Mitochondrial Dysfunction and
Nicotinamide Dinucleotide Catabolism as
Mechanisms of Cell Death and Promising
Targets for Neuroprotection
Tibor Kristian,1*Irina Balan,1Rosemary Schuh,2,3and Mitch Onken1
1Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research,
School of Medicine, University of Maryland Baltimore, Baltimore, Maryland
2Department of Neurology, School of Medicine, University of Maryland Baltimore, Baltimore, Maryland
3Research Services, Maryland VA Healthcare System, Baltimore, Maryland
Both acute and chronic neurodegenerative diseases
are frequently associated with mitochondrial dysfunc-
tion as an essential component of mechanisms leading
to brain damage. Although loss of mitochondrial func-
tions resulting from prolonged activation of the mito-
chondrial permeability transition (MPT) pore has been
shown to play a significant role in perturbation of cellu-
lar bioenergetics and in cell death, the detailed mecha-
nisms are still elusive. Enzymatic reactions linked to
glycolysis, the tricarboxylic acid cycle, and mitochon-
drial respiration are dependent on the reduced or oxi-
dized form of nicotinamide dinucleotide [NAD(H)] as a
cofactor. Loss of mitochondrial NAD1resulting from
MPT pore opening, although transient, allows detrimen-
tal depletion of mitochondrial and cellular NAD1pools
by activated NAD1glycohydrolases. Poly(ADP-ribose)
polymerase (PARP) is considered to be a major NAD1
degrading enzyme, particularly under conditions of
extensive DNA damage. We propose that CD38, a main
cellular NAD1level regulator, can significantly contrib-
ute to NAD1catabolism. We discuss NAD1catabolic
and NAD1synthesis pathways and their role in different
strategies to prevent cellular NAD1degradation in
brain, particularly following an ischemic insult. These
therapeutic approaches are based on utilizing endoge-
nous intermediates of NAD1metabolism that feed into
the NAD1salvage pathway and also inhibit CD38
C 2011 Wiley-Liss, Inc.
Key words: NAD catabolism; CD38; mitochondria; cell
death; acute neurodegenerative disease
The mechanisms of acute and chronic neurodege-
nerative diseases are not understood in detail. However,
several lines of evidence suggest the involvement of
mitochondrial dysfunction and bioenergetic failure (for
review see Fiskum, 2000, 2004; Kristal et al., 2004;
Kristian, 2004; Beal, 2005; Sullivan et al., 2005; Stav-
rovskaya and Kristal, 2005; Yang et al., 2008; Dumont
et al., 2010; Morais and De Strooper, 2010). Although
the significance of the mitochondrial role in cell death
is well established, the underlying mechanisms remain
unclear. One of the extensively studied aspects of mito-
chondrial dysfunction is a phenomenon called the mito-
chondrial permeability transition (MPT). The MPT is char-
acterized by opening of an inner membrane channel
permeable to solutes with molecular masses of approxi-
mately 1,500 Da or lower (for review see Zoratti and
Szabo, 1995; Bernardi, 1999; Bernardi et al., 2001;
Crompton et al., 2002; Halestrap et al., 2002). A pro-
longed MPT results not only in dissipation of the mi-
tochondrial electrochemical hydrogen ion gradient and
swelling of mitochondria but also depletion of pyridine
nucleotides from the matrix (Di Lisa et al., 2001; Kris-
tian and Fiskum, 2004). Loss of mitochondrial nicotina-
mide adenine dinucleotide (NAD1) is one of the most
detrimental outcomes of MPT. This is because NAD1
is an essential cofactor in most enzymatic reactions sup-
porting fundamental mitochondrial functions, including
oxidative phosphorylation and enzymatic reactions of
the tricarboxylic acid cycle (TCA cycle; Fig. 1). Thus
Contract grant sponsor: NIH; Contract grant number: R21 NS0585556
(to T.K.); Contract grant number: T32 GM075776 (to I.B.); Contract
grant sponsor: CDA-02 Biomedical R&D grant and Rehabilitation R&D
REAP from the VA Research Service (to R.S.).
*Correspondence to: Tibor Kristian, Department of Anesthesiology, Uni-
versity of Maryland Baltimore, 685 W. Baltimore Street, MSTF 534, Bal-
timore, MD 21201. E-mail: email@example.com
Received 9 December 2010; Revised 7 January 2011; Accepted 17
Published online 12 April 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/jnr.22626
Journal of Neuroscience Research 89:1946–1955 (2011)
' 2011 Wiley-Liss, Inc.
when NAD1is lost, respiration is inhibited, even in
the presence of sufficient substrate, and the mitochon-
dria become incapable of ATP synthesis. In fact, they
actively consume ATP by reversing the ATP synthase
in a futile attempt to maintain the electrochemical gra-
dient across the inner membrane. This results in a loss
of cellular metabolic integrity and can potentially lead
to cell death.
MPT IN NEUROLOGICAL DISEASES
It is commonly accepted that the activation of
MPT results from the interaction and conformational
changes of several mitochondrial proteins (for review see
Crompton, 2003). This process is catalyzed by cyclophi-
lin D (cypD), a matrix peptidyl-propyl cis-trans isomer-
ase (PPIase). The activity of this enzyme is inhibited by
the immunosuppressant compound cyclosporin A (CsA;
Crompton et al., 1988; Halestrap and Davidson, 1990;
The significant role of cypD in controlling MPT
and in the function of MPT in brain pathology was
examined by using transgenic mice in which the cypD-
encoding gene had been eliminated (Basso et al., 2005;
Baines et al., 2005; Nakagawa et al., 2005). Mitochon-
dria from cypD null mice displayed normal respiratory
functions but had a striking desensitization to Ca21-
induced damage (Basso et al., 2005; Nakagawa et al.,
2005). However, the PPI activity of cypD is not neces-
sarily required for MPT induction, since the MPT pore
opening can be triggered by calcium overload in mito-
chondria isolated from cypD null mice (Basso et al.,
An important role for MPT in mechanisms associ-
ated with ischemic brain damage is clearly supported by
the dramatic reduction in infarct volume following focal
ischemia in cypD knockout animals (Schinzel et al.,
2005). Furthermore, cypD deficiency improved mito-
chondrial and synaptic function by increasing mitochon-
drial resistance to amyloid-b protein toxicity in trans-
genic Alzheimer’s disease-type mice (Du et al., 2009)
and protected axons in experimental autoimmune en-
cephalomyelitis, an animal model of multiple sclerosis
(Forte et al., 2007). However, absence of cypD in the
Huntington’s disease R6/2 transgenic mouse model did
not show any protective effect regardless of a significant
increase in calcium uptake capacity by brain mitochon-
dria in these animals (Perry et al., 2010).
