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Cardiac glycosides could protect brain cells from stroke
Neriifolin, a cardiac glycoside, has
been shown to have neuroprotective
effects in ex-vivo and in-vivo models
of cerebral ischaemia. A team of
researchers led by Donald Lo (Duke
University Medical Center, NC, USA)
discovered this drug candidate using
a novel tissue-based, high-content
assay model for ischaemic stroke. “In
my mind, the more important aspect
of this study is not the discovery of
a cardiac glycoside that provides
neuroprotection against ischaemic
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Neriifolin is structurally related to the digitalis class of cardiac glycosides
Brain repairs itself after 19 years in minimally conscious state
A study of the brain of a man
who “woke up” after 19 years in a
minimally conscious state (MCS)
has suggested that axonal regrowth
and reconnection could underlie the
patient’s recovery. These findings are
likely to rekindle the debate about
outcomes for patients with disorders
of consciousness.
Three years ago, the 39-year-old
patient —who had been in MCS
since a traumatic brain injury in a car
crash in 1984—regained fluent, but
dysarthritic speech. Over a period
of several months, the man showed
further recovery in speech and some
functional recovery of his left arm and
lower limbs.
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stroke, but the method by which it
was discovered”, explains Doojin Kim
(University of California, LA, USA).
Lo’s team developed their model
using biolistic transfection of visual
reporter proteins into cortical brain slice
explants from rats. An advantage is that
this hypothesis-neutral approach allows
for investigation of a large number
of molecules with different pathways
(PNAS 2006; 103: 10461–66).
The investigators used the screening
platform to survey a chemical genetic
collection of small molecules with
known pharmacological properties
after oxygen and glucose deprivation
in the brain slices. Ten previous
candidate stroke drugs assayed showed
only modest neuroprotective effects.
Two compounds were found to have
dose-dependent properties and good
levels of efficacy. They were further
shown to have delayed therapeutic
time windows of 5–10 h or more in
providing increased neuronal survival
after oxygen and glucose deprivation.
Neuroprotective activity of one of
these compounds, neriifolin, was then
confirmed in a second brain-tissue
explant model for ischaemic injury. The
In most cases, MCS is a transient
condition that lasts only about
60–90 days, but a small minority
of patients will remain in MCS
permanently. To shed light on the
mechanisms underlying this patient’s
exceptional recovery, Henning Voss
(Weill Medical College of Cornell
University, New York, USA) and
colleagues examined the patient using
diffusion tensor MRI and PET. The
patient was scanned 8 months after
he first began to emerge from MCS,
and again 18 months later. Findings
were compared with those from a
brain-injured patient who had been in
MCS for 6 years without recovery and
20 normal individuals.
http://neurology.thelancet.com Vol 5 August 2006
role of Na+K+ ATPase, the presumptive
target of neriifolin, was supported in
this second model in which several
other cardiac glycoside drugs were
also shown to be effective, including
the FDA-approved drug digoxin.
Neriifolin was subsequently shown to
provide significant neuroprotection
in a neonatal model of hypoxia and
ischaemia as well as in an adult middle
cerebral artery occlusion model of
transient focal ischaemia.
Whether neriifolin provides neuro-
protective effects in the clinical
setting remains to be seen. However,
the cardiac glycosides could prove to
be a tractable starting point for the
development of new classes of stroke
drug candidates. “That our unbiased
screen for stroke drug candidates
pointed us towards new classes of
stroke drug targets and revealed
limitations of those that have been
tried in the past underscores the
values of hypothesis-neutral drug
screening strategies in the discovery
and development of new treatments
for ischaemic stroke”, explained Lo.
Laura Thomas
MRI imaging showed increased
fractional anisotropy compared with
controls in the least injured areas
of the brain, which the researchers
interpreted as increased myelinated
fibre density (J Clin Invest 2006;
116: 1005–11). These regions also
showed greater glucose metabolism,
reflecting regrowth of neurons. The
time interval of changes in these areas
correlated with the patient’s recovery.
This study should lead to a change in
thinking about neural plasticity, says
Steven Laureys (University of Liege,
Belgium). “It forces us to no longer
think about neural plasticity as being
something limited to the acute and
subacute state. In some patients there

are things happening even many years
after the insult”, he says.
