The development of neuroprotective drugs
is essential for the treatment or manage-
ment of various neurological disorders.
These disorders range from acute stroke
and head or spinal-cord trauma to more
chronic neurodegenerative diseases such
as Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease, amyotrophic lateral
sclerosis, multiple sclerosis, HIV-associated
dementia and glaucoma. However, clinical
use of potential neuroprotective treatments
has been limited owing to serious side
effects. These include cognitive problems,
hallucinations and even coma1–3, all of
which can occur as a result of interference
of the drugs with normal brain function.
Indeed, because the brain is a complex
organ that is capable of many intricate
functions, it has proved difficult to develop
drugs for the treatment of neurodegenera-
tive disorders that do not interfere with the
normal functioning of the nervous system.
Although many factors, including
absorption, distribution, metabolism,
excretion (ADME) and pharmacokinetics,
complicate drug development in general,
brain function is particularly susceptible
to disruption because many of the targets
for drug action exert normal physiological
actions in unaffected parts of the brain.
Strong inhibition of these targets can block
normal as well as abnormal activity.
In this Perspective, I delineate strategies
for the development of novel neuroprotective
drugs that are clinically well tolerated. These
strategies are based on the principle that
drugs should interact with their target only
during states of pathological activation but
not interfere with the target if it functions
normally. Such drugs should therefore
exhibit little inhibition of normal physiologi-
cal function. Drugs that have been devel-
oped using these strategies have been coined
pathologically activated therapeutic (PAT)
drugs4,5. The design of PAT drugs is based
on mechanistic insights into their mode of
action. These drugs can home in on and
antagonize receptor channels, enzymes or
other molecules that are excessively activated
under pathological conditions. For instance,
an allosteric modulator site on a drug target
that remains cryptic under normal condi-
tions may become exposed during excessive
activation in pathological circumstances.
This allows the PAT drug to inhibit the
unwanted activity of the target, whereas it
has little or no effect on the target’s normal
physiological activity (FIG. 1).
Some older drugs are also known to
act selectively in pathological tissue. For
example, lidocaine, dilantin and dihydropy-
ridines act, at least in part, by preferentially
blocking Na+ channels (in the case of
lidocaine and dilantin) or Ca2+ channels (in
the case of dihydropyridines) on cells that
are pathologically activated. In the case of
lidocaine, this results in its local anaesthetic
Pathologically activated therapeutics
Stuart A. Lipton
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.
Nature Reviews | Neuroscience
Figure 1 | Uncompetitive, pathologically activated therapeutic drugs. The target molecule
harbours a cryptic allosteric site that only becomes exposed to the antagonist on pathological activa-
tion of the target, such as by oxidative stress or by an excessive agonist if the target is a receptor. An
uncompetitive antagonist can then bind to the site, inhibiting the activity of the target molecule and
bringing it back towards normal levels. When the pathological insult is removed, the binding site on
the target becomes hidden again. Note that a relatively fast off-rate is often important for drug action
in this case so that the antagonistic effect is not too prolonged.
NATurE rEVIEwS | neUroscience
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55. Ikejiri, M. et al. Potent mechanism‑based inhibitors for
matrix metalloproteinases. J. Biol. Chem. 280,
56. Gu, Z. et al. S‑Nitrosylation of matrix
metalloproteinases: signaling pathway to neuronal cell
death. Science 297, 1186–1190 (2002).
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).
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
59. Yong, V. W. Metalloproteinases: mediators of
pathology and regeneration in the CNS. Nature Rev.
Neurosci. 6, 931–944 (2005).
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).
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).
62. Jian Liu, K. & Rosenberg, G. A. Matrix
metalloproteinases and free radicals in cerebral
ischemia. Free Radic. Biol. Med. 39, 71–80 (2005).
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).
64. Montaner, J. et al. Matrix metalloproteinase
expression after human cardioembolic stroke:
temporal profile and relation to neurological
impairment. Stroke 32, 1759–1766 (2001).
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,
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).
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).
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,
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).
70. Zhao, B. Q. et al. Role of matrix metalloproteinases in
delayed cortical responses after stroke. Nature Med.
12, 441–445 (2006).
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).
72. Satoh, T. & Lipton, S. A. Redox regulation of neuronal
survival mediated by electrophilic compounds. Trends
Neurosci 30, 37–45 (2007).
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).
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).
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,
This article would not have been possible without the insight‑
ful 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
Competing interests statement
The author declares competing financial interests:
see web version for details.
Alzheimer’s disease | amyotrophic lateral sceloris |
Huntington’s disease | multiple sclerosis | Parkinson’s disease
ePO | HIF1α | HMOX1 | MMP2 | MMP9
stuart A. Lipton’s homepage:http://www.burnham.org/
All links Are AcTive in The online Pdf
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