Recently, we demonstrated that there is variability
in cypD expression in numerous brain regions and
Fig. 1. Diagram illustrating mitochondrial permeability transition
(MPT)-induced loss of matrix NAD1as a mechanism of inhibition of
mitochondrial metabolic and respiratory functions. A: NADH donates
electrons to respiratory chain complexes (RC) that generate a hydro-
gen ion gradient across the inner mitochondrial membrane. The
NAD1is reduced back to NADH by intramitochondrial dehydroge-
nases and is an essential cofactor for enzymatic reactions within the tri-
carboxylic acid cycle (TCA). The energy stored in the hydrogen ion
gradient drives the ATP-synthase that generates ATP from ADP and
phosphate (Pi). B: Opening of the MPT leads to translocation of ma-
trix NAD1into the cytosol, where it can be hydrolyzed by NAD1
glycohydrolases (PARP-1, CD38, and SIRT). The products of NAD1
hydrolysis are ADP-ribose derivatives plus nicotinamide (Nam).
Marked reduction in intramitochondrial NAD(H) levels leads to inhi-
bition of respiratory functions and TCA cycle reactions. Furthermore,
because of the MPT pore opening, the mitochondria become depolar-
ized, reversing the ATP synthase. Although the MPT pore closes
before mitochondria lose their morphological integrity, a significant
loss of NAD1will prevent normal oxidative phosphorylation.
Role of NAD Degradation in Neurological Disease 1947
Journal of Neuroscience Research
between different cell types in normal adult mouse brain
(Hazelton et al., 2009). Interestingly, high levels of cypD
immunoreactivity were observed predominantly in a
subpopulation of GABAergic interneurons. In addition
to neurons, nonneuronal cells demonstrated positive im-
munoreactivity to cypD (see also Naga and Geddes,
2007). These were mainly subpopulations of astrocytes
and NG2 cells (Hazelton et al., 2009). These data from
our laboratory and others suggest that the sensitivity of
mitochondria to MPT-inducing conditions can vary
among cell types and brain regions. Therefore, it is im-
portant to recognize and examine the mechanisms of
mitochondrial dysfunction as they relate to specific cell
types. To date, there is very little information regarding
identification of cell-type specific MPT-related mito-
chondrial pathology in the brain.
LOSS OF MITOCHONDRIAL NAD1AS A
CONSEQUENCE OF PATHOLOGIC MPT
In addition to swelling, MPT also leads to deple-
tionof the matrixpyridine
NADP; Di Lisa et al., 2001; Kristian and Fiskum,
2004). Interestingly, the MPT pore can be activated
in isolated mitochondria transiently by weaker or brief
stimuli without irreversible damage to their membranes
(Crompton et al., 1987; Petronilli et al., 1994; Shal-
buyeva et al., 2006). Similar transient MPT activation
and cristae remodeling were observed in neurons
exposed to short glutamate treatments (Shalbuyeva
et al., 2006). Mitochondria can release NAD1via the
large-conductance MPT pore without damage to inner
and outer membranes. Thus, significant loss of matrix
mitochondrial respiration but without irreversible dam-
age to the respiratory complexes or mitochondrial
CATABOLISM OF CELLULAR AND
NAD1is an important cofactor involved in mul-
tiple metabolic reactions (Brennan et al., 2006). NAD1
and NADH have central roles in cellular metabolism
and energy production as electron-accepting and elec-
tron-donating cofactors. Furthermore, there are several
NAD1-dependent enzymes that use NAD1as the sub-
strate for their functions, including the histone deacety-
lase sirtuin 1 (SIRT1), poly(ADP-ribose) polymerase 1
(PARP1), and ADP-ribosyl cyclase (CD38; Belenky
et al., 2007). Therefore, maintenance of normal cellular
NAD1levels is essential for tissue bioenergetic metabo-
lism and several cell functions. A prominent role for
NAD1catabolism in cell death mechanisms is sup-
ported by the observation that, after excitotoxic insult
or in in vivo models of brain ischemia, epilepsy, and
Alzheimer’s disease, a significant decrease in total cellu-
levels occurs prior to neuronal death
(Greene and Greenamyre, 1996; Endres et al., 1997;
Mattson, 2004; Liu et al., 2008). It has been proposed
that uncontrolled PARP1 activation might deplete in-
tracellular NAD1and consequently ATP, leading to
mitochondrial depolarization and cell death (Pieper
et al., 1999; Chiarugi and Moskowitz, 2002; for review
see Szabo and Dawson, 1998). However, because the
major fraction of NAD1is compartmentalized within
the mitochondrial matrix, the significant reduction of
cellular NAD1content must be preceded by opening
of the MPT pore and translocation of NAD1from the
mitochondrial matrix into the cytosol, where it can be
degraded by activated NAD1glycohydrolases (see Fig.
1). This notion is supported by data presented by
Alano et al. (2004, 2010) showing that NAD1deple-
tion and MPT are sequential and necessary steps in
reports showing localization of PARP in mitochondria
that could contribute to mitochondrial NAD1deple-
tion in the absence of MPT (Lai et al., 2008).
Recently, it was suggested that not only PARP1 activ-
ity contributes to NAD1catabolism but also the activ-
ity of NAD1-dependent histone deacetylases, particu-
larly SIRT1. It was proposed that these enzymes can
compromise neuronal survival because of utilization of
NAD1as their substrate (Liu et al., 2009). Although it
has been recognized that CD38 is a major NAD1gly-
cohydrolase and has a significant role in the regulation
of cellular NAD1levels (Iqbal et al., 2006; Aksoy
et al., 2006; Young et al., 2006), no systematic studies
have examined the contribution of this enzyme to
NAD1catabolism in neurodegenerative diseases.
CD38 IS A MAJOR NAD1GLYCOHYDROLASE
CD38 is an ectoenzyme that uses NAD1to gener-
ate cyclic ADP-ribose (cADPR) or ADP-ribose, and
nicotinamide (Nam). CD38 can also use NADP to gen-
erate nicotinic acid dinucleotide phosphate (NAADP;
for review see Malavasi et al., 2008). These products
then act as potent second messengers that release calcium
from intracellular stores (Galione, 1993). CD38 is highly
expressed in the brain as well as in a variety of blood
cells, including T cells, B cells, monocytes, and platelets.
