Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

In situ electrochemical generation of nitric oxide for neuronal modulation

Nature Nanotechnology volume 15, pages 690–697 (2020)Cite this article

Subjects

Abstract

Understanding the function of nitric oxide, a lipophilic messenger in physiological processes across nervous, cardiovascular and immune systems, is currently impeded by the dearth of tools to deliver this gaseous molecule in situ to specific cells. To address this need, we have developed iron sulfide nanoclusters that catalyse nitric oxide generation from benign sodium nitrite in the presence of modest electric fields. Locally generated nitric oxide activates the nitric oxide-sensitive cation channel, transient receptor potential vanilloid family member 1 (TRPV1), and the latency of TRPV1-mediated Ca2+ responses can be controlled by varying the applied voltage. Integrating these electrocatalytic nanoclusters with multimaterial fibres allows nitric oxide-mediated neuronal interrogation in vivo. The in situ generation of nitric oxide in the ventral tegmental area with the electrocatalytic fibres evoked neuronal excitation in the targeted brain region and its excitatory projections. This nitric oxide generation platform may advance mechanistic studies of the role of nitric oxide in the nervous system and other organs.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Fe3S4 and Pt-Fe3S4 nanocatalysts for the electrochemical reduction of NO2– to NO.
Fig. 2: Electrochemically produced NO triggers TRPV1.
Fig. 3: Signalling pathways mediated by electrocatalytic NO generation in vitro.
Fig. 4: Fabrication and characterization of the NO delivery fibre.
Fig. 5: Neuronal stimulation mediated by NO delivery through implanted fibres in vivo.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding authors upon reasonable request.

Code availability

All scripts are available from the corresponding author upon reasonable request.

References

  1. Bredt, D. S. & Snyder, S. H. Nitric oxide: a physiologic messenger molecule. Annu. Rev. Biochem. 63, 175–195 (1994).

    CAS  Google Scholar 

  2. Mustafa, A. K., Gadalla, M. M. & Snyder, S. H.Signaling by gasotransmitters. Sci. Signal. 2, (2009).

  3. Yoshida, T. et al. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat. Chem. Biol. 2, 596 (2006).

    CAS  Google Scholar 

  4. Lundberg, J. O., Weitzberg, E. & Gladwin, M. T. The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nat. Rev. Drug Discov. 7, 156–167 (2008).

    CAS  Google Scholar 

  5. Calabrese, V. et al. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat. Rev. Neurosci. 8, 766 (2007).

    CAS  Google Scholar 

  6. Huang, Z. et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265, 1883–1885 (1994).

    CAS  Google Scholar 

  7. Liu, V. W. T. & Huang, P. L. Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc. Res. 77, 19–29 (2008).

    CAS  Google Scholar 

  8. Yoshida, T., Limmroth, V., Irikura, K. & Moskowitz, M. A. The NOS inhibitor, 7-nitroindazole, decreases focal infarct volume but not the response to topical acetylcholine in pial vessels. J. Cereb. Blood Flow Metab. 14, 924–929 (1994).

    CAS  Google Scholar 

  9. Wang, P. G. et al. Nitric oxide donors: chemical activities and biological applications. Chem. Rev. 102, 1091–1134 (2002).

    CAS  Google Scholar 

  10. Jen, M. C., Serrano, M. C., Van Lith, R. & Ameer, G. A. Polymer-based nitric oxide therapies: recent insights for biomedical applications. Adv. Funct. Mater. 22, 239–260 (2012).

    CAS  Google Scholar 

  11. Xiang, H. J., Guo, M. & Liu, J. G. Transition-metal nitrosyls for photocontrolled nitric oxide delivery. Eur. J. Inorg. Chem. 2017, 1586–1595 (2017).

    CAS  Google Scholar 

  12. Feelisch, M. The use of nitric oxide donors in pharmacological studies. Naunyn Schmiedebergs Arch. Pharmacol. 358, 113–122 (1998).

    CAS  Google Scholar 

  13. Miller, M. R. & Megson, I. L. Recent developments in nitric oxide donor drugs. Br. J. Pharmacol. 151, 305–321 (2007).

    CAS  Google Scholar 

  14. Zhou, E. Y. et al. Near-infrared photoactivatable nitric oxide donors with integrated photoacoustic monitoring. J. Am. Chem. Soc. 140, 11686–11697 (2018).

    CAS  Google Scholar 

  15. Suchyta, D. J. & Schoenfisch, M. H. Controlled release of nitric oxide from liposomes. ACS Biomater. Sci. Eng. 3, 2136–2143 (2017).

    CAS  Google Scholar 

  16. Simon, J. & Klotz, M. G. Diversity and evolution of bioenergetic systems involved in microbial nitrogen compound transformations. Biochim. Biophys. Acta Bioenerg. 1827, 114–135 (2013).

    CAS  Google Scholar 

  17. Einsle, O. et al. Structure of cytochrome c nitrite reductase. Nature 400, 476–480 (1999).

    CAS  Google Scholar 

  18. Tocheva, E. I., Rosell, F. I., Mauk, A. G. & Murphy, M. E. P. Side-on copper-nitrosyl coordination by nitrite reductase. Science 304, 867–870 (2004).

