Negotiating brain anoxia survival in the turtle
Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
* Author for correspondence (e-mail: lutz{at}fau.edu)
Accepted 26 April 2004
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Summary |
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Key words: anoxia tolerance, ATP expenditure, GABA, heat shock protein, turtle, Trachemys scripta
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Introduction |
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In contrast to the high vulnerability of the mammalian brain to hypoxia (as
well as most other vertebrates), the brain of the freshwater turtle
Trachemys scripta is able to withstand anoxia for days at room
temperature (Lutz et al.,
2003a; Bickler et al., 2002). Recent research shows that this
ability is not simply one of passive tolerance but is due to a fascinating,
interlocking cluster of adaptations that produce a state of deep
hypometabolism, the most effective of all hypoxia defense strategies
(Hochachka and Lutz, 2001
).
The current review discusses some recent advances in our understanding of how
the turtle more effectively uses some of the early protective mechanisms
activated in the mammal and how the turtle brain defends against the
catastrophic events of anoxic failure.
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Constitutive factors for anoxia survival |
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The turtle brain is remarkable in having glycogen concentrations about
fivefold greater than that of the rat or the anoxia-intolerant rainbow trout
(Lutz et al., 2003a).
Presumably, this provides an immediately accessible store of glucose for
anaerobic glycolysis until adequate glucose supplies are liberated (recruited)
from the large glycogen stores in the liver.
In general, the turtle has much lower aerobic enzyme activities and ion
channel densities than the mammal, at levels that roughly match the difference
in their metabolic intensities (Lutz et
al., 2003a). For example, the maximal binding capacity
(Bmax) of the turtle brain adenosine A1
receptor is only 1020% that of the rat brain
(Lutz and Manuel, 1999
),
Na+/K+-ATPase activities are
40%
(Suarez et al., 1989
) and the
density of voltage-dependent Na+ channels is
30%
(Edwards et al., 1989
). By
contrast, some receptors that have protective roles are much more abundant.
The turtle appears to have a comparatively high intrinsic inhibitory potential
since its cerebral hemispheres have the same density of inhibitory
GABAA receptors as the rat
(Lutz and Kabler, 1995
).
Moreover, Xia and Haddad
(2001
) found that the
Bmax for the
-opioid receptor in the turtle cortex
is more than four times that of the rat. As
-opioid receptors protect
neurons against glutamate, they speculate that the turtle brain may be
pre-protected from glutamate excitotoxicity
(Xia and Haddad, 2001
).
Indeed, there is evidence that turtle brain is indeed more resistant to
glutamate toxicity (Wilson and Kreigstein,
1991
). The level of the pituitary adenylate cyclase activating
polypeptide, PACAP 38, may be the most striking example of constitutive
protection, being 10100-fold higher in the turtle brain than in rat and
human brain (Reglodi et al.,
2001
). PACAP has a neuroprotective role in ischemia, and there is
evidence that the high levels may help protect against anoxia-induced neuronal
damage in the turtle retina (Rabl et al.,
2002
).
Heat shock proteins are an important class of molecular adaptations that
protect against physiological stressors. They act as molecular chaperones,
protecting against the denaturation of proteins or refolding unfolded
proteins, and those associated with the Hsp70 family are particularly
important in providing protection from hypoxia-related damage
(Snoeckx et al., 2001). One
member, Hsc73, is regarded as a cognate or constitutive protein because it is
present in non-stressed tissues and is only slightly inducible by stress
(Snoeckx et al., 2001
). The
inducible heat shock protein Hsp72 is hardly seen in unstressed conditions in
the mammalian brain (Snoeckx et al.,
2001
). By contrast, in the turtle brain, both Hsp72 and Hsc73 are
found at high levels in normoxia (Prentice
et al., in press
). Interestingly, the inducement of Hsp72 by a
short mild exposure to ischemia/hypoxia is thought to be an important feature
of preconditioning, providing temporary protection for subsequent otherwise
injurious ischemic/anoxic insults (Marber
et al., 1993
). In this regard, the high constitutive levels of
Hsp72 in normoxic turtle brain indicate that the turtle has an element of
preconditioning already expressed.
In the mammal, nuclear factor B (NF-
B) is an important
transcription regulator of many genes that play a role in recovery from acute
or chronic trauma (Haddad,
2002
). In particular, it is central to the expression of
stress-responsive genes in the face of inflammatory and oxidative damage,
protects against reactive oxygen species (ROS) damage and has an
anti-apoptotic function (Haddad,
2002
). The turtle has high normoxic levels of NF-
B
(Lutz and Prentice, 2002
),
which might correspond to a constitutive pro-survival state.
Finally, the freshwater turtle brain may show an enhanced predisposition to
fight reoxygenation damage. The turtle brain has greater concentrations of
ascorbic acid compared with mammals, levels in cortex being 23 times
greater than in the mammalian cortex (Rice
et al., 1995). The freshwater turtle also has high constitutive
activities of catalase, superoxide dismutase (SOD) and alkyl hydroperoxide
reductase (Willmore and Storey,
1997
). This enhanced store of antioxidants may be a built-in
protection against free radicals (ROS) produced when the brain is reoxygenated
after anoxia or even after normal breath-hold dives where arterial oxygen
partial pressure (PO2) can routinely fall to
2.7 kPa (Lutz, 1992
).
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Surviving anoxia and aerobic recovery |
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The first line of defense against anoxic brain failure is a drastic
suppression of ATP use during the first 12 h of anoxia, lowering energy
consumption to such a degree (7080%) that brain energy needs can be
fully met by anaerobic glycolysis
(Hochachka and Lutz, 2001).
Catastrophe is avoided by a coordinated and tightly regulated downshift in the
pathways for ATP demand and supply so that the turtle brain is able to
maintain ATP levels and ionic gradients during this dynamic period of energy
cost suppression.
The second line of defense involves maintaining, over hours to days, the integrity of the deeply depressed brain at an order of magnitude lower than normoxic levels. In this regard, the brain is much more complicated than other tissues, having to preserve functional activity through a continued interplay between excitation and inhibition and having to defend the intricate architecture of synaptic network connections. As degenerative processes will continue, essential tightly regulated and controlled countermeasures must remain active. Here, the turtle brain is in a minimal or basal state for neuronal survival and can be used to identify those processes fundamental to survival, processes that almost certainly are of wide and general relevance but are not amenable to investigation in the anoxia-intolerant mammalian model.
The third phase is recovery. When O2 supply is restored, there must be a coordinated and comparatively rapid reactivation of the suppressed neuronal activities in order that the animal can function again for fight, flight and feeding. At this time, the brain must also have in effect defenses against the putative massive generation of destructive reoxygenation-generated ROS. To date, little is known about this aspect of brain recovery, a comparatively neglected area.
To survive, all of these phases must be successfully negotiated, which requires different responses at each step. Responses occur at the molecular, cellular and intercellular levels.
Hypoxia-induced molecular changes
One of the most important hypoxia-driven factors, the hypoxia-inducible
HIF-1, plays a major role in coordinating many adaptive response to
hypoxia in the mammal (Haddad,
2002
). More than two dozen HIF-1 target genes are known, including
genes involved in vascular biology, such as vascular endothelial growth factor
(VEGF), and genes involved in glucose uptake and glycolysis, such as
glucose transporter 1 and phosphofructokinase L
(Wenger, 2002
). Under normoxic
conditions, HIF-1
is hydroxylated by oxygen-dependent propyl
hydroxylases and targeted for proteolytic destruction. But, under hypoxic
conditions, HIF-1
is stabilized, translocates into the nucleus and
activates gene expression (Wenger,
2002
). Interestingly, a semi-quantitative RT-PCR analysis found no
changes in HIF-1
mRNA during anoxia and subsequent reoxygenation
(Prentice et al., 2003
), which
is consistent with the findings in mammalian systems that HIF-1 regulation
does not occur at the transcriptional level but primarily at the
post-translational level. That post-translational regulation is also occurring
in the turtle is suggested by preliminary observations of DNA binding activity
specific to an HIF-1 DNA consensus sequence in the anoxic turtle brain.
It has been widely reported that hypoxia/ischemia produces an increase in
the inducible Hsp72 in the mammalian brain, where it is thought to provide
protection (Lipton, 1999). In
the turtle brain, Hsp72 is also induced in early anoxia, peaking at
8 h
anoxia and then falling to normoxic levels at 12 h anoxia
(Prentice et al., in press
).