Although the enzyme is located mainly in the cellular
plasma membrane, immunogold staining also revealed
CD38 localization in the outer mitochondrial mem-
brane, nuclear envelop, and rough endoplasmic reticu-
lum (ER) membranes (Yamada et al., 1997). The intra-
cellular localization of CD38 was confirmed by detecting
NADase activity in mitochondrial, microsomal, and nu-
clear membrane fractions (Aksoy et al., 2006). There-
fore, it is most likely that cADPR generated by plasma
membrane CD38 may be released in the extracellular
space and/or transferred in the intracellular space (Franco
et al., 1996). Alternatively, cADPR synthesized inside
the cells may function as a modulator to control the in-
tracellular Ca21homeostasis via ryanodine receptors
This enzyme was originally identified as a human
lymphocytic surface antigen whose activity is required for
1948Kristian et al.
Journal of Neuroscience Research
proper lymphocyte chemotaxis (Reinherz et al., 1980).
Expression of CD38 in the brain can be found in specific
populations of neurons, as well as astrocytes and microglia
(Yamada et al., 1997; Mayo et al., 2008). Immunohisto-
chemistry showed labeling of the plasma membrane and
cell organelles such as ER, mitochondria, and nuclear en-
velope. Interestingly, immunolabeling was more intense
in astrocytes compared with neurons (Yamada et al.,
1997). Little is known about regulation of ADP-ribosyl
cyclase or CD38 expression in neuronal cells. Astrocytes
overexpress CD38 when cocultured with neurons as a
result of glutamate released from activated neurons (Bruz-
zone et al., 2001). Formation of cADPR is enhanced by
nitric oxide (NO) and cyclic GMP (cGMP; Galione,
1993). NO and cGMP are formed in response to neuro-
transmitters, so the cADPR level may be indirectly con-
trolled by receptors through a cascade that culminates in
activation of cytosolic ADP-ribosyl cyclase by cGMP-de-
pendent protein phosphorylation (Clementi et al., 1996;
Willmott et al., 1996). These findings are also supported
by data showing protein kinase C (PKC)- and protein ki-
nase A (PKA)-dependent activation of CD38 in microglia
(Franco et al., 2006).
We detected NAD1glycohydrolase activity in iso-
lated synaptosomes and also in intact brain mitochondria
(Balan et al., 2009), confirming localization of CD38
also in outer mitochondrial membranes (see also Boyer
et al., 1993; Ziegler, 2000; Di Lisa et al., 2001). Interest-
ingly, the NAD1glycohydrolase activity appeared to be
much higher in nonsynaptic mitochondria compared
with mitochondria isolated from synaptosomes (Mas-
moudi et al., 1988). Insofar as nonsynaptic mitochondria
represent mitochondria from both neurons and non-
neuronal brain cells (e.g., astrocytes, oligodendroglia and
microglia), this finding is in agreement with the report
that astrocytes and microglia are the main CD38-
expressing cells in brain (Salmina et al., 2008). Taken to-
gether, these data suggest that NAD1depletion can
occur more rapidly in astrocytes following ischemic
insult, compromising the ability of astrocytes to support
neuronal functions. Interestingly, the NAD1catabolic
activity is higher in brain regions that are vulnerable to
ischemic insult (Fig. 2). Furthermore, the CD38 NAD1
glycohydrolase activity is significantly increased in post-
ischemic tissue, and the immunohistochemistry shows
overexpression of this enzyme preferentially in neuroglial
cells (Fig. 2). Thus, the data suggest that the increased
CD38 NADase activity is at least partially the result of
higher expression of this enzyme in postischemic tissue.
Only a very few studies have examined the mecha-
nisms of CD38 activation. In murine mesanglial cells or
cardiomyocytes, the activation of CD38 by angiotensin
(ANG) II involves ANG II type 1 receptor, phospho-
inositide 3-kinase, protein tyrosine kinase, and phospho-
lipase C-g1 (Kim et al., 2008). In astrocytes the CD38
activation by b-adrenergic stimulation is transduced via
G proteins (Hotta et al., 2000). Finally, in microglia, li-
popolysaccharide induces phosphorylation of CD38,
mediated by multiple protein kinases (PKC and PKA),
resulting in significant enhancement of CD38 ADPR
cyclase activity (Franco et al., 2006).
NAD1METABOLISM: GLIA AND NEURON
The distribution of NAD1in cells and the loca-
tions of NAD1synthesis have recently received new
consideration. NAD1can be generated in cells by de
novo synthesis from tryptophan, or it can be resynthe-
sized from nicotinamide (Nam) via a salvage pathway
(Fig. 3). Recently, a third vitamin precursor of NAD1
was discovered: nicotinamide riboside (NR) that is taken
up by cells and phosphorylated to nicotinamide mono-
phosphate (NMN) by NR kinases (Nrk1 and Nrk2; Bie-
ganowski and Brenner, 2004; Belenky et al., 2009).
NMN is then adenylated to form NAD1by nicotina-
mide nucleotide adenylyltransferase (Nmnat; Fig. 3; for
review see Belenky et al., 2007). Nmnat has three iso-
forms; Nmnat-1 is localized to nuclei (Berger et al.,
2005), Nmnat-2 is in Golgi, and Nmnat-3 is present in
mitochondria (Berger et al., 2005). Thus, it can be
inferred that Nmnat activity is required to complete all
salvage and de novo pathways of NAD1biosynthesis
and that mammalian cell NAD1is compartmentalized.
Cellular fractionation studies have shown that mitochon-
dria maintain relatively high NAD1concentrations and
that mitochondrial NAD1does not readily leak across
the inner membrane (Di Lisa and Ziegler, 2001). In
contrast, the majority of cytosolic NAD1is made within
the nucleus of cells and then redistributed to the cytosol
by passive diffusion through nuclear pores (Berger et al.,
2005). The efficiency of de novo and salvage pathways
is greater in glia compared with neurons (Ruddick et al.,
2006). Downstream intermediates of NAD1biosynthesis
and NAD1itself could provide a potent delay in neuro-
nal Wallerian degeneration assays (Araki et al., 2004;
Sasaki et al., 2006). Wallerian degeneration refers to the
ordered process of axonal degeneration and occurs when
the axon is severed from the cell body (Glass et al.,
1993). Addition of nicotinic acid (Na) or nicotinamide
(Nam) to these neuronal explants failed to delay Waller-
ian degeneration unless the salvage pathway enzymes
Nampt or Nmnat were overexpressed. Furthermore,
Nampt1, which initiates NAD1biosynthesis by using
Nam, is transcriptionally induced after sciatic nerve
transection in mice, in which glia are present. Addition-
(Nampt and Nnmat) are located almost exclusively in
glial cells (Kohler et al., 1988; but see Zhang et al.,
2010). These studies clearly revealed the rate-limiting
nature of the Nam-Nampt pathway in controlling
NAD1biosynthesis specifically in neurons (Sasaki et al.,
2006). Because the NAD1salvage pathway enzymes are
expressed mainly in glia, they may play important roles
in both synthesis of NAD1from Na or Nam and deliv-
ery of NAD1to neurons in vivo. However, neurons
preferentially use NR as a precursor to maintain intracel-
lular NAD1levels (Sasaki et al., 2006).
