Brain
drugs of the future Susan Greenfield, professor.
Department
of Pharmacology, University of Oxford, Oxford OX1 3QT
People
have been using drugs to alter brain states since the dawn of time. But the use
of specific drugs to combat specific brain problems is a hallmark of this
century. In previous eras doctors reached for laudanum to combat hysteria,
oblivious to the underlying neurocheMagnetic resonance scan of coronal section
of brain in Parkinson's disease
Today
we owe much to the work of Henry Dale and Otto Loewi, who established that
chemicals act as transmitters to relay a signal from one neurone to the next.1
The guiding principle of modern neuropharmacology is to mimic, block, amplify,
or reduce the availability of certain transmitters, believed to be pivotal to
the disease to be treated. Yet herein lies the problem.
Summary
points
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One
transmitter may be linked to many disorders, and one disorder to many
transmitters
------------------------------------------------------------------------
Classic
transmitters have non-classic modulatory functions too
------------------------------------------------------------------------
Substances
such as nitric oxide and acetylcholinesterase have unexpected signalling
properties
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Neurodegeneration
might be an aberrant form of development, so drugs promoting neuronal
regeneration should be approached with caution
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Drugs
in the future could be used as a Rosetta stone for linking brain and mind
<Immagine> The
promiscuous transmittermistry.
However,
in Paris the famous neurologist Charcot purposely gave belladonna to patients
with Parkinson's disease to combat the constant salivation that accompanies loss
of motor control because women of the time who used the drug to dilate their
pupils complained of a dry mouth. Surprisingly, this anticholinergic drug proved
effective in combating not just the dribbling but the motor symptoms of
Parkinson's disease.
There
is no one to one matching of a single chemical system to a disease. Consider,
for example, the well known transmitter dopamine. In Parkinson's disease there
is a deficit of dopamine in the substantia nigra, hence prompting administration
of the precursor L-dopa, and eventual mimicry of the effects of dopamine with
the use of an agent such as bromocriptine to stimulate dopamine receptors
directly. But such treatment risks psychotic side effects such as visual
hallucinations and thus a distortion of reality reminiscent of schizophrenia<Immagine:
--->a condition associated with a functional excess of dopamine and thus
treated with dopamine receptor blockers such as chlorpromazine.
Dopamine
is far from being the transmitter for movement. Rather, its role in both the
generation of movement and indeed the aberrations seen in schizophrenia is in
conjunction with other transmitters. The reason that Charcot's chance treatment
was effective not just in quelling dribbling but in inspiring a treatment for
Parkinson's disease, is that the cholinergic and dopaminergic systems work as a
chemical see-saw in the basal ganglia, such that reducing the brain
concentrations of acetylcholine to a value commensurate with the reduced
dopamine is effective enough to have been the preferred drug treatment for half
a century. Now we know that dopamine interacts with other key systems such as
glutamate,2 hence the rationale for pallidotomies, which will diminish the net,
overexcitatory input of glutamate on to the dwindling dopamine neurones. Perhaps
once these multiway see-saws are exhaustively understood they will be programmed
and processed accurately. A polypharmacy could then be developed that
circumvents side effects because it exploits the specific interactions and
balances that constitute a neurochemical signature for any one particular brain
region.
The
multichemical basis of brain disorders
Just
as one transmitter such as dopamine can play a part in a variety of different
diseases, so any one disorder, such as Parkinson's disease, can be regarded as
the product of an interaction of a number of diverse transmitters. Alzheimer's
disease is another example in which the problem is unlikely to be attributable
to a single deficient system. Despite the popularity of the cholinergic
hypothesis of Alzheimer's disease, and the appeal of cholinergic promoting drugs
such as donepezil hydrochloride,3 acetylcholine is unlikely to be the
transmitter for holding dementia at bay. In the brain certain populations of
cholinergic neurones remain intact in Alzheimer's disease, while other non-cholinergic
cell populations are lost.4
There
must therefore be more to Alzheimer's disease than a simple and generic
malfunction of cholinergic neurones. And just as a simple drug targeting a
single transmitter system is unlikely to cure a disease of failing memory, so it
is similarly unlikely to enhance memory specifically in non-degenerating brains.
Despite the recent excitement over such cognitive enhancers,3 the rationale is
again to work simply at the level of disembodied transmitter systems<Immagine:
--->if not of acetylcholine then of an amino acid such as glutamate<Immagine:
--->or on the general mechanisms involved in plasticity of neuronal
connections.3 But since there is no transmitter for a complex net function such
as memory, then the manipulation of such basic and ubiquitous components of the
brain will be non-specific and side effects inevitable. The same problem at an
even more reductionist level would also apply to targeting a gene thought to be
for some final, sophisticated brain function or malfunction.
