ACR. Dose-response studies revealed a dose-dependent increase in both the MSR and DRR. A single injection of 50 mg/kg ACR caused an increase in both the MSR and DRR within 15 min and continued for over 3 h. These data are paradoxical since chronic administration of ACR results in decreased function. Two possible mechanisms are proposed. First, calcium ion regulation may be involved in both the acute and chronic effects of ACR on spinal cord reflexes. Second, a depolarization of the neurons is occurring just prior to cell injury or death.
Acrylamide neurotoxicity: Altered spinal monosynaptic responses to quipazine, a serotonin agonist, in cats
1985, Toxicology and Applied Pharmacology
The effects of the serotonin agonist quipazine on the spinal monosynaptic reflex (MSR) were investigated in acrylamide-treated cats. Cats were administered 30 mg/kg acrylamide (ACR) for 10 days, and the MSR and spontaneous ventral root discharge (VRD) were recorded on the tenth day (ACR 10) or 10 days subsequent to the last injection (ACR 20). Cumulative doses of quipazine were administered to increase the MSR and VRD. It was found that the MSR in ACR 10 cats was significantly depressed by ACR while the ACR 20 cats showed increased MSRs with double peaks. Dose-response relationships between quipazine and the area-under-the-MSR showed a significant shift to the right in the ACR 10 from control and no significant change in the ACR 20 from control. Dose-response curves of quipazine vs VRD showed no significant difference in either group from control. These data suggest that the α-motoneuron in ACR-treated cats was responding normally to quipazine while the primary afferent terminal was not.
An electrophysiologic and ultrastructural study of the phenylmethanesulfonyl fluoride protection against a delayed organophosphorus neuropathy
1983, Toxicology and Applied Pharmacology
The delayed organophosphorus neuropathy caused by diisopropylfluorophosphate (DFP) can be prevented by pretreatment with phenylmethanesulfonyl fluoride (PMSF). A single injection of DFP (2 mg/kg) into a cat femoral artery produced a delayed neuropathy in the injected leg. Clinical neurotoxic signs in the DFP treated leg were most prominent at 21 to 28 days after DFP administration: a high-step gait with some tip-toe walking. During that time the capacity of the cat soleus α-motor nerve terminals to generate a stimulus-evoked repetitive discharge, known as SBR, was greatly attenuated. At that time, the ultrastructure of the motor nerve terminals demnostrated prominent alterations that correlated well with the motor nerve terminal SBR deficit. These alterations included the presence of extensive whorls in nerve terminals and axoplasms, the retraction and disruption of nerve terminals from the synaptic cleft, and a widening of secondary junctional folds. From the sampled population, the incidence of normal terminals in soleus muscles of the DFP-treated leg was only 2%. Cats which received PMSF (30 mg/kg ip) 24 hr before DFP administration did not develop any neurotoxic signs. Motor movements were normal. The SBR function of the soleus α-motor nerve terminals was not lost and its incidence approached normal values. Moreover, the ultrastructure was normal in 86% of examined neuromuscular junctions in the PMSF pretreated DFP cats. Thus, in this model, pretreatment with PMSF protected cats against the delayed neurotoxic effects of organophosphorus poisoning.
Prevention of the organophosphorus neuropathy by glucocorticoids
1982, Experimental Neurology
The effects of an intensive glucocorticoid regimen on the delayed organophosphorus neuropathy were investigated in the hind limb of cats injected intraarterially with 2 mg/kg diisopropylfluorophosphate (DFP). In this model of a delayed peripheral neuropathy, the animals develop a peculiar high-step gait. This sign initially appears in 14 days and is maximal 21 to 28 days after DFP administration. Concommitantly, the capacity of soleus α-motor nerve terminals to generate repetitive discharges after high-frequency conditioning is severely attenuated. In cats that received an i.v. injection of methylprednisolone (90 mg/kg) 5 to 10 min after DFP administration and seven doses of triamcinolone (8 mg/kg, i.m.) once every 3 days starting on the 2nd day after DFP, no clinical signs of a neuropathy were observed for 70-day intervals. Furthermore, in these glucocorticoid-treated cats administered DFP, the incidence of high-frequency conditioned repetitive discharges was normal. Electromicroscopy showed that the ultrastructure of the neuromuscular junction was normal. Thus, the glucocorticoid regimen protected cats against the delayed neurotoxic effect of organophosphorus poisoning.

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^☆: This work was supported by a grant to H.E. Lowndes from the Pharmaceutical Manufacturers Association Foundation and by research funds from New Jersey Medical School.

^☆☆: A preliminary account of this research has been communicated at F.A.S.E.B., Atlantic City, April, 1975.

^∗∗∗: Dept. Pharmacology, Cornell University Medical College, New York, New York, U.S.A.

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Studies on drug-induced neuropathies. III. Motor nerve deficit in cats with experimental acrylamide neuropathy☆,☆☆

Abstract

European J. Pharmacol.

European J. Pharmacol.

The ultrastructure of tri-ortho-cresyl phosphate poisoning. I. Studies on myelin and axonal alterations in the sciatic nerve

Acta Neuropathol.

Peripheral nerve changes in ortho-cersyl phosphate poisoning in the cat

J. Pathol. Bact.

The significance of the ‘dying-back’ process in experimental and huamn neurological disease

Intern. Rex. Exptl. Pathol.

Electrophysiological and histological on peripheral nerves in acrylamide poisoning in man

J. Neurol. Neurosurg. Psychiat.

Peripheral neuropathy in rats produced by acrylamide

Brit. J. Indust. Med.

Six cases of acrylamide poisoning

Brit. J. Med.

The effect of acrylamide on the peripheral nervous system of the baboon

J. Neurol. Neurosurg. Psychiat.

Motor and sensory conduction velocity in the baboon; normal values and changes during acrylamide neuropathy

J. Neurol. Neurosurg. Psychiat.

Conduction in unmyelinated fibers in experimental neuropathy

J. Neurol. Neurosurg. Psychiat.

Effects of acrylamide on the central nervous system of the cat

J. Pharmacol. Exptl. Therap.