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.

Pathologically activated therapeutics for neuroprotection

A Corrigendum to this article was published on 01 November 2007

Abstract

Many drugs that have been developed to treat neurodegenerative diseases fail to gain approval for clinical use because they are not well tolerated in humans. In this article, I describe a series of strategies for the development of neuroprotective therapeutics that are both effective and well tolerated. These strategies are based on the principle that drugs should be activated by the pathological state that they are intended to inhibit. This approach has already met with success, and has led to the development of the potentially neuroprotective drug memantine, an N-methyl-D-aspartate (NMDA)-type and glutamate receptor antagonist.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Uncompetitive, pathologically activated therapeutic drugs.
Figure 2: Uncompetitive antagonism by memantine.
Figure 3: Relatively fast off-rate of a pathologically activated therapeutic drug.
Figure 4: Targeted delivery of a pathologically activated therapeutic drug.
Figure 5: Activation of a pathologically activated therapeutic (PAT) drug by its target.
Figure 6: Regulation of protein activity by electrophilic pro-drugs.

References

  1. Lipton, S. A. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nature Rev. Drug Discov. 5, 160–170 (2006).

    CAS  Article  Google Scholar 

  2. Koroshetz, W. J. & Moskowitz, M. A. Emerging treatments for stroke in humans. Trends Pharmacol. Sci. 17, 227–233 (1996).

    CAS  Article  Google Scholar 

  3. Kemp, J. A. & McKernan, R. M. NMDA receptor pathways as drug targets. Nature Neurosci. 5, 1039–1042 (2002).

    CAS  Article  Google Scholar 

  4. Lipton, S. A. Concepts: turning down, but not off. Nature 428, 473 (2004).

    CAS  Article  Google Scholar 

  5. Lipton, S. A. & Chen, H.-S. V. Paradigm shift in neuroprotective drug development: clinically tolerated NMDA receptor inhibition by memantine. Cell Death Differ. 11, 18–20 (2004).

    CAS  Article  Google Scholar 

  6. Butterworth, J. F. & Strichartz, G. R. Molecular mechanisms of local anesthesia: a review. Anesthesiology 72, 711–734 (1990).

    CAS  Article  Google Scholar 

  7. Bean, B. P. Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proc. Natl Acad. Sci. USA 81, 6388–6392 (1984).

    CAS  Article  Google Scholar 

  8. Bean, B. P. Neurophysiology: stressful pacemaking. Nature 447, 1059–1060 (2007).

    CAS  Article  Google Scholar 

  9. Chan, C. S. et al. 'Rejuvenation' protects neurons in mouse models of Parkinson's disease. Nature 447, 1081–1086 (2007).

    CAS  Article  Google Scholar 

  10. Chen, H.-S. V. & Lipton, S. A. Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism. J. Physiol. 499, 27–46 (1997).

    CAS  Article  Google Scholar 

  11. Chen, H.-S. V. et al. Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J. Neurosci. 12, 4427–4436 (1992).

    CAS  Article  Google Scholar 

  12. Lipton, S. A. & Rosenberg, P. A. Mechanisms of disease: Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 330, 613–622 (1994).

    CAS  Article  Google Scholar 

  13. Choi, D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623–634 (1988).

    CAS  Article  Google Scholar 

  14. Meldrum, B. & Garthwaite, J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol. Sci. 11, 379–387 (1990).

    CAS  Article  Google Scholar 

  15. Rothman, S. M. & Olney, J. W. Excitotoxicity and the NMDA receptor — still lethal after eight years. Trends Neurosci. 18, 57–58 (1995).

    CAS  PubMed  Google Scholar 

  16. Mattson, M. P. Pathways towards and away from Alzheimer's disease. Nature 430, 631–639 (2004).

    CAS  Article  Google Scholar 

  17. Lipton, S. A. Molecular mechanisms of trauma-induced neuronal degeneration. Curr. Opin. Neurol. Neurosurg. 6, 588–596 (1993).

    CAS  PubMed  Google Scholar 

  18. Lipton, S. A. & Gendelman, H. E. Dementia associated with the acquired immunodeficiency syndrome. N. Engl. J. Med. 332, 934–940 (1995).

    CAS  Article  Google Scholar 

  19. Kaul, M., Garden, G. A. & Lipton, S. A. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410, 988–994 (2001).

    CAS  Article  Google Scholar 

  20. Dreyer, E. B. & Lipton, S. A. New perspectives on glaucoma. JAMA 281, 306–308 (1999).

    CAS  Article  Google Scholar 

  21. De Felice, F. G. et al. Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem. 282, 11590–11601 (2007).

    CAS  Article  Google Scholar 

  22. Lacor, P. N. et al. Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J. Neurosci. 27, 796–807 (2007).

    CAS  Article  Google Scholar 

  23. Shankar, G. M. et al. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27, 2866–2875 (2007).

    CAS  Article  Google Scholar 

  24. Lipton, S. A. NMDA receptors, glial cells, and clinical medicine. Neuron 50, 9–11 (2006).

    CAS  Article  Google Scholar 

  25. Chen, H.-S. V. & Lipton, S. A. The chemical biology of clinically tolerated NMDA receptor antagonists. J. Neurochem. 97, 1611–1626 (2006).