    CAS  Google Scholar 

  19. Rosca, V., Duca, M., de Groot, M. T. & Koper, M. T. M. ChemInform abstract: nitrogen cycle electrocatalysis. ChemInform 40, 2209–2244 (2009).

    Google Scholar 

  20. Joo, J. et al. Generalized and facile synthesis of semiconducting metal sulfide nanocrystals. J. Am. Chem. Soc. 125, 11100–11105 (2003).

    CAS  Google Scholar 

  21. Gadde, R. R. & Bruckenstein, S. The electroduction of nitrite in 0.1 M HClO4 at platinum. J. Electroanal. Chem. 50, 163–174 (1974).

    CAS  Google Scholar 

  22. Savannah, W., Company, R. & River, S. Electrochemical reduction of nitrates and nitrites in alkaline nuclear waste solutions. J. Appl. Electrochem. 26, 1–9 (1996).

    Google Scholar 

  23. Bard, A. J., Parsons, R. & Jordan, J. Standard Potentials in Aqueous Solution (CRC Press, 1985).

  24. Kojima, H. et al. Fluorescent indicators for imaging nitric oxide production. Angew. Chem. Int. Ed. 38, 3209–3212 (1999).

    CAS  Google Scholar 

  25. Eberhardt, M. et al.H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway. Nat. Commun. 5, (2014).

  26. Thomas, D. D., Liu, X., Kantrow, S. P. & Lancaster, J. R. The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2. Proc. Natl Acad. Sci. USA 98, 355–360 (2001).

    Google Scholar 

  27. Goldstein, S. & Czapski, G. Mechanism of the nitrosation of thiols and amines by oxygenated ·NO solutions: the nature of the nitrosating intermediates. J. Am. Chem. Soc. 118, 3419–3425 (1996).

    CAS  Google Scholar 

  28. Goldstein, S. & Czapski, G. Kinetics of nitric oxide autoxidation in aqueous solution in the absence and presence of various reductants. The nature of the oxidizing intermediates. J. Am. Chem. Soc. 117, 12078–12084 (1995).

    CAS  Google Scholar 

  29. Miyamoto, T., Dubin, A. E., Petrus, M. J. & Patapoutian, A. TRPV1 and TRPA1 mediate peripheral nitric oxide-induced nociception in mice. PLoS ONE 4, e7596 (2009).

    Google Scholar 

  30. Valenzano, K. J. et al. N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I. In vitro characterization and pharmacokinetic properties. J. Pharmacol. Exp. Ther. 306, 377–386 (2003).

    CAS  Google Scholar 

  31. Jaffrey, S. R., Erdjument-Bromage, H., Ferris, C. D., Tempst, P. & Snyder, S. H. Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat. Cell Biol. 3, 193 (2001).

    CAS  Google Scholar 

  32. Hermenegildo, C. et al. Chronic hyperammonemia impairs the glutamate–nitric oxide–cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur. J. Neurosci. 10, 3201–3209 (1998).

    CAS  Google Scholar 

  33. Hardingham, N., Dachtler, J. & Fox, K. The role of nitric oxide in pre-synaptic plasticity and homeostasis. Front. Cell. Neurosci. 7, 190 (2013).

    Google Scholar 

  34. Canales, A. et al. Multifunctional fibers for simultaneous optical, electrical and chemical interrogation of neural circuits in vivo. Nat. Biotechnol. 33, 277 (2015).

    CAS  Google Scholar 

  35. Park, S. et al. One-step optogenetics with multifunctional flexible polymer fibers. Nat. Neurosci. 20, 612 (2017).

    CAS  Google Scholar 

  36. Stoychev, D., Papoutsis, A., Kelaidopoulou, A., Kokkinidis, G. & Milchev, A. Electrodeposition of platinum on metallic and nonmetallic substrates — selection of experimental conditions. Mater. Chem. Phys. 72, 360–365 (2001).

    CAS  Google Scholar 

  37. Lammel, S. et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212 (2012).

    CAS  Google Scholar 

  38. Chen, R., Romero, G., Christiansen, M. G., Mohr, A. & Anikeeva, P. Wireless magnetothermal deep brain stimulation. Science 347, 1477–1480 (2015).

    CAS  Google Scholar 

  39. Gunaydin, L. A. et al. Natural neural projection dynamics underlying social behavior. Cell 157, 1535–1551 (2014).

    CAS  Google Scholar 

  40. Nugent, F. S., Penick, E. C. & Kauer, J. A. Opioids block long-term potentiation of inhibitory synapses. Nature 446, 1086 (2007).

    CAS  Google Scholar 

  41. Iravani, M. M., Kashefi, K., Mander, P., Rose, S. & Jenner, P. Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. Neuroscience 110, 49–58 (2002).

    CAS  Google Scholar 

  42. Sagar, S. M., Sharp, F. R. & Curran, T. Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science 240, 1328–1331 (1988).

