Acute Neuronal Injury: The Role of Excitotoxic Programmed Cell Death Mechanisms

212 Pages·2018·6.392 MB·English

by  Denson G. Fujikawa

Denson G. Fujikawa
Editor
Acute Neuronal
Injury
The Role of Excitotoxic Programmed
Cell Death Mechanisms
Second Edition
Acute Neuronal Injury
Denson G. Fujikawa
Editor
Acute Neuronal Injury
The Role of Excitotoxic Programmed
Cell Death Mechanisms
Second Edition
Editor
Denson G. Fujikawa
Department of Neurology
VA Greater Los Angeles Healthcare System
North Hills, CA, USA
Department of Neurology and Brain Research Institute
David Geffen School of Medicine
University of California at Los Angeles
Los Angeles, CA, USA
ISBN 978-3-319-77494-7 ISBN 978-3-319-77495-4 (eBook)
https://doi.org/10.1007/978-3-319-77495-4
Library of Congress Control Number: 2018942497
© Springer International Publishing AG, part of Springer Nature 2010, 2018
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Cover Caption: AIF translocation in vivo following global ischemia is prevented by overexpression of
calpastatin. Representative immunofluorescence of apoptosis-inducing factor (AIF, red) from non-
ischemic CA1 (a) or 72 h after global ischemia (b– d). AAV–calpastatin, a calpain inhibitory protein
(c, d), or the empty vector (b) was infused 14 d before ischemia, and brain sections were double-label
immunostained for AIF (red) and calpastatin overexpression (green, d). Note that the majority of CA1
neurons lost normal localization of AIF after ischemia (b, arrows), but AIF translocation was rare in
calpastatin-overexpressed CA1 (c, d, arrows). Scale bars, 50 µm. (From Cao et al. 2007)
Printed on acid-free paper
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of Springer Nature.
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
This book is dedicated to the memory of John
W. Olney, M.D. (1932–2015), the father of
excitotoxicity.
Introduction
In the Introduction to the first edition of this book, the history behind the concept of
excitotoxicity was described, from John Olney’s initial descriptions of the phenom-
enon (Olney 1969, 1971; Olney et al. 1974) through subsequent studies identifying
the mechanisms by which excessive glutamate release presynaptically and by rever-
sal of astrocytic glutamate uptake results in postsynaptic neuronal death. A synaptic
mechanism was identified in 1983 (Rothman 1983), followed by identification of
calcium entry via the n-methyl-d-aspartate (NMDA) subtype of glutamate receptor
(MacDermott et al. 1986) and excessive calcium entry through the NMDA receptor-
operated cation channel as the mechanism by which neurons died (Choi 1987; Choi
et al. 1987). Early electron-microscopic studies of neuronal death from experimen-
tal cerebral ischemia (McGee-Russell et al. 1970), hypoglycemia (Auer et al. 1985a,
b; Kalimo et al. 1985) and status epilepticus (Griffiths et al. 1983; Ingvar et al.
1988) showed electron-dense, shrunken neurons with pyknotic nuclei containing
irregular chromatin clumps and dilated mitochondria, which the authors called
“dark-cell degeneration.” These were morphologically identical to the neurons that
Olney found following exposure to glutamate or its analogues. We now call these
neurons “necrotic,” to differentiate them from “apoptotic” neurons (Fujikawa 2000,
2002), both of which die from different programmed mechanisms.
As was emphasized in the First Edition, excitotoxicity underlies all acute neuro-
nal injuries, from cerebral ischemia, traumatic CNS injury, status epilepticus and
hypoglycemia (Fujikawa 2010). Excessive intracellular calcium activates the cyto-
solic calcium-dependent enzymes calpain I and neuronal nitric oxide synthase
(nNOS). Among other actions, calpain I is responsible for mitochondrial release of
cytochrome c, apoptosis-inducing factor (AIF) and endonuclease G (endoG), and
lysosomal release of cathepsins B and D and DNase II, all of which translocate to
the neuronal nucleus and participate in its destruction. nNOS uses l-arginine as a
substrate to form nitric oxide (NO), which reacts with superoxide (O−) to form the
2
toxic free radical peroxynitrite (ONOO−). Peroxynitrite, with other free radicals
generated by mitochondria exposed to the high intracellular calcium concentration
(Beal 1996), damages the plasma membrane, mitochondrial and lysosomal mem-
branes and causes double-stranded nuclear DNA cleavage.
vii
viii Introduction
The nuclear DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) pro-
duces poly(ADP-ribose) (PAR) polymers to repair DNA double-strand breaks, and
excess PAR polymers exit nuclei and translocate to mitochondria membranes,
where they, in addition to calpain I, trigger the exit of AIF from mitochondrial mem-
branes to neuronal nuclei (Andrabi et al. 2006; Yu et al. 2006), where it recruits
migration inhibitory factor (MIF), a PARP-1-dependent, AIF-associated nuclease
(PAAN) to the nucleus, where MIF cleaves single-stranded DNA into large-scale
DNA fragments (Wang et al. 2016). Ted and Valina Dawson in their chapter provide