    CAS  Article  Google Scholar 

  26. Das, S. et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393, 377–381 (1998).

    CAS  Article  Google Scholar 

  27. Sucher, N. J. et al. Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain. J. Neurosci. 15, 6509–6520 (1995).

    CAS  Article  Google Scholar 

  28. Wong, H. K. et al. Temporal and regional expression of NMDA receptor subunit NR3A in the mammalian brain. J. Comp. Neurol. 450, 303–317 (2002).

    CAS  Article  Google Scholar 

  29. Chatterton, J. E. et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415, 793–798 (2002).

    CAS  Article  Google Scholar 

  30. Wada, A., Takahashi, H., Lipton, S. A. & Chen, H.-S. V. NR3A modulates the outer vestibule of the “NMDA” receptor channel. J. Neurosci. 26, 13156–13166 (2006).

    CAS  Article  Google Scholar 

  31. Hess, D. T., Matsumoto, A., Kim, S. O., Marshall, H. E. & Stamler, J. S. Protein S-nitrosylation: purview and parameters. Nature Rev. Mol. Cell Biol. 6, 150–166 (2005).

    CAS  Article  Google Scholar 

  32. Stamler, J. S., Singel, D. J. & Loscalzo, J. Biochemistry of nitric oxide and its redox-activated forms. Science 258, 1898–1902 (1992).

    CAS  Article  Google Scholar 

  33. Choi, Y. B. et al. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nature Neurosci. 3, 15–21 (2000).

    CAS  Article  Google Scholar 

  34. Lei, S. Z. et al. Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex. Neuron 8, 1087–1099 (1992).

    CAS  Article  Google Scholar 

  35. Lipton, S. A. et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626–632 (1993).

    CAS  Article  Google Scholar 

  36. Kim, W. K. et al. Attenuation of NMDA receptor activity and neurotoxicity by nitroxyl anion, NO. Neuron 24, 461–469 (1999).

    CAS  Article  Google Scholar 

  37. Takahashi, H. et al. Hypoxia enhances S-nitrosylation-mediated NMDA receptor inhibition via a thiol oxygen sensor motif. Neuron 53, 53–64 (2007).

    CAS  Article  Google Scholar 

  38. Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A. & Freeman, B. A. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc. Natl Acad. Sci. USA 87, 1620–1624 (1990).

    CAS  Article  Google Scholar 

  39. Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S. & Snyder, S. H. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl Acad. Sci. USA 88, 6368–6371 (1991).

    CAS  Article  Google Scholar 

  40. Jaakkola, P. et al. Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    CAS  Article  Google Scholar 

  41. Bruick, R. K. & McKnight, S. L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).

    CAS  Article  Google Scholar 

  42. Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J. & Whitelaw, M. L. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295, 858–861 (2002).

    CAS  Article  Google Scholar 

  43. Digicaylioglu, M. & Lipton, S. A. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades. Nature 412, 641–647 (2001).

    CAS  Article  Google Scholar 

  44. Maiese, K., Li, F. & Chong, Z. Z. New avenues of exploration for erythropoietin. JAMA 293, 90–95 (2005).

    CAS  Article  Google Scholar 

  45. Brines, M. & Cerami, A. Emerging biological roles for erythropoietin in the nervous system. Nature Rev. Neurosci. 6, 484–494 (2005).

    CAS  Article  Google Scholar 

  46. Lipton, S. A. Erythropoietin for neurologic protection and diabetic neuropathy. N. Engl. J. Med. 350, 2516–2517 (2004).

    CAS  Article  Google Scholar 

  47. Bernaudin, M. et al. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 19, 643–651 (1999).

    CAS  Article  Google Scholar 

  48. Jelkmann, W. Erythropoietin: structure, control of production, and function. Physiol. Rev. 72, 449–489 (1992).

    CAS  Article  Google Scholar 

  49. Finch, C. A. Erythropoiesis, erythropoietin, and iron. Blood 60, 1241–1246 (1982).

    CAS  PubMed  Google Scholar 

  50. Digicaylioglu, M. et al. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc. Natl Acad. Sci. USA 92, 3717–3720 (1995).

    CAS  Article  Google Scholar 

  51. Masuda, S. et al. Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J. Biol. Chem. 268, 11208–11216 (1993).

    CAS  PubMed  Google Scholar 

  52. Bernaudin, M. et al. Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia 30, 271–278 (2000).

    CAS  Article  Google Scholar 

  53. Morishita, E., Masuda, S., Nagao, M., Yasuda, Y. & Sasaki, R. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76, 105–116 (1997).

    CAS  Article  Google Scholar 

  54. Ehrenreich, H. et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol. Med. 8, 495–505 (2002).

    CAS  Article  Google Scholar 

  55. Ikejiri, M. et al. Potent mechanism-based inhibitors for matrix metalloproteinases. J. Biol. Chem. 280, 33992–34002 (2005).