Role of NAD Degradation in Neurological Disease1949
Journal of Neuroscience Research
Fig. 2. Ischemia-induced changes in tissue NAD(H) levels and CD38
NADase activity and immunoreactivity. Brains from sham-operated
animals or animals subjected to 10 min of global cerebral ischemia
and 24 hr of reperfusion were used to determine the tissue NAD(H)
levels in different brain regions. The parietal cortex; striatum; and
CA1, CA3, and DG subregions of the hippocampus were dissected.
After perchloric acid extraction, the NAD(H) content was deter-
mined (A). Similarly, the tissues of corresponding brain regions from
sham or postischemic animals were homogenized, and after a low-
speed spin the CD38 activity in the supernatant was determined (B).
C shows CD38 immunoreactivity in control and postischemic tissue
(left: CA1 subregion; right: dentate gyrus of the hippocampus).#P <
0.05, *P < 0.01 compared with the corresponding sham group (n 5
6). Scale bar 5 100 lm.
1950Kristian et al.
Journal of Neuroscience Research
OVERACTIVATION OF CD38 CAN PLAY A
SIGNIFICANT ROLE IN ACUTE AND
Activation of CD38 can lead to rapid and almost
complete tissue NAD1depletion (Balan et al., 2010).
The importance of this enzyme in controlling the cellu-
lar NAD1pools was confirmed in CD38 null mice that
showed 10–20-fold higher tissue NAD1levels compared
with wild-type animals (Aksoy et al., 2006). As men-
tioned above, CD38 plays an important role in the
immune system response because of its high level of
expression in dendritic cells and regulation of their acti-
vation. Both astrocytes and microglia show abundant
CD38 expression, so, in addition to NAD1glycohydro-
lase activity, this enzyme plays an important role in
astrocyte and microglial activation (Franco et al., 2006;
Mayo et al., 2008; Kou et al., 2009). Microglia, the resi-
dent immune cells of the CNS, enter the CNS during
the early postnatal period (Kershman, 1939). After enter-
ing the CNS, these cells disseminate through the paren-
chyma and transform into resting microglia.
After acute brain injury, microglia become acti-
vated (for review see Heneka et al., 2010). CD38 partic-
ipates in microglial activation that gradually transforms
these cells into motile, secretory, and potentially cyto-
toxic phagocytes (Hoffmann et al., 2003). Thus, overac-
tivation of CD38 not only can lead to potentially cata-
strophic depletion of cellular NAD1pools but also pro-
motes pathologic activation of neuroglia that can
culminate in a chronic inflammatory response and aggra-
vation of brain tissue damage.
NAD1PRECURSORS AS THERAPEUTIC
COMPOUNDS FOR NEURODEGENERATION
Several strategies can be utilized to inhibit the
reduction in tissue NAD1levels during pathologic con-
ditions. Insofar as the majority of cellular NAD1is
localized in mitochondria and opening of the MPT pore
leads to release of NAD1from the matrix to the cytosol,
MPT inhibition can prevent mitochondrial and conse-
quently cellular NAD1depletion. However, even tran-
sient opening of the MPT pore leading to NAD1leak
from mitochondria can have adverse effects on mito-
chondrial functions, particularly respiration. It has been
shown that ischemia diminishes brain mitochondrial res-
piration (Almeida et al., 1995; Kuroda et al., 1996; Can-
evari et al., 1997; Anderson et al., 1999). Interestingly,
inhibition of mitochondrial respiration following tran-
sient ischemia was observed at the end of the ischemic
period, which was followed by partial recovery and de-
velopment of secondary failure (Kuroda et al., 1996;
Kristian et al., 1998). This reduction in mitochondrial
respiratory capacity may be the result of transient matrix
NAD1depletion. Experiments in our laboratory support
the concept that ischemia/reperfusion can result in
extensive catabolism of tissue NAD1(Balan et al., 2010)
that may be at least partially responsible for mitochon-
drial respiratory inhibition. We assessed the NAD1levels
in brain subregions following transient forebrain ischemia
at 24 hr of recovery before an imminent cell death
occurred. In all vulnerable areas, the tissue NAD(H) lev-
els were significantly reduced (Fig. 2). However, mito-
chondrial respiratory dysfunction can also be due to py-
(Martin et al., 2005; Vereczki et al., 2006; Richards
et al., 2006).
Another approach to maintaining cellular NAD1
levels following an ischemic insult is administration of
NAD1precursors to facilitate NAD1generation by the
salvage pathway or to reduce ROS-induced DNA dam-
age that results in extensive PARP1 activity and NAD1
depletion. It was shown that administration of nicotina-
Fig. 3. Schematic diagram illustrating NAD1biosynthesis and catab-
olism in neurons and glia. Two metabolic pathways can generate
NAD1. The de novo pathway synthesizes NAD1in eight steps from
tryptophan (Trp). The salvage pathway utilizes nicotinamide (Nam),
a product of NAD1glycohydrolases (CD38, PARP-1, sirtuins). Nam
is converted to nicotinamide monophosphate (NMN) by nicotina-
mide phosphoribosyltransferase (Nampt). NMN is then converted to
NAD1by nicotinamide nucleotide adenylyltransferase (Nmnat). The
salvage pathway can also utilize nicotinamide riboside (NR) that is
converted to NMN by NR kinases (Nrk1, -2). Because Nmnat is
preferentially localized in glia, Nam administration supports NAD1
generation mainly in nonneuronal cells, and the neurons depend on
NAD1supplied by glia. NR can directly support NAD1biosynthesis
Role of NAD Degradation in Neurological Disease1951
Journal of Neuroscience Research
mide (Nam) increases tissue NAD1levels (Klaidman
et al., 1996; Yang et al., 2002; Sadanaga-Akiyoshi et al.,
2003; for review see Bogan and Brenner, 2008). Nam
rapidly penetrates the blood–brain barrier (Spector and
Kelley, 1979) and was demonstrated to improve ener-
getics following ischemia or oxidative stress (Ayoub
et al., 1999; Mokudai et al., 2000; Ayoub and Maynard,
2002; Sakakibara et al., 2002; Yang et al., 2002). The
mechanisms of Nam’s protective effect are still elusive;
however, it was reported to exert a number of pharma-
cological effects, including prevention of ATP depletion
(Klaidman et al., 1996, 2003; Yang et al., 2002), inhibi-
tion of PARP-1 (Klaidman et al., 1996; Szabo and Daw-
son, 1998; Yang et al., 2002), lipid peroxidation
(Mukherjee et al., 1997; Klaidman et al., 2001; Chong
et al., 2002), antiinflammatory activity (Ungerstedt et al.,
2003), and prevention of apoptosis (Klaidman et al.,
1996; Mukherjee et al., 1997). Thus, Nam crosses the
blood–brain barrier and is converted to NAD1in the
brain. At present, however, it is not known whether
Nam is an NAD1precursor in neuronal or nonneuronal
cells (Spector and Johanson, 2007).