The
subtlety of non-classic neurochemical systems
The
drugs of the future will exploit mechanisms in the brain other than the classic
processes of synaptic transmission. Over recent years, we have seen enormous
advances in our understanding of such non-classic mechanisms that play crucial
parts in neurone operations. For example, dopamine is secreted from dendrites of
key populations of neurones in a fashion that is far more diffuse and modulatory
than at the tightly regulated synaptic cleft.5 The concept of modulation itself
is a relative newcomer: the basic idea is that a compound may not in itself
produce a response but rather bias neurones for a limited sphere of time and
space (fig 1). Drugs might be developed that put neurones on red alert and are
thus contingent on specific, physiological signals for the effects to be
realised. Such drugs would hold the
promise of acting less like a sledgehammer since their action
would occur only among neurones in which some subsequent, independent event took
place within a given time frame.
Fig
1. Two ways in which the excitability of cells can be modulated by
one chemical. In both cases the neurones were stimulated electrically (dot in
upper trace, step in lower trace) to generate action potentials. In the thalamic
neurone it makes the potential difference more negative (centre), which is a
prerequisite for activation of calcium entry into the neurone and in turn causes
the neurone to generate more action potentials. In the hippocampic neurone,
however, acetylcholine stops positively charged potassium ions from leaving the
cell. Because potassium does not leave the cell the potential difference remains
more positive than when acetylcholine is absent (see record on left) so that
more action potentials are generated. When acetylcholine is washed off (right),
both neurones revert to their original responses. Adapted from Greenfield12
In
addition, to familiar neurochemicals working in unfamiliar, more sophisticated
contexts, whole new classes of bioactive substances are being discovered that do
not behave in the same way as the more familiar transmitters. Fifteen years ago
who would have thought that a gas, nitric oxide, might be psychoactive?6 And at
the other end of the scale in terms of size, there are peptides. Peptides were
the centrepiece of many grant applications in the 1970s because they are often
stored with the classic transmitters (fig 2). So consistent yet surprising was
this observation that peptides were hailed as modulators, a separate class of
substance distinct from a transmitter.
Fig 2. Top: Comparison of classic transmitters and peptides.
When a neurone generates only a modest number of action potentials (middle
trace), transmitter alone is released. As the firing rate increases so both
transmitter and peptide are released. When the firing rate becomes high, peptide
release dominates. Bottom: Peptide is stored with transmitter in large vesicles
(triangle plus dot) and is released outside the synaptic cleft unlike
transmitter (dots alone). Reproduced from Hokfelt7 with permission
Such
a distinction should be much more blurred. Transmitters, such as dopamine,
serotonin, and acetylcholine, can all act in a more modulatory way, whereas in
certain cases<Immagine: --->such as in pain<Immagine: --->peptides
such as substance P seem to have a more defined and specific role. That said,
the peptides as molecules do have certain properties not displayed by their more
familiar counterparts. They tend to be released only when a neurone is very
active, as opposed to being a faithful reflection of any degree of neuronal
activity7; moreover, the release is often outside of the synapse itself,
suggesting a diffuse and promiscuous action. In addition, many peptides can be
bilingual, functioning as hormones and thus with different time scales and
possible targets beyond the brain into the rest of the body. In a recent book
Candace Pert mused that peptides might be responsible for emotions<Immagine:
--->indeed, that there might be a peptide for each emotion.8 Once again the
trap opens up, of reductionism of a complex brain state to molecular structure.
On the other hand, the role of peptides in more generalised body functions, and
indeed the interaction they might have with the immune system, present
tantalising possibilities for the development of future drugs.
