CHAPTER 1 An Introduction to the Brain and its Biological Inorganic Chemistry R. J. P. WILLIAMS a AND J. J. R. FRAU ´ STO DA SILVA b a Inorganic Chemistry Laboratory, Oxford University, South Parks Road, Oxford OX1 3QR, UK; b Instituto Superior Tecnico, Universidade Tecnica de Lisboa, Lisbon, Portugal 1.1 Introduction The brain is a complex structure, composed of many zones organised as compartments that are apparently isolated by the manner of folding of the outer structure and by the packing and types of cells in the structures (Figure 1.1 and Table 1.1). 1,2 The functions of the compartments and the chemicals in them, distinguished by staining, apart from their physical characteristics, give ways of delineating them. It is also possible to describe the zones by the size of their differentiated electrical responses stimulated by actual or experimental outside events. A more detailed level of division of the description of the zones is by the cellular and membrane structures and their differences. There are two major classes of cell types in all zones, neurons and glia, and we shall describe them in turn, at first as if they were independent cell types. Each neuron appears to be separated from all others spatially and by several surrounding glial cells except for deliberate connection made between neurons at synaptic junctions. In this general introduction we draw special attention to the part played by metal ions and their enzymes. RSC Drug Discovery Series No. 7 Neurodegeneration: Metallostasis and Proteostasis Edited by Danilo Milardi and Enrico Rizzarelli r Royal Society of Chemistry 2011 Published by the Royal Society of Chemistry, www.rsc.org 1 Downloaded on 10 March 2013 Published on 24 June 2011 on http://pubs.rsc.org | doi:10.1039/9781849733014-00001
Transcript
CHAPTER 1
An Introduction to the Brainand its Biological InorganicChemistry
R. J. P. WILLIAMSa AND J. J. R. FRAUSTO DA SILVAb
a Inorganic Chemistry Laboratory, Oxford University, South Parks Road,Oxford OX1 3QR, UK; b Instituto Superior Tecnico, Universidade Tecnicade Lisboa, Lisbon, Portugal
1.1 Introduction
The brain is a complex structure, composed of many zones organised ascompartments that are apparently isolated by the manner of folding of theouter structure and by the packing and types of cells in the structures (Figure1.1 and Table 1.1).1,2 The functions of the compartments and the chemicals inthem, distinguished by staining, apart from their physical characteristics, giveways of delineating them. It is also possible to describe the zones by the size oftheir differentiated electrical responses stimulated by actual or experimentaloutside events. A more detailed level of division of the description of the zonesis by the cellular and membrane structures and their differences. There are twomajor classes of cell types in all zones, neurons and glia, and we shall describethem in turn, at first as if they were independent cell types. Each neuronappears to be separated from all others spatially and by several surroundingglial cells except for deliberate connection made between neurons at synapticjunctions. In this general introduction we draw special attention to the partplayed by metal ions and their enzymes.
RSC Drug Discovery Series No. 7
Neurodegeneration: Metallostasis and Proteostasis
Edited by Danilo Milardi and Enrico Rizzarelli
r Royal Society of Chemistry 2011
Published by the Royal Society of Chemistry, www.rsc.org
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1.2 The Structure of Neurons
The simple description of a neuron is that it is made of a central nuclear body ofill-defined shape but considerable volume, see Figure 1.2(a) and (b), with longvery thin tubular extensions called axons. The extensions have termini, which
Figure 1.1 A general outline of the zones of the human brain; see Table 1.1 for theirsituation in the three major parts of the brain.
Table 1.1 Divisions and zones of the brain.