    CAS  Article  Google Scholar 

  56. Gu, Z. et al. S-Nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297, 1186–1190 (2002).

    CAS  Article  Google Scholar 

  57. Gu, Z. et al. A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J. Neurosci. 25, 6401–6408 (2005).

    CAS  Article  Google Scholar 

  58. Yong, V. W., Power, C., Forsyth, P. & Edwards, D. R. Metalloproteinases in biology and pathology of the nervous system. Nature Rev. Neurosci. 2, 502–511 (2001).

    CAS  Article  Google Scholar 

  59. Yong, V. W. Metalloproteinases: mediators of pathology and regeneration in the CNS. Nature Rev. Neurosci. 6, 931–944 (2005).

    CAS  Article  Google Scholar 

  60. Lukes, A., Mun-Bryce, S., Lukes, M. & Rosenberg, G. A. Extracellular matrix degradation by metalloproteinases and central nervous system diseases. Mol. Neurobiol. 19, 267–284 (1999).

    CAS  Article  Google Scholar 

  61. Yang, Y., Estrada, E. Y., Thompson, J. F., Liu, W. & Rosenberg, G. A. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J. Cereb. Blood Flow Metab. 27, 697–709 (2007).

    CAS  Article  Google Scholar 

  62. Jian Liu, K. & Rosenberg, G. A. Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic. Biol. Med. 39, 71–80 (2005).

    CAS  Article  Google Scholar 

  63. Campbell, I. L. & Pagenstecher, A. Matrix metalloproteinases and their inhibitors in the nervous system: the good, the bad and the enigmatic. Trends Neurosci. 22, 285–287 (1999).

    CAS  Article  Google Scholar 

  64. Montaner, J. et al. Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke 32, 1759–1766 (2001).

    CAS  Article  Google Scholar 

  65. Romanic, A. M., White, R. F., Arleth, A. J., Ohlstein, E. H. & Barone, F. C. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29, 1020–1030 (1998).

    CAS  Article  Google Scholar 

  66. Asahi, M. et al. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J. Cereb. Blood Flow Metab. 20, 1681–1689 (2000).

    CAS  Article  Google Scholar 

  67. Asahi, M. et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J. Neurosci. 21, 7724–7732 (2001).

    CAS  Article  Google Scholar 

  68. Gasche, Y. et al. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood–brain barrier dysfunction. J. Cereb. Blood Flow Metab. 19, 1020–1028 (1999).

    CAS  Article  Google Scholar 

  69. Heo, J. H. et al. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J. Cereb. Blood Flow Metab. 19, 624–633 (1999).

    CAS  Article  Google Scholar 

  70. Zhao, B. Q. et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nature Med. 12, 441–445 (2006).

    CAS  Article  Google Scholar 

  71. Satoh, T. et al. Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic phase II inducers. Proc. Natl Acad. Sci. USA 103, 768–773 (2006).

    CAS  Article  Google Scholar 

  72. Satoh, T. & Lipton, S. A. Redox regulation of neuronal survival mediated by electrophilic compounds. Trends Neurosci 30, 37–45 (2007).

    CAS  Article  Google Scholar 

  73. Itoh, K., Tong, K. I. & Yamamoto, M. Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic. Biol. Med. 36, 1208–1213 (2004).

    CAS  Article  Google Scholar 

  74. Kraft, A. D., Johnson, D. A. & Johnson, J. A. Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J. Neurosci. 24, 1101–1112 (2004).

    CAS  Article  Google Scholar 

  75. Shih, A. Y., Li, P. & Murphy, T. H. A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J. Neurosci. 25, 10321–10335 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This article would not have been possible without the insightful work of my colleagues, present and former, H.-S. V. Chen, Y.-B. Choi, D. Zhang, N. Nakanishi, M. Digicaylioglu, T. Satoh, Z. Gu, S. Mobashery and J. S. Stamler, to whom I am extremely grateful. The work was supported in part by grants from the NIH, the Institute for the Study of Aging, and a Senior Scholar Award in Aging Research from the Ellison Medical Foundation.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

S.A.L. is the named inventor on patents for the use of the clinically approved and marketed drug memantine (Namenda), in the treatment of neurodegenerative diseases. He has no direct ownership in memantine, but under the rules of the institution where this work was performed, Harvard University, he participates in a royalty sharing plan administered by Harvard Medical School and Children's Hospital, Boston. S.A.L. is also a named inventor on patents for the use of erythropoietin, matrix metalloproteinase inhibitors, and electrophilic compounds for the treatment of neurodegenerative and related disorders. These patents are assigned to the Burnham Institute for Medical Research in La Jolla, California, USA.

CFI url: http://www.nature.com/nrn/journal/v8/n10/box/nrn2229_audecl.html

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

amyotrophic lateral sceloris

Huntington's disease

multiple sclerosis

Parkinson's disease

FURTHER INFORMATION

Stuart A. Lipton's homepage

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lipton, S. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 8, 803–808 (2007). https://doi.org/10.1038/nrn2229

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2229

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing