Immunosuppressant Analogs in Neuroprotection

390 Pages·2003·9.088 MB·English

by  Marcus F. Keep, Hiroyuki Uchino, Eskil Elmér (auth.), Cesario V. Borlongan PhD, Ole Isacson Dr Med Sci, Paul R. Sanberg PhD, DSc (eds.)

Immunosuppressant Analogs
in N europrotection
Immunosuppressant
Analogs in
N europrotection
Edited by
Cesario V. Borlongan,
PhD
National Institute on Drug Abuse, Baltimore, MD
Ole Isacson,
Dr Med Sci
Neuroregeneration Laboratories,
McLean Hospital/Harvard Medical School
Belmont, MA
Paul R. Sanberg,
PhD,DSc
University of South Florida College of Medicine, Tampa, FL
Foreword by
Solomon H. Snyder, and Bahman Aghdasi,
MD PhD
Johns Hopkins University School of Medicine, Baltimore, MD
Springer Science+
Business Media, LLC
ISBN 978-1-4684-9742-7 ISBN 978-1-59259-315-6 (eBook)
DOI 10.1007/978-1-59259-315-6
© 2003 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 2003
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Cover iHustration: (A) (Background on cover) From Fig. 3 D in Chapter 4 "Effects of Neuroimmunophilin Ligands an
Parkinson's Disease and Cognition," by Joseph P. Steiner et al. (B) (Foreground an cover) From Fig 2 A, B in Chapter
13 "Immunosuppressants in Traumatic Brain Injury," by David O. Okonkwo and John T. Povlishock.
Cover design by Patricia F. Cleary
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Library of Congress Cataloging in Publication Data
Immunosuppressant analogs in neuroprotection / edited by Cesario V. Borlongan, Ole
Isacson, Paul R. Sanberg ; foreword by Solomon H. Snyder and Bahman Aghdasi.
p. ;cm.
Includes bibliographical references and index.
1. Nervous system-Degeneration-Chemoprevention. 2. Immunosuppressant agents. 3.
Nervous system-Regeneration. 1. Borlongan, Cesario V. II. Isacson, Ole. III. Sanberg,
PaulR.
[DNLM: 1. Immunosuppressive Agents-therapeutic use. 2. Immunophilins. 3.
Neuroprotective Agents-pharmacology. QW 920 1326 20021
RC365 .146 2002
616.8'0651-dc21 2002190244
To Christine and Mia
(Cesar)
To patients with neurological diseases and their families
(Ole)
To my brothers and sisters: Steven, Susan, Donald, and Jennifer
(Paul)
Foreword
Why are Immunophilin Ligands Neurotrophic?
Solomon H. Snyder and Bahman Aghdasi
Scientists are too compartmentalized. Each of us is an expert in our own
microdomain yet ignorant of advances in nearby fields. The immunophilin
story elegantly exemplifies this situation. Cyclosporin A was introduced
into clinical use in the 1970s, revolutionizing organ transplantation, while
FK506 appeared in the 1980s. By 1990 cyclophilins and the FKBPs were
identified as receptors respectively for cyclosporin A and FK506. In the vast
majority of studies the only tissues examined were lymphocytes or compa
rable cells of the immune system (1). Though immunophilins were one
among the hottest areas of research in immunology, most neuroscientists
had never heard of their existence. Such was the status of the field when one
of us (SHS) read the elegant paper by Siekierka et al. (2) identifying FKBP12
as the receptor for the actions of FK506 based on its binding [3H] FK506
with high affinity and selectivity. Using an experimental sample of [3H]
FK506 from NEN-DuPont, Joseph Steiner in our lab examined its binding
to a wide range of rat tissues and discovered marked regional variations
within the brain with some areas displaying FKBP12 densities up to 50 times
more than those of immune tissues (3). We noted dramatic augmentation of
FKBP 12 expression in the facial nucleus of the brain stem in rats subjected
to facial nerve crush (4). The time course of these changes closely mimicked
similar alterations in GAP-43, a protein known to be involved in neural
regrowth. This led to our demonstration that FK506, rapamycin, and
cyclosporin A all stimulate neurite outgrowth in cultures of PC12 cells as
well as in sensory ganglia (5). Subsequently, we and others observed neu
rotrophic effects of immunosuppressant drugs in multiple systems in intact
animals (6-9). The observation that nonimmunosuppressant ligands of the
immunophilins were just as neurotrophic as the immunosuppressant drugs
( 10) led to the development of nonimmunosuppressant molecules substan
tially smaller than classic immunosuppressant drugs that augment the regrowth
of damaged peripheral and central neurons in intact animals. These drugs are
also neuroprotective in conditions such as stroke (11).
vii
viii Foreword
The beneficial effects of immunophilin ligands in most models of neuronal
damage may lead to utility in neurodegenerative diseases. Previous efforts to
stimulate neuronal regrowth clinically have employed neurotrophic proteins
such as nerve growth factor. Delivery of such proteins into the central nervous
system presents major hurdles. By contrast, immunophilin ligands in current
clinical trial are water-soluble small molecules that readily penetrate the
blood-brain barrier. Moreover, whereas neurotrophic proteins stimulate nor
mal as well as damaged neurons, which can lead to adverse effects [such as
hyperalgesia elicited by nerve growth factor (12)], the immunophilin ligands
appear to act only on damaged neurons.
Influences of immunophilin ligands in multiple models of neurologic dis
ease are the focus of the various chapters in Immunosuppressant Analogs in
Neuroprotection. This essay will attempt to explicate challenges in trying to
understand the molecular mechanisms whereby neurotrophic effects are
achieved. Whetherneuroprotective actions in cerebral ischemia and traumatic
brain injury involve the same or similar mechanisms is unclear. Interestingly,
neurotrophic proteins can also be neuroprotective. Since cerebral ischemia
can be elicited via an extraordinary array of biochemical alterations, potential
mechanisms for neuroprotection are comparably diverse. By contrast, there
are only a limited number of known mechanisms for stimulating nerve growth,
and so we will focus on the neurotrophic side of the story.
A unitary hypothesis for neurotrophic actions of immunophilin ligands must
explain several phenomena. For instance, all three classes of immunosuppres
sants have been shown to be neurotrophic, including cyclosporin A, FK506, and
rapamycin. Accordingly, both cyclophilins and FKBPs must presumably play
a role in neurotrophic effects. Immunosuppressive effects of these drugs stem
from the drug-immunophilin complex binding to and inhibiting calcineurin.
FK506 and cyclosporin derivatives that bind to the immunophilins but fail to
inhibit calcineurin are neurotrophic, which rules out calcineurin as a mediator.
One of the reasons for positing an immunosuppressant target downstream of the
immunophilins was the need to invoke a gain-of-function to account for the
great potency of immunosuppressants. Thus, FKBP12 and cyclophilin concen
trations in most tissues are extremely high, up to 1% of soluble protein, so that
low nanomolar concentrations of drugs could only occupy a small percentage
of tissue immunophilin ( 1). Though cyclophilin and FKB 12 show no similarity
in amino acid sequence, they both share peptide prolylisomerase activity, which
is inhibited by immunosuppressant drugs providing an initial hypothesis for
immunosuppressant effects. However, at therapeutic concentrations of the drug,
one would inhibit only a small fraction of the total tissue content of
immunophilin-mediated isomerase activity. By contrast, a drug could bind to a
Foreword ix
minor percentage of total tissue immunophilin, but the drug-immunophilin
complex could still exert a crucial influence on calcineurin activity. Utilizing the
analogy with calcineurin inhibition, one might expect neurotrophic actions to
employ a molecular target providing a similar gain off unction, especially as low
nanomolar concentrations of drugs stimulate neurite outgrowth. Such a target
would presumably respond to the rapamycin-FKBPl2 complex as well as to
immunophilin complexes with cyclosporin A and FK506. Rapamycin binds
with high affinity to FKBPI2, but the drug-immunophilin complex does not
interact with calcineurin. Instead, the complex binds to a unique target protein
designated FRAP (FK506 and rapamycin activated protein), RAFT (rapamycin
and FK506 target), or mammalian TOR (target ofrapamycin)(1 ,6). Crystallo
graphic studies show how FK506 interacting with FKBP12 facilitates second
ary interactions with calcineurin, interactions not feasible in the presence of
rapamycin. One would have to propose a different sort of binding mechanism
for a neurotrophic target that could accommodate rapamycin in the same way
as FK506. Alternatively, one could argue that rapamycin might act differently
than FK506. There are two components to neurotrophic effects. One involves
inhibition ofc ell division and the second involves neurite extension. Rapamycin
was first developed as a cancer chemotherapeutic agent, as it potently inhibits
cell division through RAFT and protein translational targets of RAFT such as
p70S6 kinase. Such actions could account for neurotrophic actions ofrapamycin,
at least in culture models (13).