Major Division Principal Zones Sub-zone
Forebrain Cerebral cortex Olfactory bulbBasal ganglia Caudate nucleus, striatumLimbic system Amygdala, hippocampusThalamus Connected to eyesHypothalamus See pituitary
Midbrain Tectum Pineal, connected to eyesRed nucleus
Tegmentum Substantia nigra, raphe nucleiHindbrain Pons Locus coeruleus, raphe nuclei
CerebellumMedulla
Taken in part from Physiology of Behaviour, ed. N. R. Clarkson, 6th edn, 1998, Allyn and Bacon,Boston.
can act as donors or acceptors of chemicals in the message system of brainstates and are seen as somewhat bulbous regions, see Figure 1.2(c). The phy-sical structure of the central region of the neuron (the soma) is that of aeukaryotic cell and has the usual compartments of organelles and vesicles. Theaxons are structured internally by conventional fibrous proteins, includingtubulins capable of allowing transfer of vesicles from the central body to thebulbous termini. The membranes of the axons in the brain cover long stretchesbetween ‘‘nodes of Ranvier’’, Figure 1.3, where there are active channels andpumps forNa andK ions. The protection is provided bymyelin proteins producedby oligodendrocytes, a special kind of glial cell. In general it is considered that theaxons are just long-range connections between the central region and the bulboustermini. Themajor components of the liquid in themare generally considered to beof the same ionic content as the cytoplasm, but have few, if any, enzymes and littlemetabolic activity.However, the nodalmembraneshave iongates andATP-ases aspumps.We return to the chemical composition at termini later since these bulbouszones have a concentration of vesicles of differing chemical contents. The outermembranes here have the usual contents and properties of the eukaryotic cell,being able to exo- and endocytose, and have numerous enzymes on the surfacesable to act in donor or acceptor capacities, especially as channels and pumps. Theaxons are able to grow independently by cellmultiplicationor replication.The cellsare physically surrounded by extracellular fluid, which in the brain is a special fluidseparated from the blood by a blood–brain barrier. Although the whole brain isaerobic andneurons require oxygen theyare also supportedwith somenutrients byglial cells. There is also extensive connective tissue composed of proteins andpolysaccharides to maintain structure.
1.3 The Chemical Activity of Neurons
The main chemical activities of the nerve cell are simply divided. The centralregion is one major supplier of small and large chemicals and energy to itsaxons and then to the bulbous termini. The axons, at active nodes, seem only to
(a) (b) (c)
Figure 1.2 An outline of a nerve cell: (a) cross-section, (b) a neuron, (c) sensory andmotor connections via synapses.
3An Introduction to the Brain and its Biological Inorganic Chemistry
require a large amount of energy to maintain their electrical activity, which istheir dominant function. The activity is a self-sustaining relay of electrostaticion flow of such a character that it allows depolarisation and repolarisation dueto the flowofNa1/K1 ions from inside to outside, and its reversal, see Figure 1.3.On allowing initial depolarisation through channels the wave of depolarisationtravels along the axon as an electrical signal, but the axon recovers immediatelyby pumping the ions back into itself. It is very important, therefore, that both theinternal cytoplasmic and the external concentrations of the fluids, see Table 1.2,are very precisely fixed. The maintenance (homeostasis) of Na1 and K1 ions is acritical factor in nerve and brain chemistry. Note that it is standard hospitalpractice to monitor these levels in humans for any sign of weakness, which couldultimately affect the brain.The depolarisation wave travels to the termini at the synapse where it acti-
vates donor events. The donation is of transmitters, which travel to acceptorcentres in the opposing neuron of an adjacent synapse after release fromstorage vesicles. The chemistry involved thereafter is complex. We shalltherefore leave aside the chemical activities in the axons while we describe those
(a)
(b)
Figure 1.3 The distribution and flow of Na1 ions carrying a message in an axon. Theneuron in (a) is not myelinated. Note: K1 flow is in the opposite sense dueto a combination of ATP-ases and gates.
