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Tetramisole and Levamisole Suppress Neuronal Activity Independently from Their Inhibitory Action on Tissue Non-specific Alkaline Phosphatase in Mouse Cortex

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Neuronal Tissue-Nonspecific Alkaline Phosphatase (TNAP)

Part of the book series: Subcellular Biochemistry ((SCBI,volume 76))

Abstract

Tissue non-specific alkaline phosphatase (TNAP) may be involved in the synthesis of GABA and adenosine, which are the main inhibitory neurotransmitters in cortex. We explored this putative TNAP function through electrophysiological recording (local field potential ) in slices of mouse somatosensory cortex maintained in vitro . We used tetramisole , a well documented TNAP inhibitor, to block TNAP activity. We expected that inhibiting TNAP with tetramisole would lead to an increase of neuronal response amplitude, owing to a diminished availability of GABA and/or adenosine. Instead, we found that tetramisole reduced neuronal response amplitude in a dose-dependent manner. Tetramisole also decreased axonal conduction velocity. Levamisole had identical effects. Several control experiments demonstrated that these actions of tetramisole were independent from this compound acting on TNAP. In particular, tetramisole effects were not stereo-specific and they were not mimicked by another inhibitor of TNAP, MLS-0038949 . The decrease of axonal conduction velocity and preliminary intracellular data suggest that tetramisole blocks voltage-dependent sodium channels . Our results imply that levamisole or tetramisole should not be used with the sole purpose of inhibiting TNAP in living excitable cells as it will also block all processes that are activity-dependent. Our data and a review of the literature indicate that tetramisole may have at least four different targets in the nervous system. We discuss these results with respect to the neurological side effects that were observed when levamisole and tetramisole were used for medical purposes, and that may recur nowadays due to the recent use of levamisole and tetramisole as cocaine adulterants.

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Notes

  1. 1.

    Note that GAD is one among multiple PLP-dependent enzymes. Approximately 60 genes encoding for enzymes using PLP as cofactor have been identified in mammals (Percudani and Peracchi 2009). In addition to GAD, some of these enzymes are directly involved in the synthesis of other neurotransmitters such as dopamine and serotonin (Ermonval et al. 2009).

  2. 2.

    Orthodromic responses could not be tested with 2 mM tetramisole: among the 4 experiments in which we used this concentration, 2 showed no measurable orthodromic response in the control condition, while in the other 2 experiments the orthodromic response obtained in the control condition failed to recover.

  3. 3.

    Adverse reactions after single levamisole or tetramisole doses have been consistently reported in veterinary medicine, and were usually attributed to their actions on ganglionic ACh receptors (reviewed in Hsu 1980).

  4. 4.

    In the context of cancer therapy, levamisole has also been reported to possess antiproliferative action in vitro (Kovach et al. 1992; Artwohl et al. 2000). However, the levamisole concentrations required to achieve significant effects in vitro appear to be much higher than the plasmatic concentration of levamisole in clinical therapy. Levamisole concentration in a range similar to the plasmatic concentration measured in patients fails to prevent the proliferation of cancer cell lines in vitro (Grem and Allegra 1989; Wiebke et al. 2003).

  5. 5.

    The epileptic seizures that have been observed in the course of chronic levamisole treatments have all been reported in children but not in adults. This offers another interesting parallel with vitamin B6 metabolism alteration: experimental studies showed that vitamin B6 deficiency results in epileptic crisis in young animals but not in the adults (Daniel et al. 1942; Guilarte 1989).

  6. 6.

    In addition to its involvement as an ectonucleotidase, TNAP could also intervene in myelination through vitamin B6 metabolism. In support for a role of PLP in myelination, it has been reported that vitamin B6 deficiency during development results in altered myelination (Lott et al. 1978; Kirksey et al. 1990). Indeed, PLP is a cofactor for two enzymes (serine palmitoyltransferase and sphingosine-1-phosphatelyase) involved in sphingolipid synthesis (Bourquin et al. 2011). Among sphingolipids, sphingomyelin, as expected from its name, happens to be particularly abundant in myelin. On the other hand, if myelination impairments observed in levamisole-induced multifocal leukoencephalopathy were consecutive to altered vitamin B6 metabolism, another PLP-dependent process, GABA synthesis, should also be impaired. This should result in occurrences of epileptic seizures in patients with levamisole-induced leukoencephalopathy, which, to our knowledge, have not been reported in case studies.

  7. 7.

    In France for example, levamisole can still be used for the treatment of pediatric nephrotic syndrome, but under very restrictive conditions.

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Acknowledgment

We would like to thank the SARA service and particularly Gregory Marsal for animal care. We acknowledge Pr José Luis Millán for his useful comments on this work while it was in progress. This work was supported by CNRS (PICS 4331), by Hypophosphatasie Europe (grant No. 88461) and by PHC Egide (Balaton 17341 UE).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Centre de Recherche Cerveau et Cognition (CerCo), Université de Toulouse UPS; CNRS UMR 5549 , Toulouse, France

    Lionel G. Nowak, Benoît Rosay & Caroline Fonta

  2. CNRS, Cerco, Toulouse, France

    Lionel G. Nowak

  3. Department of Physiology and Neurobiology, Eötvös Loránd University, Budapest, Hungary

    Dávid Czégé

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  1. Lionel G. Nowak
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Correspondence to Lionel G. Nowak or Caroline Fonta .

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  1. National Centre for Scientific Research (CNRS), University of Toulouse-UPS, Toulouse, France

    Caroline Fonta

  2. Wigner Research Centre for Physics, Hungarian Academy of Sciences, Budapest, Hungary

    László Négyessy

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Nowak, L.G., Rosay, B., Czégé, D., Fonta, C. (2015). Tetramisole and Levamisole Suppress Neuronal Activity Independently from Their Inhibitory Action on Tissue Non-specific Alkaline Phosphatase in Mouse Cortex. In: Fonta, C., Négyessy, L. (eds) Neuronal Tissue-Nonspecific Alkaline Phosphatase (TNAP). Subcellular Biochemistry, vol 76. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-7197-9_12

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