However, unlike mammals, where Hsc73 is only slightly inducible, in the turtle
brain Hsc73 is progressively elevated over 12 h anoxia
(Prentice et al., in press
).
This differential expression of Hsp proteins suggests that Hsp72 and Hsc73
have different roles during brain anoxia. The (comparatively) short-term rise
and fall in Hsp72 indicates that it may have a protective role during the
initial transition to the hypometabolic state, a period of substantial
metabolic changes. The continued and increased presence of Hsc73 during
long-term anoxia suggests that this protein may be involved in `housekeeping'
roles that are necessary to ensure the functional integrity of the neuronal
network during the long-term hypometabolic phase.
In mammals, activity levels of NF-B are increased in both neurons
and glia following ischemic stroke and may induce multiple protective genes
related to immune function, inflammation, apoptosis and protection against ROS
damage (Haddad, 2002
;
Martindale and Holbrook,
2002
). Interestingly, in the anoxic turtle brain, NF-
B
shows maximal DNA binding at 6 h of anoxia
(Lutz and Prentice, 2002
). It
is possible that the late translocation of NF-
B to consensus DNA
binding sites in the turtle brain is part of a preemptive defense mechanism
against reoxygenation ROS damage and incipient apoptosis.
Ion channels
Since ion pumping accounts for more than 50% of the energy requirements of
the normoxic neuron, a reduction in ion permeability can have important
savings in anoxia, and indeed there is evidence of a decrease in
K+, Na+ and Ca2+ channel activities early in
anoxia.
Potassium channels are responsible for setting the resting potential,
determining the rate of repolarization and for neuronal firing rates
(Meir et al., 1999). And,
indeed, potassium flux is reduced by
50% over the first hour of anoxia
and falls to
35% of normoxic levels by 2 h anoxia, after which no further
decline is seen (Fig. 1; Chih et al., 1989
;
Pek and Lutz, 1998
). Activated
KATP channels mediate the downregulation of K+ efflux
during the initial energy crisis period when ATP is depleted
(Pek and Lutz, 1998
), and
adenosine A1 receptors are also involved in this process
(Pek and Lutz, 1998
).
Voltage-gated K+ channels (Kv channels) are key determinants of
brain electrical activity (Levitan et al., 1998), and several are thought to
act as oxygen sensors (Meir et al.,
1999
). In the mammal, there is evidence that these channels are
reversibly blocked by acute hypoxia (Levitan et al., 1998). We have found in
the anoxic turtle brain that the gene transcription of Kv1 channels was
reduced to 18.5% of normoxic levels
(Prentice et al., 2003
). At
least part of the reduction in K+ efflux may be related to the
downregulation of Kv1 channel protein, as Kv channels are known to have a
rapid turnover. A reduction in Kv channel gene expression may be a critical
component in the orchestrated reduction in brain energy demand since it would
reduce excitability. Kv1 channel mRNA levels were restored following
subsequent reoxygenation, indicating that gene transcription of brain Kv
channels is reversibly regulated by oxygen supply
(Prentice et al., 2003
).
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The action potential is generated by voltage-gated Na+ channels
(Meir et al., 1999). There is
a 42% decrease in the density of voltage-gated Na+ channels in the
anoxic turtle cerebellum (Perez-Pinzon et
al., 1992
), a probable cause of the corresponding elevation in the
action potential threshold (Sick et al.,
1993
). This would result in a fall in neuronal activity through
`spike' arrest (Sick et al.,
1993
).
NMDA receptor activity is also progressively reduced during anoxia. Its
activity falls by 5060% over the first 18 min anoxia, thereby
providing immediate protection against uncontrolled glutamate-activated
Ca2+ influx (Bickler et al.,
2000). This rapid decrease in NMDA receptor activity appears to be
controlled by activation of phosphatase 1 or 2A
(Bickler and Donohoe, 2002
).
Adenosine also has a role in promoting NMDA receptor suppression
(Buck and Bickler, 1998
). As
anoxia progresses, the NMDA receptor activity is further depressed but not
eliminated (Bickler et al.,
2000
). This additional decrease in NMDA receptor activity is due
to a removal/internalization of receptors from the cell membrane
(Bickler et al., 2000
).