of the bulbous zones. These terminal zones have outer membranes, whichdirectly or indirectly are stimulated by the depolarisation wave to allow calciumion entry into the cytoplasm of the bulb. In turn the calcium ions cause afilamentous action to move the vesicles holding transmitters to the cellmembrane where they discharge either their small molecules or ions into theextracellular fluid, directed as much as is possible toward a bulbous zone of areceptor cell. This cell then initiates a second Na1/K1 wave down its axon,using the ion gradients. The outside concentrations are shown in Table 1.2while the inside concentrations are: K1 approx. 100 and Na1 approx. 5 mEqper kg H2O. The small molecules and ions, e.g. Zn21, are both called trans-mitters. The donor bulbous region must now quickly recover its restingchemical content by filling its depleted stores in vesicles; see also Glial Cells.The energy required for the passage of a signal is considerable.The chemical content of particular interest lies in the packaging of trans-
mitters in the vesicles, which can contain a vast number of different organic andinorganic ions. Different neurons have different vesicle contents. Analysisindicates that these include both positive, e.g. adrenaline (epinephrine), andnegative, e.g. glutamic acid, or even zwitterions, e.g. g-amino butyric acid andsmall cations such as Zn21. We have listed some of them in Table 1.3. Notesome of the brain amino acids are D- not the conventional L- of the main body.The peptides may not be present in a simple immediately available form, butmay be part of larger peptides or proteins, e.g. chromogranin A, which arehydrolysed on external release to give statin-like peptides.3 The differentlycharged transmitters cannot be stored without molecules carrying the oppositecharge. Adrenaline is stored with adenosine triphosphate (ATP), which in thiscase is free from Mg21, but there is some Ca21 in the vesicle. The storage ofacidic transmitters appears to be with Na1 (not K1).A second activity of the neuron does not concern ions ormolecules but a variety
of proteins and some enzymes. They include those in the central area, those in thesynapse bulbs and those in the axons. The enzymes in the central zone catalysetubulin synthesis for extension as the axon grows. Axon growth occurs onlywith repeated electrical activity of the neuron and is therefore associated with
Table 1.2 Elements in rat brain cerebrospinal fluid (CSF) and organs (mEqper kg H2O).
long-termmemory. The proteins necessary in the synaptic bulbs for storage of themessenger molecules, transmitters, are transported along the tubulin from thecentral region to the bulbs. Hence the central region is responsible for transmittersynthesis, but transmitter recoveryoccurs at the synapses (seeGlialCells).Analysisof a nerve cell is a basic task but in the brain it is essential that, as well as generalanalysis, we can image where any type of neuron including its synapse is located.The study of the locations depends on: (1) direct methods for metal ions contents,including single atommicroscopes, assuming that different neurons have differention contents, (2) use of such tools as direct fluorescence or fluorescence of addeddyes which may reflect contents of neurotransmitters directly as they are at highconcentration in bulbous regions. Typically the presence of free or very weaklybound zinc can be detected by very high resolution electron microscopy or by theuse of the dye-stuff dithizone. A very interesting example of a parallel but differentdirect spectroscopy analysis of vesicles of cells is that of the adrenal gland. Thevesicles of the gland release transmitters in much the same fashion as the neuronsdo. The cells of this gland resemble neurons in that they contain adrenaline, somecorticosteroids, adenosine triphosphate and a protein, chromogranin A, which isthe source of certain peptide hormonalmolecules such as enkephalin.Much of thecontent of the vesicles of the whole organ can be visualised by nuclear magneticresonance (NMR),3 including all four types ofmessengermolecule. It is possible touse brain slices to perform similar NMR analyses.
Table 1.3 Messenger compounds between cells in the brain.
