ZPT-related distal axonopathy: Behavioral and electrophysiologic correlates in rats

Ross, Joseph F.; Lawhorn, Gerald T.

doi:10.1016/0892-0362(90)90128-y

Cited by 18 publications

(5 citation statements)

References 18 publications

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“…However, similar [Ca 2ϩ ] i elevations in other, more sensitive cell types could be deleterious (Tymianski, 1996;Sattler and Tymianski, 2000). Thus, the neurotoxic effects of NaP in rodents (Snyder et al, 1979;Ross and Lawhorn, 1990) could be explained in part by its action on [Ca 2ϩ ] i . Consistent with this hypothesis, we have found application of NaP to rat motor neurons in vitro not only causes an elevation of [Ca 2ϩ ] i , but also results in the death of a significant number of these cultured neurons (manuscript in preparation).…”

Section: Figurementioning

confidence: 99%

“…Pyrithione has been found to produce reversible neurotoxicity in rodents. This effect is characterized by the failure of transmission at the neuromuscular junction (Ross and Lawhorn, 1990) and by biochemical and histopathological changes in peripheral motor nerves. This is followed by subsequent histopathological changes in the associated skeletal muscles that are innervated by these nerves (Snyder et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

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Activation of a calcium entry pathway by sodium pyrithione in the bag cell neurons of Aplysia

et al. 2004

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The ability of sodium pyrithione (NaP), an agent that produces delayed neuropathy in some species, to alter neuronal physiology was accessed using ratiometric imaging of cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in fura PE-filled cultured Aplysia bag cell neurons. Bath-application of NaP evoked a [Ca(2+)](i) elevation in both somata and neurites with an EC(50) of approximately 300 nM and a Hill coefficient of approximately 1. The response required the presence of external Ca(2+), had an onset of 3-5 min, and generally reached a maximum within 30 min. 2-Methyl-sulfonylpyridine, a metabolite and close structural analog of NaP, did not elevate [Ca(2+)](i). Under whole-cell current-clamp recording, NaP produced a approximately 14 mV depolarization of resting membrane potential that was dependent on external Ca(2+). These data suggested that NaP stimulates Ca(2+) entry across the plasma membrane. To minimize the possibility that a change in cytosolic pH was the basis for NaP-induced Ca(2+) entry, bag cell neuron intracellular pH was estimated with the dye 2',7'-bis(carboxyethyl-5(6)-carboxy-fluorescein acetoxy methylester. Exposure of the neurons to NaP did not alter intracellular pH. The slow onset and sustained nature of the NaP response suggested that a cation exchange mechanism coupled either directly or indirectly to Ca(2+) entry could underlie the phenomenon. However, neither ouabain, a Na(+)/K(+) ATPase inhibitor, nor removal of extracellular Na(+), which eliminates Na(+)/Ca(2+) exchanger activity, altered the NaP-induced [Ca(2+)](i) elevation. Finally, the possibility that NaP gates a Ca(2+)-permeable ion channel in the plasma membrane was examined. NaP did not appear to activate two major forms of bag cell neuron Ca(2+)-permeable ion channels, as Ca(2+) entry was unaffected by inhibition of voltage-gated Ca(2+) channels using nifedipine or by inhibition of a voltage-dependent, nonselective cation channel using a high concentration of tetrodotoxin. In contrast, two potential store-operated Ca(2+) entry current inhibitors, SKF-96365 and Ni(2+), attenuated NaP-induced Ca(2+) entry. We conclude that NaP activates a slow, persistent Ca(2+) influx in Aplysia bag cell neurons.

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Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of a calcium entry pathway by sodium pyrithione in the bag cell neurons of Aplysia

et al. 2004

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“…Systemic symptoms include haematological changes and hind limb muscle atrophy or paralysis [ 12 , 144 , 171 ]. Hind limb functional effects were reversible, however electrophysiological dysfunction was still detectable [ 172 ]. Atrophy is reportedly due to muscle disuse, secondary to neurological effects [ 173 , 174 ], specifically involving peripheral axonopathy which in vitro studies indicate may be mediated by neuronal calcium influx [ 175 , 176 ].…”