In searching for potential neurotrophic targets, one should bear in mind
proteins that are already known to bind to immunophilins. These include the
inositoll,4,5-trisphosphate (IP receptor (II) as well as the ryanodine recep
3)
tor (14,15), both of which are major intracellular calcium channels. FKBP12
appears to be a physiologic subunit of the channels stabilizing their conduc
tance state. Stripping FKBPl2 off the channels makes them more "leaky" to
calcium. Such leakiness would presumably adversely affect cellular function.
Accordingly, FK506, which causes FKBP12 to dissociate from the channels,
would be expected to worsen neurotoxicity. On the other hand, once the chan
nel is open, the ability ofFKBP12 to increase its inertia would make it more
difficult to close so that FK506 might decrease calcium release from the
damaged cell. However, micromolar concentrations ofFK506 are required
to dissociate FKBP 12 (14). Moreover, cyclophilins have not yet been demon
strated to be associated with any calcium channels so that one would not be
able to explain neurotrophic effects of cyclosporin A. Members of the TGF~
receptor are also "targets" ofFKBPI2. Other members ofthe family include
receptors for bone morphogenetic protein (BMP), activin, and inhibin as well
as proteins such as ALK-7 for which there is not yet a known physiologic
x Foreword
ligand ( 16-19). FKBP12 appears to be a physiologic subunit of these receptors
that normally inhibits signaling (17,20). Members of the TGF~ family can be
neurotrophic as well as neuroprotective (21). FK506 causes the dissociation
of FKBP12 from members of the TGFf:) receptor family leading to augmented
signaling. Some members of the FK506 family elicit this dissociation at con
centrations as low as 10 nM, consistent with potencies relevant to neurotrophic
effects (20,22).
One component of neurotrophic actions is turning off the cell cycle. Inter
estingly, we recently demonstrated that targeted deletion of FKBP I 2 leads to
cell cycle arrest in the G 1 phase (23). This is a direct consequence of loss of
FKBP12 as the effect is rescued by transfection with FKBPI2. The arrest
arises from up-regulation of p21 whose activity is well known to cause growth
arrest. The p21 stimulation derives from overactivity ofTGF~ receptor sig
naling secondary to loss of the inhibitory actions of FKBPI2. TGF~ signals
primarily through three pathways: SMAD, p38 kinase, and MAP kinase. Cell
cycle arrest is attributed to overactivation of p38 kinase in the FKBPl2 defi
cient cells, because it is selectively prevented by an inhibitor of p38 kinase,
whereas inhibitors of other pathways have no effect.
Since several members of the TGF~ receptor family have been associated
with neurotrophic actions, any given one of them might be a target for actions
of FKBP12 ligands. However, none are known to be associated with
cyclophilin, so this particular model cannot explain the neurotrophic effects
of such drugs.
One complication in any model attempting to explain neurotrophic actions
of immunophilin ligands is the sheer multiplicity of the immunophilins. There
exist at least 15 discrete members of the FKBPI2 family and a comparable
number of cyclophilins (2,24-32). These vary markedly in their intracellular
localization, molecular weight, and association with other proteins. Though
we know a great deal about FKBP12 and cyclophilin A, few functions have
been clarified for the other immunophilins.
Elucidating the molecular mechanisms for the neurotrophic actions of drugs
will certainly enhance greatly our understanding of what causes neurons to grow
normally and to regrow following damage. Such insights will likely lead to new
generations oftherapeutic agents. Unfortunately, at the present time no single
theory can adequately explain the neurotrophic effects of these agents.
ACKNOWLEDGMENTS
Supported by USPHS grant DA00266 and Research Scientist Award
DA-00074 to SHS.
Foreword xi
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