The main enzymes of the neurons are in the three groups of the normal com-plement of aerobic eukaryotic cells, so they can catalyse the common activities ofglycolysis, the Krebs cycle and conventional syntheses. The neurons havemitochondria and the usual vesicles of the endoplasmic reticulum. In additionthey must have the ability to synthesise the transmitters. In so far as the trans-mitters are specialised in different neurons so their enzymesmust be present in thespecific cell central region. Themajor separation of transmitters is into those thatrequire specific oxidation, e.g. adrenaline and amidated peptides, and those thatdo not, e.g. glutamate. Oxidation enzymes are usually iron-containing in thecytoplasm and copper-containing in vesicles or externally. The analysis locallyfor copper and iron and their enzymes is therefore very useful. Some of theseenzymes should be in higher concentration than in other cells. Zinc enzymeanalysis, equally important, is confused by local concentrations of free zinc invesicles. Enzymes other than those containing metal ions must be recognised byfluorescent products. We return to the distribution in the different neurons whenwe have described the analysis of the brain’s zones.A peculiarity of nerve cells generally but very importantly in neurons is the
synthesis of the myelin sheath. Myelin is 80% lipid and 20% protein, holdingthe multi-layered membrane rigid. The protein somewhat resembles an outerskin of keratin and its final cross-linked state requires copper oxidases. It is veryunusual for an internal cell to have such protection. Note that vitamin B12
(cobalamine is the active form of vitamin B12) is necessary to protect thesynthesis of myelin.Neurons in the brain need to grow to make new contacts so as to create long-
term memory. Short-term memory may not need such growth. These nervescontain the proteins enabling extension of the axon, the cell. They musttherefore have not only tubulins but actomyosin filaments and these proteinsmust be carried down the axons. The actomyosin proteins are also responsiblefor the ejection of chemical transmitters from the vesicles as their contractilefunction, linked to calcium stimulus, moves the vesicles to the outer membranefor discharge. The activity of the actomyosin contraction is mediated by ATPhydrolysis, which is generally of the Mg–ATP complex where Mg acts as arequired unit. This activity of a kinase is dependent on calcium entry into theneuron synapse bulk. There are several metal ions of great importance in thebrain and nervous system, especially sodium, potassium, magnesium, calcium,iron, copper, zinc, cobalt and manganese. The details of their distribution asfree ions or in enzymes, the metallomes, in different brain zones must be amajor area for future research.
1.5 Glial Cells
The glial cells (glia)2 which occur in the central nervous system (CNS) andin the peripheral nervous system (PNS) are much more abundant than theneurons and occupy one half of the volume of the brain. Their number in
7An Introduction to the Brain and its Biological Inorganic Chemistry
the human neocortex is about 36–39 000 000 000, and they can reproduce.For many years they were thought to have only the function of supporting theneurons physically (their name derives from the Greek glia, glue), but it is nowknown that besides this function they are essential to maintain and repair theneuronal system, to control the formation of the synapses and to participate inthe mechanism of production of energy in the CNS, besides transportingessential ion and organic molecules to the neurons.In effect there are five different kinds of glial cell: the astrocytes, the oligo-
dendrocytes, the Schwann cells, the microglial cells and the satellite cells.The astrocytes (the name is derived from their star shape) are very relevant,linked to the functions of the neurons, and it can be said that they control theformation of the synapses, which they isolate, forming a kind of externalbarrier. The same happens near the nodes of Ranvier, near where the Na1 andK1 channels are concentrated. As mentioned above, these cells also transportions and other substances required in an intercellular pathway by the neuronsand participate in the mechanism of production of energy in the CNS, pro-viding energetic substrates in an activity-dependent manner (pyruvate, lactate,glucose). They also regulate the level of glutamate in the synaptic space,removing K1 from these spaces, regulate the pH of the cerebrospinal fluidand connect the synaptic activity with the blood flux. Finally they protectagainst oxidation stress and remove toxic substances (such as ammoniaand cell detritus). Note that a Mn21 enzyme (glutamine synthetase) occursspecifically in the astrocytes and converts glutamate and ammonia to gluta-mine. The astrocytes and the neurons communicate via intercellular holesor channels that allow the trafficking of ions and small molecules in theso-called ‘‘gap junctions’’ but they can also act by extracellular trafficking ofions and signalling molecules. In this way they help to produce a kind ofnetwork in which information circulates in the relevant areas of the brain as achain of reactions.Two other kinds of glial cell are the oligodendrocytes (in the CNS of evolved
vertebrates) and the Schwann cells (in the PNS), both of which producethe myelin layers that coat the neuronal axons, isolating them from electroniceffects and controlling the concentration of the ionic Na1/K1 channels inthe nodes of Ranvier. The fourth kind of glial cell is the group of the smallmicroglial cells that have a neuroimmunological function, responding todisease or aggression, phagocytosing cell detritus and providing anti-inflammatory responses; they have, therefore, a function of protection of othercells. The last of the five glial cells, the satellite cells, give physical support to theneurons in the PNS and help in the regulation of the external chemicalenvironment.All these five kinds of glial cell act as an integrated functional unit, but
the production of vasodilators, including nitric oxide, carbon monoxide, ade-nosine, arachidonic acid, etc., derives from the activity of the neurons.The metal ion and metalloenzyme content of the glial cells is not knownbut their specialist functions will demand a differentiated distribution of ionsin them.