    CAS  Google Scholar 

  43. Christoph, G. R., Leonzio, R. J. & Wilcox, K. S. Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. J. Neurosci. 6, 613–619 (1986).

    CAS  Google Scholar 

  44. Monai, H. et al. Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain. Nat. Commun. 7, 11100 (2016).

    CAS  Google Scholar 

  45. Furchgott, R. F. & Jothianandan, D. Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. J. Vasc. Res. 28, 52–61 (1991).

    CAS  Google Scholar 

  46. Zacharia, I. G. & Deen, W. M. Diffusivity and solubility of nitric oxide in water and saline. Ann. Biomed. Eng. 33, 214–222 (2005).

    Google Scholar 

  47. Gentet, L. J., Stuart, G. J. & Clements, J. D. Direct measurement of specific membrane capacitance in neurons. Biophys. J. 79, 314–320 (2000).

    CAS  Google Scholar 

  48. Franklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates 3rd edn (Academic Press, 2008).

Download references

Acknowledgements

We thank D. Kim and F. Zhang for the generous gifts of the plasmids and cell lines. This work was funded in part by the National Institute of Neurological Disorders and Stroke (5R01NS086804) and the National Institutes of Health (NIH) BRAIN Initiative (1R01MH111872). This work made use of the MIT MRSEC Shared Experimental Facilities under award number DMR-14-19807 from the National Science Foundation (NSF). Funding for this research was also provided by the Department of Chemical Engineering at MIT. J.P. is a recipient of a scholarship from the Kwanjeong Educational Foundation. J.H.M. and Z.J.S. are supported by NSF Graduate Research Fellowships under grant number 1122374. T.T. was supported by the NEC Corporation. S.R. acknowledges funding support from the NIH Pathway to Independence Award (National Institute of Mental Health 1K99MH120279-01) and a grant from the Simons Foundation to the Simons Center for the Social Brain at MIT.

Author information

Author notes

  1. These authors contributed equally: Jimin Park, Kyoungsuk Jin.

Authors and Affiliations

  1. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jimin Park, Yoel Fink & Polina Anikeeva

  2. Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jimin Park, Atharva Sahasrabudhe, Po-Han Chiang, Florian Koehler, Dekel Rosenfeld, Siyuan Rao, Tomo Tanaka, Tural Khudiyev, Yoel Fink & Polina Anikeeva

  3. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jimin Park, Atharva Sahasrabudhe, Po-Han Chiang, Florian Koehler, Dekel Rosenfeld, Siyuan Rao & Polina Anikeeva

  4. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Kyoungsuk Jin, Joseph H. Maalouf, Zachary J. Schiffer & Karthish Manthiram

  5. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA

    Atharva Sahasrabudhe

  6. Institute of Biomedical Engineering, National Chiao Tung University, Taiwan, Taiwan

    Po-Han Chiang

  7. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Florian Koehler

  8. Simons Center for Social Brain, Massachusetts Institute of Technology, Cambridge, MA, USA

    Siyuan Rao

  9. System Platform Research Laboratories, NEC Corporation, Tsukuba, Japan

    Tomo Tanaka

  10. Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, MA, USA

    Tural Khudiyev & Yoel Fink

  11. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

    Ofer Yizhar

  12. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

    Polina Anikeeva

Authors
  1. Jimin Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyoungsuk Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Atharva Sahasrabudhe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Po-Han Chiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joseph H. Maalouf
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Florian Koehler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dekel Rosenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Siyuan Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tomo Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tural Khudiyev
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zachary J. Schiffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoel Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ofer Yizhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Karthish Manthiram
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Polina Anikeeva
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.P., K.J., K.M. and P.A. designed all experiments and performed all analyses. K.J. and J.H.M. synthesized the nanocatalysts and evaluated their electrocatalytic activity for NO generation. K.J. and Z.J.S. calculated diffusion profiles of NO. A.S., T.T., and T.K. fabricated the NO-delivery fibre. Y.F. offered insights into fibre fabrication. J.P., K.J. and P.C. performed in vitro TRPV1 modulation using the electrochemical NO delivery system. J.P. and P.C. conducted in vivo neuronal stimulation with the NO-delivery fibre. J.P., S.R. and D.R. performed immunohistochemistry analyses. J.P., F.K. and O.Y. conducted the electrophysiology analyses. J.P. and D.R. performed the cGMP assays. All co-authors contributed to the writing of the manuscript.

Corresponding authors

Correspondence to Karthish Manthiram or Polina Anikeeva.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Nanotechnology thanks Fabio Benfenati, Jennifer Dionne and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary methods, Figs. 1–29 and refs. 1–7.

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, J., Jin, K., Sahasrabudhe, A. et al. In situ electrochemical generation of nitric oxide for neuronal modulation. Nat. Nanotechnol. 15, 690–697 (2020). https://doi.org/10.1038/s41565-020-0701-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41565-020-0701-x

This article is cited by

Search

Advanced search

Quick links

Find nanotechnology articles, nanomaterial data and patents all in one place. Visit Nano by Nature Research