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Pacific Ciguatoxin Induces Excitotoxicity and Neurodegeneration in the Motor Cortex Via Caspase 3 Activation: Implication for Irreversible Motor Deficit

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Abstract

Consumption of fish containing ciguatera toxins or ciguatoxins (CTXs) causes ciguatera fish poisoning (CFP). In some patients, CFP recurrence occurs even years after exposure related to CTXs accumulation. Pacific CTX-1 (P-CTX-1) is one of the most potent natural substances known that causes predominantly neurological symptoms in patients; however, the underlying pathogenies of CFP remain unknown. Using clinically relevant neurobehavioral tests and electromyography (EMG) to assess effects of P-CTX-1 during the 4 months after exposure, recurrent motor strength deficit occurred in mice exposed to P-CTX-1. We detected irreversible motor strength deficits accompanied by reduced EMG activity, demyelination, and slowing of motor nerve conduction, whereas control unexposed mice fully recovered in 1 month after peripheral nerve injury. Finally, to uncover the mechanism underlying CFP, we detected reduction of spontaneous firing rate of motor cortical neurons even 6 months after exposure and increased number of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Increased numbers of motor cortical neuron apoptosis were detected by dUTP-digoxigenin nick end labeling assay along with activation of caspase 3. Taken together, our study demonstrates that persistence of P-CTX-1 in the nervous system induces irreversible motor deficit that correlates well with excitotoxicity and neurodegeneration detected in the motor cortical neurons.

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Acknowledgements

This work is supported in part by The Health and Medical Research Fund (HMRF), Food and Health Bureau, Hong Kong Special Administrative Region Government (Ref. No: 01122016 and 12134101), GRF grants from the Research Grant Council of the Hong Kong Special Administrative Region Government (CityU 11100015 and CityU 160813), SRG (7004587) and ARG (9667149) grants from the City University of Hong Kong award to Chi Ma, and the Collaborative Research Fund, the Research Grant Council of Hong Kong (C1012-15G) award to Paul Lam.

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Authors and Affiliations

  1. Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Hong Kong, Hong Kong

    Pallavi Asthana, Ni Zhang, Gajendra Kumar, Virendra Bhagawan Chine, Kunal Kumar Singh, Leo Lai Chan & Chi Him Eddie Ma

  2. State Key Laboratory in Marine Pollution, City University of Hong Kong, Tat Chee Avenue, Hong Kong, Hong Kong

    Yim Ling Mak, Leo Lai Chan, Paul Kwan Sing Lam & Chi Him Eddie Ma

  3. Shenzhen Key Laboratory for the Sustainable Use of Marine Biodiversity, Research Centre for the Oceans and Human Health, City University of Hong Kong Shenzhen Research Institute, Shenzhen, China

    Yim Ling Mak, Leo Lai Chan & Paul Kwan Sing Lam

  4. Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Hong Kong, Hong Kong

    Paul Kwan Sing Lam

  5. Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Tat Chee Avenue, Hong Kong, Hong Kong

    Chi Him Eddie Ma

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  1. Pallavi Asthana
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  2. Ni Zhang
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  3. Gajendra Kumar
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  4. Virendra Bhagawan Chine
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  9. Chi Him Eddie Ma
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Contributions

PA conducted in vivo electrophysiological study, NMJ and MBP quantification, performed sciatic nerve surgery and tissue harvest. NZ carried out the neurobehavioral assessments and data analysis with PA. GK performed single cell neuronal recording and GFAP staining. VBC and KKS performed experiments to confirm cell death. YLM performed P-CTX-1 extraction and tissue distribution analysis with expertise and resources provided by LLC and PKSL CHEM conceived the project and designed the study. PA, GK, and CHEM wrote the manuscript with inputs from all authors. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chi Him Eddie Ma.

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Asthana, P., Zhang, N., Kumar, G. et al. Pacific Ciguatoxin Induces Excitotoxicity and Neurodegeneration in the Motor Cortex Via Caspase 3 Activation: Implication for Irreversible Motor Deficit. Mol Neurobiol 55, 6769–6787 (2018). https://doi.org/10.1007/s12035-018-0875-5

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  • DOI: https://doi.org/10.1007/s12035-018-0875-5

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