Another
promising molecule, dear to my own heart and even bigger than the peptide
family, is the enzyme acetylcholinesterase, which has a well known role in
cholinergic transmission. Evidence is accruing that this familiar chemical might
have a completely different function<Immagine: --->modulation of non-cholinergic
neurones.4 One such non-cholinergic role seems to be in development of the brain
since diverse reports now suggest that acetylcholinesterase can enhance neurite
outgrowth in certain parts of the brain (fig 3). Furthermore,
acetylcholinesterase makes a transient appearance in certain brain regions in
development, vanishes in maturity, but reappears after insults.4 Clearly,
acetylcholinesterase itself might hold promise for exploitation once its
non-enzymatic actions are better understood. But, in addition, the reappearance
of what seems to be a developmental marker after injury adds weight to a
fascinating idea: that neurodegeneration might be an aberrant form of
development.9
Fig 3. Non-classic action of acetycholinesterase. Both
sections show slides from organotypic tissue cultures of substantia nigra in
which the cells have been stained for the synthetic enzyme dopamine tyrosine
hydroxylase. Top: Cells were incubated with echothiophate, which blocks only the
catalytic site of acetycholinesterase. Bottom: Comparable cells were treated
with an agent BW284C51, which also blocks non-enzymatic sites of
acetycholinesterase. Only the non-classical blocker has had a dramatic influence
on cell survival. Reproduced from Jones et al13 with permission
The
future
This
hypothesis, if true, would have enormous implications for another currently
attractive idea for future treatments for neurodegeneration<Immagine:
--->mimicking trophic agents, a class of compounds which, like
acetylcholinesterase, can enhance neurone survival in culture and encourage
rapid growth.10 The problem with these trophic factors, however, is that they
are too large to cross the blood-brain barrier and thus would need some kind of
implant. But beyond the resource and delivery problems involved, I think that
caution should be exercised in assuming that agents which promote the survival
of young neurones will automatically have the effect of arresting death in the
aged brain. Even within a week the tolerance of growing neurones to large
influxes of calcium (a common trigger in development) drops by a third. We now
know that neurons can die by activation of an internal self destruct programme
(apoptosis) as opposed to by necrosis, in which factors exterior to the neurone
play a part that affects a cell population more globally. So, it may well be one
thing to shut off an apoptotic mechanism in tissue culture and quite another to
prevent necrotic cell death downstream, necrosis resulting from direct and
indirect factors beyond the machinations within any one neurone. At the very
least, such indirect factors, above and beyond apoptosis, contribute to the net
effect of cell death, say, in Parkinson's disease.2
Transmission
electron micrograph of a synapse
The
key principle for guiding future drug design must surely be to remember that the
chemicals in question function in a context. They are a nested hierarchy of
circuits that are changeable over time and constitute brain regions, which in
turn are not the centres for something but rather make complementary
contributions to brain function and dysfunction, like instruments in an
orchestra.
Drugs
offer a powerful bridge between linking our knowledge of what goes on in our
brains with how we feel. But the what goes on must be seen in the context not of
isolated transmitter systems or single synapses but in the site specificity of a
three dimensional brain. Brain imaging will provide a valuable resource to place
the actions of the drugs in their true physiological context.11 In the future,
brain drugs may be given not only as treatment against a wider backdrop of brain
organisation but to provide insights into the basic nature of consciousness
itself.
References
1.Marshall
L, Magoun HW. Discoveries of the human brain. Totowa, NJ: Humana ,
1998.2.Greenfield SA. Cell death in Parkinson's disease. Essays in Biochemistry
1992; 27: 103-118[Medline].3.Geary J. Should we just say no to smart drugs?
Time 1997 May 5:46-7.4.Greenfield SA. Non-classical actions of
cholinesterases: role in cellular differentiation, tumorigenesis and Alzheimer's
disease: a critique. Neurochem Int 1996; 28: 485-490[Medline].5.Cragg SJ,
Greenfield SA. Differential autoreceptor control of somatodendritic and axon
terminal dopamine release in substantia nigra and ventral tegmental area in
vitro. J Neurosci 1997; 17: 5738-5746[Abstract/Full Text].6.Zhang J, Synder GH.
Nitric oxide in the nervous system. Am Rev Pharmacol Toxicol 1995; 35:
213-233[Medline].7.Hokfelt T. Neuropeptides in perspective: the last ten years.
Neuron 1991; 7: 867-879[Medline].8.Pert C. Molecules of emotion. London: Simon
and Schuster , 1997.9.Woolf NJ, Butcher LL. Dysdifferentiation of structurally
plastic neurons initiates the pathological cascade of Alzheimer's disease. In:
Steriade M, Biesold D, eds. Brain cholinergic systems. Oxford: Oxford University
Press, 1990:387-426.10.Lemin GR, Barde Y-A. Physiology of the neurotrophins. Ann
Rev Neurosci 1996; 19: 289-317[Abstract].11.Toga AW, Mazziotta JC. Brain
mapping: the methods. London: Academic , 1996.12.Greenfield SA. Journey to the
centres of the mind: toward a science of consciousness. New York: W H Freeman ,
1995.13.Jones SA, Holmes C, Budd TC, Greenfield SA. The effect of
acetylcholinesterase on outgrowth of dopaminergic neurons in organotypic slice
culture of rat mid-brain. Cell Tissue Res 1995; 279: 323-330[Medline].
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