“Clinically, this gives us some
important clues as to the mechanism
underlying late recovery of function
following severe traumatic brain
injury”, adds Joseph Giacino (New
Jersey Neuroscience Institute, Edison,
NJ, USA), who is one of the researchers.
“Once we understand the mechanism,
we can begin to develop treatments
that may expedite or extend the
recovery process.”
Laureys adds that this study should
help to change perceived notions
Hierarchy of reward
The various subunits comprising
nictotinic acetylchoine receptors
(nAChRs) on dopamine neurons affect
the response of these neurons to
nicotine and may play an important
part in reward mechanisms associated
with addiction and cognition. The
results of study by Swedish and
French researchers show that the β2
subunits have the most prominent
role, determining whether or not
dopaminergic neurons respond to
nicotine; other subunits control
subtle shifts in the nature of these
neurons’ response to the drug. The
findings not only provide new insight
into the mechanisms of reward, but
also pinpoint potential targets for
treatment of addiction.
“These experiments lead to the
demonstration that one particular
nicotinic receptor type, the β2 subunit,
plays a hierarchically dominant role
over the other types in the control of
dopamine neurons firing in response to
nicotine or endogenous acetylcholine”,
explains researcher Jean-Pierre
Changeux (Pasteur Institute, Paris,
France). Previous studies had shown
that in mice lacking the β2 subunit
of nAChRs, nicotine no longer elicits
dopamine release, and the animals
stop self-administering nicotine.
In their recent study, Mameli-Engval
and colleagues first characterised
http://neurology.thelancet.com Vol 5 August 2006
about the futility of treating MCS
patients.
“The problem with these patients is
that they are viewed as a homogeneous
and a hopeless group of patients. There
is no framework where these patients
can benefit from therapeutic options.
The trend for therapeutic nihilism is
very real. But I think this should change
because these patients do exist, and
will continue to exist, and we should
increase our research efforts to study
these patients”, he says.
He stresses, however, that recovery
of this type is only possible in patients
the neuronal firing of dopaminergic
neurons in wild-type mice and found
four distinct patterns of firing (Neuron
2006; 50: 911–21). The researchers
used genetically modified mice
lacking either of two subunits of
nAChRs, first the β2 subunit, then
the α7 subunit. In mice lacking the
β2 subunit, dopamine neurons all
fired at the lowest level of excitation
without the burst firing associated
with dopamine release, but in mice
lacking α7 subunits, the neurons fired
at either the highest or the lowest
pattern of activity. In β2 knockout
mice, burst firing was restored by
introduction of the gene encoding
the subunit in the ventral tegmental
area (VTA) in which the dopamine
neuron cell bodies are located. “These
experiments clearly demonstrate that
the β2 subunit is required for the
burst firing of dopamine neurons and
thus for dopamine release excited
by endogenous acetylcholine”, says
Changeaux.
In an accompanying commentary
(Neuron 2006; 50: 815–16), Mark
Ugless and Stephanie Cragg (University
of Oxford, UK) point out that although
the finding might explain the diversity
of receptor subunits of nAChRs,
because these receptors are also
expressed on GABAergic neurons
in the VTA further investigation is
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who have at least some level of
consciousness—not those in an
irreversible vegetative state, who show
only reflex behaviour. “We should not
give the impression to the community
that the vegetative state does not exist
and that we should, in all patients, at
all price, at all times, give full therapy.
There are patients where treatment
becomes futile, and the long legal
and ethical battle to obtain the right
to withdraw treatment should not be
menaced.”
Helen Frankish
needed “to tease out the contribution
of β2 receptors in each cell type”.
This study was aimed at investigating
the molecular mechanisms involved
in the acute effects of nicotine that
lead to self administration, which
the authors explain is analogous to
reward system of repetitive cigarette
smoking. “But it is also known”,
Changeaux told The Lancet Neurology,
“that addiction derives from the
repeated administration of the drug.”
The researchers now plan to use the
same techniques to study the long-
term effects of nicotine that result in
long-lasting addiction.
Peter Hayward
Receptor subunit chain of command determines rewards of chain smoking
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