details of the PARP-1 pathway.
Two new areas are covered in the current edition: the role of extra-synaptic
NMDA receptors in excitotoxic necrosis and a separate necrotic pathway uncovered
by inhibition of caspase-8 in vitro: necroptosis. The first topic was first described
14 years ago (Hardingham and Bading 2002) but was not covered in the first edition
of the book. Evidence was put forth that it is extra-synaptic NMDA receptors that
are responsible for excitotoxicity by inhibiting cAMP-response element binding
protein (CREB) activity and brain-derived neurotrophic factor (BDNF) gene expres-
sion, whereas synaptic NMDA receptors did the opposite and actually provides a
neuroprotective effect that is overwhelmed by extra-synaptic NMDA-receptor acti-
vation (Hardingham and Bading 2002). Dr. Michel Baudry in his chapter reinforces
this concept and gives evidence that calpain I (also known as μ-calpain) is activated
by synaptic NMDA receptors, whereas calpain II (also known as m-calpain) is acti-
vated by extra-synaptic NMDA receptors. On the other hand, Dr. Jun Chen’s group
in their chapter of the First Edition provided evidence that calpain I activation acti-
vates AIF by cleaving it in the mitochondrial membrane, which results in its exit
from the mitochondrial membrane and translocation to neuronal nuclei; they have
updated their chapter for this edition.
In recent years another necrotic pathway has been described, which has been
dubbed “necroptosis” (Degterev et al. 2005). In cell culture, after inhibition of cas-
pases with a broad-spectrum caspase inhibitor (z-VAD.fmk), investigators have
found that cells subjected to a lethal insult had a necrotic morphology, and that the
pathway involved three key proteins: receptor-interacting protein 1 and 3 (RIP1 and
RIP3; also known as RIP1 kinase and RIP3 kinase) and mixed lineage kinase
domain-like protein (MLKL) (Degterev et al. 2008; Sun et al. 2012). This pathway
has been shown to occur in vivo in cerebral ischemia (Yin et al. 2015; Miao et al.
2015; Xu et al. 2016; Vieira et al. 2014) and traumatic brain injury (Liu et al. 2016).
Drs. Vieira and Carvalho in their chapter provide evidence that oxygen-glucose
deprivation (OGD) of hippocampal neurons in vitro and transient global cerebral
ischemia (TGCI) in vivo up-regulate RIP3 and induce necroptotic neuronal necro-
sis. Overexpression of RIP3 worsened and knock-down of RIP3 reduced necropto-
sis in OGD. Dr. Tao in his chapter shows that the necroptotic pathway is activated
following traumatic brain injury and that Necrostatin-1 (Nec-1), a RIP1 inhibitor, is
neuroprotective.
If both the excitotoxic and necroptotic pathways are activated following acute
neuronal injury, do each contribute separately to neuronal necrosis, producing an
additive effect, or are there interactions between the two, and if so, what are they
Introduction ix
and what is the outcome? The non-competitive NMDA-receptor antagonist MK-801
and the nNOS inhibitor 7-nitroindazole both reduced RIP3 nitrosylation and neuro-
nal necrosis in the hippocampal CA1 region following TGCI (Miao et al. 2015). On
the other hand, cathepsin B release from lysosomes, which occurs in excitotoxicity,
was reduced by Nec-1 following TGCI (Yin et al. 2015). So there appears to be
cross-talk between the two programmed necrotic pathways. Further interactions
between the two pathways and their consequences will undoubtedly be elucidated
in future research.
Department of Neurology Denson G. Fujikawa
VA Greater Los Angeles Healthcare System
North Hills, CA, USA
Department of Neurology and Brain Research Institute
David Geffen School of Medicine,
University of California at Los Angeles
Los Angeles, CA, USA
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Contents
Part I G eneral Considerations
1 Excitotoxic Programmed Cell Death Involves
Caspase-Independent Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Ted M. Dawson and Valina L. Dawson
2 To Survive or to Die: How Neurons Deal with it . . . . . . . . . . . . . . . . . 19
Yubin Wang, Xiaoning Bi, and Michel Baudry
Part II T raumatic Brain Injury
3 Oxidative Damage Mechanisms in Traumatic
Brain Injury and Antioxidant Neuroprotective Approaches . . . . . . . 39
Edward D. Hall, Indrapal N. Singh, and John E. Cebak
4 Mitochondrial Damage in Traumatic CNS Injury. . . . . . . . . . . . . . . . 63
W. Brad Hubbard, Laurie M. Davis, and Patrick G. Sullivan
5 Neuroprotective Agents Target Molecular Mechanisms
of Programmed Cell Death After Traumatic Brain Injury . . . . . . . . . 83
Lu-Yang Tao
Part III Focal Cerebral Ischemia
6 Involvement of Apoptosis-Inducing Factor (AIF)
in Neuronal Cell Death Following Cerebral Ischemia . . . . . . . . . . . . . 103
Nikolaus Plesnila and Carsten Culmsee
Part IV Transient Global Cerebral Ischemia
7 Apoptosis-Inducing Factor Translocation
to Nuclei After Transient Global Ischemia . . . . . . . . . . . . . . . . . . . . . . 117
Yang Sun, Tuo Yang, Jessica Zhang, Armando P. Signore,
Guodong Cao, Jun Chen, and Feng Zhang
xi