Section: Toxicity Assessmentmentioning

confidence: 99%

Targeted Delivery of Zinc Pyrithione to Skin Epithelia

Mangion

Holmes

Roberts

2021

IJMS

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Zinc pyrithione (ZnPT) is an anti-fungal drug delivered as a microparticle to skin epithelia. It is one of the most widely used ingredients worldwide in medicated shampoo for treating dandruff and seborrheic dermatitis (SD), a disorder with symptoms that include skin flaking, erythema and pruritus. SD is a multi-factorial disease driven by microbiol dysbiosis, primarily involving Malassezia yeast. Anti-fungal activity of ZnPT depends on the cutaneous availability of bioactive monomeric molecular species, occurring upon particle dissolution. The success of ZnPT as a topical therapeutic is underscored by the way it balances treatment efficacy with formulation safety. This review demonstrates how ZnPT achieves this balance, by integrating the current understanding of SD pathogenesis with an up-to-date analysis of ZnPT pharmacology, therapeutics and toxicology. ZnPT has anti-fungal activity with an average in vitro minimum inhibitory concentration of 10–15 ppm against the most abundant scalp skin Malassezia species (Malassezia globosa and Malassezia restrica). Efficacy is dependent on the targeted delivery of ZnPT to the skin sites where these yeasts reside, including the scalp surface and hair follicle infundibulum. Imaging and quantitative analysis tools have been fundamental for critically evaluating the therapeutic performance and safety of topical ZnPT formulations. Toxicologic investigations have focused on understanding the risk of local and systemic adverse effects following exposure from percutaneous penetration. Future research is expected to yield further advances in ZnPT formulations for SD and also include re-purposing towards a range of other dermatologic applications, which is likely to have significant clinical impact.

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“…These tests have been shown to be sensitive to several types of environmental toxicants or experimental manipulations, and many of these procedures have been described by others ( Arezzo et al, 2011 ; Howard, 2013 ; McNeil et al, 2013 ) and will only be briefly described here. Perhaps the simplest test is of spontaneous EMG activity, which often increases in the presence of neurotoxicity or disease ( Hnik et al, 1982 ; Ross and Lawhorn, 1990 ; Daube and Rubin, 2009 ). Stimulation of motor nerves allows recording of muscle action potentials (M-wave), which can be altered in the presence of neurotoxicity ( Ross and Lawhorn, 1990 ).…”

Section: Presentmentioning

confidence: 99%

“…Perhaps the simplest test is of spontaneous EMG activity, which often increases in the presence of neurotoxicity or disease ( Hnik et al, 1982 ; Ross and Lawhorn, 1990 ; Daube and Rubin, 2009 ). Stimulation of motor nerves allows recording of muscle action potentials (M-wave), which can be altered in the presence of neurotoxicity ( Ross and Lawhorn, 1990 ). The elapsed time from the stimulus to the recorded neurophysiological response is known as the distal latency, and reflects the conduction velocity of the motor fibers in the stimulated nerve when the M-wave is recorded ( Mallik and Weir, 2005 ).…”

Section: Presentmentioning

confidence: 99%

The Future of Neurotoxicology: A Neuroelectrophysiological Viewpoint

Herr

2021

Front. Toxicol.

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Neuroelectrophysiology is an old science, dating to the 18th century when electrical activity in nerves was discovered. Such discoveries have led to a variety of neurophysiological techniques, ranging from basic neuroscience to clinical applications. These clinical applications allow assessment of complex neurological functions such as (but not limited to) sensory perception (vision, hearing, somatosensory function), and muscle function. The ability to use similar techniques in both humans and animal models increases the ability to perform mechanistic research to investigate neurological problems. Good animal to human homology of many neurophysiological systems facilitates interpretation of data to provide cause-effect linkages to epidemiological findings. Mechanistic cellular research to screen for toxicity often includes gaps between cellular and whole animal/person neurophysiological changes, preventing understanding of the complete function of the nervous system. Building Adverse Outcome Pathways (AOPs) will allow us to begin to identify brain regions, timelines, neurotransmitters, etc. that may be Key Events (KE) in the Adverse Outcomes (AO). This requires an integrated strategy, from in vitro to in vivo (and hypothesis generation, testing, revision). Scientists need to determine intermediate levels of nervous system organization that are related to an AO and work both upstream and downstream using mechanistic approaches. Possibly more than any other organ, the brain will require networks of pathways/AOPs to allow sufficient predictive accuracy. Advancements in neurobiological techniques should be incorporated into these AOP-base neurotoxicological assessments, including interactions between many regions of the brain simultaneously. Coupled with advancements in optogenetic manipulation, complex functions of the nervous system (such as acquisition, attention, sensory perception, etc.) can be examined in real time. The integration of neurophysiological changes with changes in gene/protein expression can begin to provide the mechanistic underpinnings for biological changes. Establishment of linkages between changes in cellular physiology and those at the level of the AO will allow construction of biological pathways (AOPs) and allow development of higher throughput assays to test for changes to critical physiological circuits. To allow mechanistic/predictive toxicology of the nervous system to be protective of human populations, neuroelectrophysiology has a critical role in our future.

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ZPT-related distal axonopathy: Behavioral and electrophysiologic correlates in rats

Cited by 18 publications

References 18 publications

Activation of a calcium entry pathway by sodium pyrithione in the bag cell neurons of Aplysia

Activation of a calcium entry pathway by sodium pyrithione in the bag cell neurons of Aplysia

Targeted Delivery of Zinc Pyrithione to Skin Epithelia

The Future of Neurotoxicology: A Neuroelectrophysiological Viewpoint

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