Nicotinamide mononucleotide (NMN) and the
recently discovered nicotinamine riboside (NR) are al-
ternative precursors for NAD1biosynthesis that are uti-
lized by the NAD1salvage pathway. Interestingly,
although NMN-utilizing enzymes are intracellular, the
NMN-generating enzyme (Nampt) is also found in sera
and is being considered as a diagnostic biomarker for
inflammation (Luk et al., 2008). NMN application leads
to increases in cellular NAD1levels by a one-step enzy-
matic reaction in which NMN is converted to NAD1
by Nmnat (Belenky et al., 2007). Furthermore, NMN
has been shown to delay Wallerian degeneration (Sasaki
et al., 2006). Measurement of NMN content in subcel-
lular fractions revealed that the nucleotide is highly
enriched in mitochondria, suggesting intramitochondrial
NAD1synthesis (Formentini et al., 2009). NMN may
also inhibit CD38 NAD1glycohydrolase activity (Snell
et al., 1984; Balan et al., 2010), reducing NAD1and
ATP depletion in cells undergoing PARP-1 hyperactiva-
tion and significantly delaying cell death (Formentini
et al., 2009). However, it is unclear how NMN enters
cells and whether it is transported as a nucleoside (NR;
Belenky et al., 2007). Regardless, all the indications are
that NMN has great therapeutic potential (Araki et al.,
2004; Sasaki et al., 2006). Our data show a remarkable
protective effect of NMN against CD38-dependent
NAD1degradation (Balan et al., 2010). Given the high
concentrations of the enzyme Nampt and NMN in
plasma, the Nam protective mechanisms could be via
NMN, in that administered Nam or at least part of the
Nam can be converted to NMN in the blood.
It is widely accepted that mitochondria play a cen-
tral role in many neurological diseases. However, the
mechanisms and cell-type-specific contribution of MPT-
dependent mitochondrial damage to brain damage is
unknown. Apart from the possibility that glial and neu-
ronal mitochondria have different sensitivity to calcium-
induced damage, there are cell-type-specific differences
in NAD1levels, NAD1biosynthesis, and NAD1catab-
olism under pathologic conditions. In addition to
PARP1 activation, cellular NAD1can be profoundly
depleted by activation of the CD38 enzyme. Because
CD38 is also engaged in regulation of the immune
response in the brain and can affect the inflammation
triggered by pathologic conditions, cell-type-specific tar-
geting of CD38 inhibition can offer new therapeutic tar-
gets for the treatment of acute or chronic neurodegener-
Aksoy P, White TA, Thompson M, Chini EN. 2006. Regulation of in-
tracellular levels of NAD: a novel role for CD38. Biochem Biophys
Res Commun 345:1386–1392.
Alano CC, Ying W, Swanson RA. 2004. Poly(ADP-ribose) polymerase-
1-mediated cell death in astrocytes requires NAD1depletion and mito-
chondrial permeability transition. J Biol Chem 279:18895–18902.
Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson
RA. 2010. NAD1depletion is necessary and sufficient for poly(ADP-
ribose) polymerase-1-mediated neuronal death. J Neurosci 30:2967–
Almeida A, Allen KL, Bates TE, Clark JB. 1995. Effect of reperfusion
following cerebral ischaemia on the activity of the mitochondrial respi-
ratory chain in the gerbil brain. J Neurochem 65:1698–1703.
Anderson RE, Tan WK, Meyer FB. 1999. Brain acidosis, cerebral blood
flow, capillary bed density, and mitochondrial function in the ischemic
penumbra. J Stroke Cerebrovasc Dis 8:368–379.
Araki T, Sasaki Y, Milbrandt J. 2004. Increased nuclear NAD biosynthe-
sis and SIRT1 activation prevent axonal degeneration. Science 305:
Ayoub IA, Maynard KI. 2002. Therapeutic window for nicotinamide fol-
lowing transient focal cerebral ischemia. Neuroreport 13:213–216.
Ayoub IA, Lee EJ, Ogilvy CS, Beal MF, Maynard KI. 1999. Nicotina-
mide reduces infarction up to two hours after the onset of permanent
focal cerebral ischemia in Wistar rats. Neurosci Lett 259:21–24.
Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton
MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J,
Molkentin JD. 2005. Loss of cyclophilin D reveals a critical role for mi-
tochondrial permeability transition in cell death. Nature 434:658–662.
Balan IS, Fiskum G, Kristian T. 2009. NAD(H) levels and NAD1glyco-
hydrolase activity in rat brain sub-regions. Soc Neurosci Abstr148.1.
Balan IS, Fiskum G, Kristian T. 2010. Visualization and quantification of
NAD(H) in brain sections by a novel histo-enzymatic nitrotetrazolium
blue staining technique. Brain Res 1316C:112–119.
Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P. 2005.
Properties of the permeability transition pore in mitochondria devoid of
cyclophilin D. J Biol Chem 280:18558–18561.
Beal MF. 2005. Mitochondria take center stage in aging and neurodegen-
eration. Ann Neurol 58:495–505.
Belenky P, Bogan KL, Brenner C. 2007. NAD1metabolism in health
and disease. Trends Biochem Sci 32:12–19.
Belenky P, Christensen KC, Gazzaniga F, Pletnev AA, Brenner C. 2009.
Nicotinamide riboside and nicotinic acid riboside salvage in fungi and
mammals. Quantitative basis for Urh1 and purine nucleoside phospho-
rylase function in NAD1metabolism. J Biol Chem 284:158–164.
Berger F, Lau C, Dahlmann M, Ziegler M. 2005. Subcellular compart-
mentation and differential catalytic properties of the three human nico-
1952 Kristian et al.
Journal of Neuroscience Research
tinamide mononucleotide adenylyltransferase isoforms. J Biol Chem
Bernardi P. 1992. Modulation of the mitochondrial cyclosporin A-sensi-
tive permeability transition pore by the proton electrochemical gradient.
Evidence that the pore can be opened by membrane depolarization.
J Biol Chem 267:8834–8839.
Bernardi P. 1999. Mitochondrial transport of cations: channels, exchang-
ers, and permeability transition. Physiol Rev 79:1127–1155.