As there is a substantial downregulation of ion channels during anoxia, one
of the first priorities when air breathing is resumed will be to reactivate
ion channel functioning. This is indicated by the upregulation of Kv
transcription within 4 h of air breathing
(Prentice et al., 2003).
Potential signals for upregulation include activated O2 sensors,
release of ROS and/or changes in mitochondrial redox status
(Prentice et al., 2003
).
Neurotransmitters
While a rapid increase in extracellular levels of glutamate and dopamine is
a hallmark of hypoxic/ischemic exposure in the mammalian brain, the turtle
brain prevents increases in these excitatory neuroactive compounds during
anoxia (Nilsson and Lutz,
1991; Milton and Lutz,
1998
).
During the first few hours of anoxia, extracellular glutamate levels are
maintained by a reduction in glutamate release (mainly due to the inhibition
of neuronal vesicular glutamate release), combined with the continued
operation of glutamate uptake transporters
(Milton et al., 2002). During
this period, the reduction in glutamate release is mediated by the activation
of adenosine receptors and the opening of K+ATP channels
(Milton et al., 2002
).
Interestingly, the activation of each pathway appears sufficient to produce
the full inhibitory effect, since it is only when both systems are antagonized
that the anoxia-induced decrease in glutamate release is prevented
(Milton et al., 2002
). This
indicates a redundancy or back up in control mechanisms during the initial
periods of anoxia when ATP levels are low. By contrast, in the energy-deprived
mammalian brain, the rapid increase in extracellular glutamate is a result of
reduced glutamate uptake combined with increased glutamate release from
vesicular and nonvesicular sources (Dawson
et al., 2000
).
As anoxia progresses, the rate of glutamate release continues to decrease
but, in contrast to the initial decrease in glutamate release, this reduction
is modulated by adenosine and GABAA receptors but not
K+ATP channels
(Thompson and Lutz, 2001). It
thus appears that the signaling/control mechanisms of glutamate release change
as the anoxic depression develops, with adenosine and
K+ATP channels being effective during the transition
period when ATP is temporarily reduced, and adenosine and GABA being important
during extended anoxic exposure after ATP levels have recovered. A similar
reduction in the effectiveness of K+ATP channels to
downregulate ion channels in late anoxia has been reported in the anoxic
turtle cortex (Pek-Scott and Lutz,
1998
).
Since the uptake of glutamate is energetically expensive, estimated at 1.5
ATP per glutamate anion (Swanson and Duan,
1999), and the turtle's basic strategy to survive anoxia is to
minimize ATP expenditures, the continued transporter activity suggests that
glutamate has an important function in anoxia survival. It may be a matter of
preserving neuronal integrity since many synaptic connections are dependant on
glutamate (Soltesz and Nusser,
2001
). If continued glutamate release is essential for the turtle,
it is also likely to be so for the mammal, and current efforts to protect
against ischemia by pharmacologically blocking the release of glutamate or
blocking glutamate receptors may be counterproductive. Indeed, while there
have been major efforts to protect against post-ischemic damage by blocking
glutamate release, to date no clinically effective glutamate antagonist has
been found (Schwartz-Bloom and Sah,
2001
). Some have harmful side effects; others are ineffective
(Schwartz-Bloom and Sah,
2001
).
Low extracellular levels of dopamine (DA) are also maintained in the turtle
brain during anoxia through a balance of release and continually active uptake
mechanisms. DA homeostasis fails early in the anoxic/ischemic mammalian brain;
unlike the widespread release of excitatory amino acids (EAAs), excessive DA
release is seen well before high energy stores are fully depleted
(Huang et al., 1994). In the
hypoxic mammalian brain, increases in extracellular DA are due primarily to
decreased reuptake into the cell coupled with increased release from
intracellular stores (Huang et al.,
1994
). By contrast, in the turtle brain during long-term anoxia,
DA is continuously released and a balance is maintained by the continued
function of reuptake mechanisms (Milton
and Lutz, 1998
). As with glutamate, this is energetically costly
and thus is likely to serve some function in maintaining neuronal circuitry
during anoxia.
By contrast to the EAAs, extracellular GABA starts to rise after about 2 h
anoxia and continues to increase for at least the next 24 h
(Nilsson and Lutz, 1991).