Bernardi P, Petronilli V, Di Lisa F, Forte M. 2001. A mitochondrial per-
spective on cell death. Trends Biochem Sci 26:112–117.
Bieganowski P, Brenner C. 2004. Discoveries of nicotinamide riboside as
a nutrient and conserved NRK genes establish a Preiss-Handler inde-
pendent route to NAD1in fungi and humans. Cell 117:495–502.
Bogan KL, Brenner C. 2008. Nicotinic acid, nicotinamide, and nicotina-
mide riboside: a molecular evaluation of NAD1precursor vitamins in
human nutrition. Annu Rev Nutr 28:115–130.
Boyer CS, Moore GA, Moldeus P. 1993. Submitochondrial localization
of the NAD1glycohydrolase. Implications for the role of pyridine nu-
cleotide hydrolysis in mitochondrial calcium fluxes. J Biol Chem
Brennan AM, Connor JA, Shuttleworth CW. 2006. NAD(P)H fluores-
cence transients after synaptic activity in brain slices: predominant role
of mitochondrial function. J Cereb Blood Flow Metab 26:1389–1406.
Bruzzone S, Franco L, Guida L, Zocchi E, Contini P, Bisso A, Usai C,
De Flora A. 2001. A self-restricted CD38-connexin 43 cross-talk affects
NAD1and cyclic ADP-ribose metabolism and regulates intracellular
calcium in 3T3 fibroblasts. J Biol Chem 276:48300–48308.
Canevari L, Kuroda S, Bates TE, Clark JB, Siesjo BK. 1997. Activity of
mitochondrial respiratory chain enzymes after transient focal ischemia in
the rat. J Cereb Blood Flow Metab 17:1166–1169.
Chiarugi A, Moskowitz MA. 2002. Cell biology. PARP-1—a perpetrator
of apoptotic cell death? Science 297:200–201.
Chong ZZ, Lin SH, Maiese K. 2002. Nicotinamide modulates mito-
chondrial membrane potential and cysteine protease activity during cer-
ebral vascular endothelial cell injury. J Vasc Res 39:131–147.
Clementi E, Riccio M, Sciorati C, Nistico G, Meldolesi J. 1996. The
type 2 ryanodine receptor of neurosecretory PC12 cells is activated by
cyclic ADP-ribose. Role of the nitric oxide/cGMP pathway. J Biol
Crompton M. 2003. On the involvement of mitochondrial intermem-
brane junctional complexes in apoptosis. Curr Med Chem 10:1473–
Crompton M, Costi A, Hayat L. 1987. Evidence for the presence of a
reversible Ca21-dependent pore activated by oxidative stress in heart
mitochondria. Biochem J 245:915–918.
Crompton M, Ellinger H, Costi A. 1988. Inhibition by cyclosporin A of
a Ca21-dependent pore in heart mitochondria activated by inorganic
phosphate and oxidative stress. Biochem J 255:357–360.
Crompton M, Barksby E, Johnson N, Capano M. 2002. Mitochondrial
intermembrane junctional complexes and their involvement in cell
death. Biochimie 84:143–152.
Di Lisa F, Ziegler M. 2001. Pathophysiological relevance of mitochondria
in NAD1metabolism. FEBS Lett 492:4–8.
Di Lisa F, Menabo R, Canton M, Barile M, Bernardi P. 2001. Opening
of the mitochondrial permeability transition pore causes depletion of
mitochondrial and cytosolic NAD1and is a causative event in the
death of myocytes in postischemic reperfusion of the heart. J Biol
Du H, Guo L, Zhang W, Rydzewska M, Yan S. 2009. Cyclophilin D
deficiency improves mitochondrial function and learning/memory in
aging Alzheimer disease mouse model. Neurobiol Aging 10.1016/j.neu-
Dumont M, Lin MT, Beal MF. 2010. Mitochondria and antioxidant tar-
geted therapeutic strategies for Alzheimer’s disease. J Alzheimers Dis
Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA. 1997. Is-
chemic brain injury is mediated by the activation of poly(ADP-ribose)-
polymerase. J Cereb Blood Flow Metab 17:1143–1151.
Fiskum G. 2000. Mitochondrial participation in ischemic and traumatic
neural cell death. J Neurotrauma 17:843–855.
Fiskum G. 2004. Mechanisms of neuronal death and neuroprotection.
J Neurosurg Anesthesiol 16:108–110.
Formentini L, Moroni F, Chiarugi A. 2009. Detection and pharmacolog-
ical modulation of nicotinamide mononucleotide (NMN) in vitro and
in vivo. Biochem Pharmacol 77:1612–1620.
Forte M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, Yu
X, Fowlkes J, Rahder M, Stem K, Bernardi P, Bourdette D. 2007.
Cyclophilin D inactivation protects axons in experimental autoimmune
encephalomyelitis, an animal model of multiple sclerosis. Proc Natl
Acad Sci U S A 104:7558–7563.
Franco L, Guida L, Bruzzone S, Zocchi E, Usai C, De Flora A. 1998.
The transmembrane glycoprotein CD38 is a catalytically active trans-
porter responsible for generation and influx of the second messenger
cyclic ADP-ribose across membranes. FASEB J 12:1507–1520.
Franco L, Bodrato N, Moreschi I, Usai C, Bruzzone S, Scarf i S, Zocchi
E, De Flora A. 2006. Cyclic ADP-ribose is a second messenger in the
lipopolysaccharide-stimulated activation of murine N9 microglial cell
line. J Neurochem 99:165–176.
Galione A. 1993. Cyclic ADP-ribose: a new way to control calcium. Sci-
Glass JD, Brushart TM, George EB, Griffin JW. 1993. Prolonged survival
of transected nerve fibres in C57BL/Ola mice is an intrinsic characteris-
tic of the axon. J Neurocytol 22:311–321.
Greene JG, Greenamyre JT. 1996. Bioenergetics and glutamate excito-
toxicity. Prog Neurobiol 48:613–634.
Halestrap AP, Davidson AM. 1990. Inhibition of Ca21-induced large-
amplitude swelling of liver and heart mitochondria by cyclosporin is
probably caused by the inhibitor binding to mitochondrial-matrix pep-
tidyl-prolyl cis-trans isomerase and preventing it interacting with the
adenine nucleotide translocase. Biochem J 268:153–160.
Halestrap AP, McStay GP, Clarke SJ. 2002. The permeability transition
pore complex: another view. Biochimie 84:153–166.
Hazelton JL, Petrasheuskaya M, Fiskum G, Kristian T. 2009. Cyclophilin
D is expressed predominantly in mitochondria of gamma-aminobutyric
acidergic interneurons. J Neurosci Res 87:1250–1259.
Heneka MT, Rodriguez JJ, Verkhratsky A. 2010. Neuroglia in neurode-
generation. Brain Res Rev 63:189–211.
Hoffmann A, Kann O, Ohlemeyer C, Hanisch UK, Kettenmann H.
2003. Elevation of basal intracellular calcium as a central element in the
activation of brain macrophages (microglia): suppression of receptor-
evoked calcium signaling and control of release function. J Neurosci
Hotta T, Asai K, Fujita K, Kato T, Higashida H. 2000. Membrane-
bound form of ADP-ribosyl cyclase in rat cortical astrocytes in culture.
J Neurochem 74:669–675.
Iqbal J, Kumar K, Sun L, Zaidi M. 2006. Selective up-regulation of the
ADP-ribosyl cyclases CD38 and CD157 by TNF but not by RANK-L
reveals differences in downstream signaling. Am J Physiol Renal Physiol
Kershman J. 1939. Genesis of microglia in the human brain. Arch Neurol
Kim SY, Gul R, Rah SY, Kim SH, Park SK, Im MJ, Kwon HJ, Kim
UH. 2008. Molecular mechanism of ADP-ribosyl cyclase activation in
angiotensin II signaling in murine mesangial cells. Am J Physiol Renal
Role of NAD Degradation in Neurological Disease1953
Journal of Neuroscience Research
Klaidman LK, Mukherjee SK, Hutchin TP, Adams JD. 1996. Nicotina-
mide as a precursor for NAD1prevents apoptosis in the mouse brain
induced by tertiary-butylhydroperoxide. Neurosci Lett 206:5–8.
Klaidman LK, Mukherjee SK, Adams JD Jr. 2001. Oxidative changes in
brain pyridine nucleotides and neuroprotection using nicotinamide.
Biochim Biophys Acta 1525:136–148.
Klaidman L, Morales M, Kem S, Yang J, Chang ML, Adams JD Jr.
2003. Nicotinamide offers multiple protective mechanisms in stroke as
a precursor for NAD1, as a PARP inhibitor and by partial restoration
of mitochondrial function. Pharmacology 69:150–157.
Kohler C, Peterson A, Eriksson LG, Okuno E, Schwarcz R. 1988. Im-
munohistochemical identification of quinolinic acid phosphoribosyl-
transferase in glial cultures from rat brain. Neurosci Lett 84:115–119.
Kou W, Banerjee S, Eudy J, Smith LM, Persidsky R, Borgmann K, Wu
L, Sakhuja N, Deshpande MS, Walseth TF, Ghorpade A. 2009. CD38
regulation in activated astrocytes: implications for neuroinflammation
and HIV-1 brain infection. J Neurosci Res 87:2326–2339.
Kristal BS, Stavrovskaya IG, Narayanan MV, Krasnikov BF, Brown AM,
Beal MF, Friedlander RM. 2004. The mitochondrial permeability tran-
sition as a target for neuroprotection. J Bioenerg Biomembr 36:309–
Kristian T. 2004. Metabolic stages, mitochondria and calcium in
hypoxic/ischemic brain damage. Cell Calcium 36:221–233.
Kristian T, Fiskum G. 2004. A fluorescence-based technique for screen-
ing compounds that protect against damage to brain mitochondria.
Brain Res Brain Res Protoc 13:176–182.
Kristian T, Gido G, Kuroda S, Schutz A, Siesjo BK. 1998. Calcium me-
tabolism of focal and penumbral tissues in rats subjected to transient
middle cerebral artery occlusion. Exp Brain Res 120:503–509.
Kuroda S, Katsura K, Hillered L, Bates TE, Siesjo BK. 1996. Delayed
treatment with alpha-phenyl-N-tert-butyl nitrone (PBN) attenuates sec-
ondary mitochondrial dysfunction after transient focal cerebral ischemia
in the rat. Neurobiol Dis 3:149–157.
Lai Y, Chen Y, Watkins SC, Nathaniel PD, Guo F, Kochanek PM, Jen-
kins LW, Szabo C, Clark RS. 2008. Identification of poly-ADP-ribosy-
lated mitochondrial proteins after traumatic brain injury. J Neurochem
Lee HC. 1997. Mechanisms of calcium signaling by cyclic ADP-ribose
and NAADP. Physiol Rev 77:1133–1164.
Liu D, Pitta M, Mattson MP. 2008. Preventing NAD1depletion pro-
tects neurons against excitotoxicity: bioenergetic effects of mild mito-
chondrial uncoupling and caloric restriction. Ann N Y Acad Sci
Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson MP. 2009. Nico-
tinamide prevents NAD1depletion and protects neurons against exci-
totoxicity and cerebral ischemia: NAD1consumption by SIRT1 may
endanger energetically compromised neurons. Neuromol Med 11:28–
Luk T, Malam Z, Marshall JC. 2008. Pre-B cell colony-enhancing factor
(PBEF)/visfatin: a novel mediator of innate immunity. J Leukoc Biol
Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E,
Vaisitti T, Aydin S. 2008. Evolution and function of the ADP ribosyl
cyclase/CD38 gene family in physiology and pathology. Physiol Rev
Martin E, Rosenthal RE, Fiskum G. 2005. Pyruvate dehydrogenase
complex: metabolic link to ischemic brain injury and target of oxidative
stress. J Neurosci Res 79:240–247.
Masmoudi A, Islam F, Mandel P. 1988. ADP-ribosylation of highly puri-
fied rat brain mitochondria. J Neurochem 51:188–193.
Mattson MP. 2004. Pathways towards and away from Alzheimer’s dis-
ease. Nature 430:631–639.
Mayo L, Jacob-Hirsch J, Amariglio N, Rechavi G, Moutin MJ, Lund
FE, Stein R. 2008. Dual role of CD38 in microglial activation and acti-
vation-induced cell death. J Immunol 181:92–103.
Mokudai T, Ayoub IA, Sakakibara Y, Lee EJ, Ogilvy CS, Maynard KI.
2000. Delayed treatment with nicotinamide (vitamin B3) improves
neurological outcome and reduces infarct volume after transient focal
cerebral ischemia in Wistar rats. Stroke 31:1679–1685.
Morais VA, De Strooper B. 2010. Mitochondria dysfunction and neuro-
degenerative disorders: cause or consequence. J Alzheimers Dis
Mukherjee SK, Klaidman LK, Yasharel R, Adams JD Jr. 1997. Increased
brain NAD prevents neuronal apoptosis in vivo. Eur J Pharmacol
Naga KS, Geddes JW. 2007. High cyclophilin D content of synaptic mi-
tochondria results in increased vulnerability to permeability transition.