Interestingly, there is evidence that Hsc73 is a controlling factor for
vesicular accumulation of GABA (Jin et
al., 2003
), so the increased Hsc73 we have noted in the turtle
brain (Prentice et al., in
press
) may also function in facilitating/controlling GABA release
in anoxia.
The rise in GABA is accompanied by an increase in GABAA receptor
number, which continues to increase for at least 24 h
(Lutz and Leone-Kabler, 1995).
The upregulation in GABAA receptors may function to increase the
effectiveness of the inhibitory action of GABA, strengthening the GABA
inhibitory tone during the basal state.
In the ischemic mammalian brain, the dysfunction of GABA neurotransmission
is a major contributor towards neuronal death
(Schwartz-Bloom and Sah, 2001)
and there are current attempts to provide neuroprotection by pharmacologically
enhancing GABA neurotransmission. These include preventing GABA reuptake (i.e.
enhance levels of extracellular GABA) and increasing GABAA receptor
activity with agonists (Schwartz-Bloom and
Sah, 2001
). As both strategies are used by the turtle, the turtle
may provide useful lessons for effective GABAergic-related strategies.
Electrical activity
Important energy savings come from an almost full suppression in turtle
brain electrical activity during anoxia, but this comes about in a complex
manner (Fernandes et al.,
1997). During the first 100 min of N2 respiration,
electroencephalogram (EEG) amplitude is progressively reduced, with
low-amplitude slow-wave activity predominating (312 Hz), and the total
EEG power spectra decreased across all frequencies to about one order of
magnitude lower than during normoxia. Most interestingly, during this period,
3 s bursts of high-voltage (24 µV), slow, rhythmic waves (38 Hz)
appeared, similar to the theta waves associated in mammals and birds with
slow-wave sleep. This synchronization of brain electrical activity may relate
to a coordinated down-switching of brain electrical activities.
During the subsequent anoxic basal state, the electrical activity is
greatly reduced, the EEG amplitude is 20% of the normoxic level and the
total EEG power is an order of magnitude lower. Corresponding to the continued
low level of electrical activity, ion pumps, although depressed, are still
active (Sick et al., 1993
).
However, this depressed activity state is periodically (0.52
min1) interrupted by short bursts (215 s) of mixed
frequency activity. The burst activity may be necessary to maintain circuit
integrity or may be part of a periodic check for a signal for arousal. The
continued release and uptake of neurotransmitters such as glutamate
(Milton et al., 2002
) and
dopamine (Milton and Lutz,
1998
) may be determinant factors for the sustained periodic burst
activity in the anoxic turtle brain.
There is a full recovery of the EEG
(Fernandes et al., 1997) and
evoked potential amplitudes (Feng et al.,
1990
) within 2 h of reoxygenation.
ROS
While transient fluctuations in ROS serve important regulatory functions,
high and sustained levels can cause severe damage to DNA, protein and lipids
and cause apoptosis and necrosis
(Martindale and Holbrook,
2002). For the turtle, free radicals pose a special problem during
the recovery period. A few minutes of anoxia are sufficient to reduce the
mitochondrial respiratory chain electron carriers to such an extent that toxic
amounts of ROS will be generated when oxygen supply is restored. Clearly, the
turtle brain is in a prime condition to experience massive amounts of ROS when
it is reoxygenated after many hours of anoxia. That the turtle brain survives
this insult is indicated by studies of neuronal cell culture, which are
unaffected by exposure to 2 days anoxia and 1 day reoxygenation, conditions
that would be fatal for mammalian neurones
(Lutz et al., 2003b
). While it
is possible that the turtle has a means to prevent ROS formation, it is more
likely that it has mechanisms to protect against ROS damage. Evidence of high
constitutive antioxidant protection in the normoxic animal was discussed above
and it is also possible that there is an upregulation of antioxidant
capacities during aerobic recovery. The translocation of NF-
B in late
anoxia could mediate the activation of antioxidant genes, since there is
evidence that, in the mammalian brain, NF-
B mediates post-ischemic free
radical damage (Lipton, 1999
).
The turtle may also have enhanced defenses against oxidative damage. For
example, in contrast to mammals, there is little evidence in the turtle of
lipid peroxidation damage during anoxia or recovery
(Willmore and Storey,
1997
).
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Conclusions |
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References |
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