J Neurosci 27:7469–7475.
Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata
H, Inohara H, Kubo T, Tsujimoto Y. 2005. Cyclophilin D-dependent
mitochondrial permeability transition regulates some necrotic but not
apoptotic cell death. Nature 434:652–658.
Perry GM, Tallaksen-Greene S, Kumar A, Heng MY, Kneynsberg A,
van Groen T, Detloff PJ, Albin RL, Lesort M. 2010. Mitochondrial
calcium uptake capacity as a therapeutic target in the R6/2 mouse
model of Huntington’s disease. Hum Mol Genet 19:3354–3371.
Petronilli V, Nicolli A, Costantini P, Colonna R, Bernardi P. 1994.
Regulation of the permeability transition pore, a voltage-dependent mi-
tochondrial channel inhibited by cyclosporin A. Biochim Biophys Acta
Pieper AA, Verma A, Zhang J, Snyder SH. 1999. Poly (ADP-ribose) po-
lymerase, nitric oxide and cell death. Trends Pharmacol Sci 20:171–
Reinherz EL, Kung PC, Goldstein G, Levey RH, Schlossman SF. 1980.
Discrete stages of human intrathymic differentiation: analysis of normal
thymocytes and leukemic lymphoblasts of T-cell lineage. Proc Natl
Acad Sci U S A 77:1588–1592.
Richards EM, Rosenthal RE, Kristian T, Fiskum G. 2006. Postischemic
hyperoxia reduces hippocampal pyruvate dehydrogenase activity. Free
Radic Biol Med 40:1960–1970.
Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA.
2006. Tryptophan metabolism in the central nervous system: medical
implications. Expert Rev Mol Med 8:1–27.
Sadanaga-Akiyoshi F, Yao H, Tanuma S, Nakahara T, Hong JS, Ibayashi
S, Uchimura H, Fujishima M. 2003. Nicotinamide attenuates focal is-
chemic brain injury in rats: with special reference to changes in nicotin-
amide and NAD1levels in ischemic core and penumbra. Neurochem
Sakakibara Y, Mitha AP, Ayoub IA, Ogilvy CS, Maynard KI. 2002.
Delayed treatment with nicotinamide (vitamin B3) reduces the infarct
volume following focal cerebral ischemia in spontaneously hypertensive
rats, diabetic and non-diabetic Fischer 344 rats. Brain Res 931:68–73.
Salmina AB, Malinovskaya NA, Okuneva OS, Taranushenko TE, Fursov
AA, Mikhutkina SV, Morgun AV, Prokopenko SV, Zykova LD. 2008.
Perinatal hypoxic and ischemic damage to the central nervous system
causes changes in the expression of connexin 43 and CD38 and ADP-
ribosyl cyclase activity in brain cells. Bull Exp Biol Med 146:733–736.
Sasaki Y, Araki T, Milbrandt J. 2006. Stimulation of nicotinamide ade-
nine dinucleotide biosynthetic pathways delays axonal degeneration af-
ter axotomy. J Neurosci 26:8484–8491.
Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J,
Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ. 2005. Cyclophilin
D is a component of mitochondrial permeability transition and mediates
neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U
S A 102:12005–12010.
1954 Kristian et al.
Journal of Neuroscience Research
Shalbuyeva N, Brustovetsky T, Bolshakov A, Brustovetsky N. 2006. Cal- Download full-text
cium-dependent spontaneously reversible remodeling of brain mito-
chondria. J Biol Chem 281:37547–37558.
Snell CR, Snell PH, Richards CD. 1984. Degradation of NAD by syn-
aptosomes and its inhibition by nicotinamide mononucleotide: implica-
tions for the role of NAD as a synaptic modulator. J Neurochem
Spector R, Johanson CE. 2007. Vitamin transport and homeostasis in
mammalian brain: focus on vitamins B and E. J Neurochem 103:425–
Spector R, Kelley P. 1979. Niacin and niacinamide accumulation by rab-
bit brain slices and choroid plexus in vitro. J Neurochem 33:291–298.
Stavrovskaya IG, Kristal BS. 2005. The powerhouse takes control of the
cell: is the mitochondrial permeability transition a viable therapeutic
target against neuronal dysfunction and death? Free Radic Biol Med
Sullivan PG, Rabchevsky AG, Waldmeier PC, Springer JE. 2005. Mito-
chondrial permeability transition in CNS trauma: cause or effect of
neuronal cell death? J Neurosci Res 79:231–239.
Szabo C, Dawson VL. 1998. Role of poly(ADP-ribose) synthetase in
inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 19:287–
Ungerstedt JS, Blomback M, Soderstrom T. 2003. Nicotinamide is a
potent inhibitor of proinflammatory cytokines. Clin Exp Immunol
Vereczki V, Martin E, Rosenthal RE, Hof PR, Hoffman GE, Fiskum G.
2006. Normoxic resuscitation after cardiac arrest protects against hippo-
campal oxidative stress, metabolic dysfunction, and neuronal death.
J Cereb Blood Flow Metab 26:821–835.
Willmott NJ, Asselin J, Galione A. 1996. Calcium store depletion poten-
tiates a phosphodiesterase inhibitor- and dibutyryl cGMP-evoked cal-
cium influx in rat pituitary GH3 cells. FEBS Lett 386:39–42.
Yamada M, Mizuguchi M, Otsuka N, Ikeda K, Takahashi H. 1997. Ul-
trastructural localization of CD38 immunoreactivity in rat brain. Brain
Yang J, Klaidman LK, Chang ML, Kem S, Sugawara T, Chan P, Adams
JD. 2002. Nicotinamide therapy protects against both necrosis and apo-
ptosis in a stroke model. Pharmacol Biochem Behav 73:901–910.
Yang JL, Weissman L, Bohr VA, Mattson MP. 2008. Mitochondrial
DNA damage and repair in neurodegenerative disorders. DNA Repair
Young GS, Choleris E, Lund FE, Kirkland JB. 2006. Decreased cADPR
and increased NAD1in the Cd382/2mouse. Biochem Biophys Res
Zhang W, Xie Y, Wang T, Bi J, Li H, Zhang LQ, Ye SQ, Ding S.
2010. Neuronal protective role of PBEF in a mouse model of cerebral
ischemia. J Cereb Blood Flow Metab 30:1962–71.
Ziegler M. 2000. New functions of a long-known molecule. Emerging
roles of NAD in cellular signaling. Eur J Biochem 267:1550–1564.
Zoratti M, Szabo I. 1995. The mitochondrial permeability transition.
Biochim Biophys Acta 1241:139–176.
Role of NAD Degradation in Neurological Disease1955
Journal of Neuroscience Research