1.6 Analysis of Cerebrospinal Fluid and Connective
Tissue
The CNS, including the spinal cord, is surrounded by a special fluid separatedfrom the rest of the body by the blood–brain barrier or series of membranes.The fluid differs in content from the normal extracellular fluids in that it con-tains very few proteins and enzymes. The major mineral content of the cere-brospinal fluid (CSF) is much the same as that outside the brain, although thecalcium seems to be somewhat lower, but the absence of proteins and enzymesimplies that the extracellular activities are extremely limited. It may be that thedemand for growth has to be restricted to zones of intense activity in responseto particular external events. It is stimulated then at the cellular level and is notmanaged as a general widespread development of the whole brain.The connective tissue appears to be composed of similar proteins and sac-
charides to this material elsewhere in the body. The synthesis of these oftencross-linked polymers requires copper oxides and the breakdown of them toallow growth needs zinc proteases. Connective tissue damage, as elsewhere inthe body, can lead to serious disease. It could be that the failing of memoryis not only related to difficulties associated with old age; see the followingchapters.
1.7 Analysis of the Whole Brain
The analysis of the whole brain is not very meaningful though it is of interest tosee how certain elements change during growth (Table 1.4). The table indicatesthat the growth of cells is very considerable relative to the extracellular fluid.There are indications that this reverses in old age as cells tend to die and are notfully replaced. Nerve–nerve connections increase rapidly immediately afterbirth. We do not give any detailed data on trace elements since, generallyspeaking, the whole brain does not differ from several other organs of the body
Table 1.4 The ionic composition during development of the human brain.
in this respect. Details of the free and bound metallomes in the cytoplasm ofcells are given in our books and relate to local and general activities. There arehowever considerable amounts in vesicles and in all cell components, includingmitochondria. Special attention has been directed to zinc,4–6 as it has beencorrelated with some hormone functions in growth.
1.8 Chemical Analysis of the Brain Regions
The analysis of the brain has to be conducted in defined regions, as it is not ahomogeneous organ. The observations so far are still limited despite the pro-gress in imaging, and so we can do no more than give an outline of what isknown and what it is desirable to know if we are to understand normal anddisturbed brains. We shall divide the topic into cell contents and the sur-rounding cerebrospinal fluids and shall refer mainly to neurons and transmit-ters, but there are a few general remarks which we can make first with regard toall the different cells, neurons, glia and others. We consider that the free ionscontent of the cytoplasm of the cells, the free metallome, is closely similar tothat of all aerobic cells (Figure 1.4). The levels of all free ions for K1, Na1 andMg21 are above 10–4 M while those for all the other cations and anions, such asCa21, are below 10–6 M. The free ions of the trace elements are extremely low,sometimes below 10–10 M. The levels in the mitochondrial cytoplasm are dif-ferent, and for example Fe21 is close to 10–6 M there. This says nothing aboutthe bound ions, the bound metallome, which is low for K1 and Na1 but isaround 10–3 M for Mg21 in all cells. The bound levels of the other trace ele-ments are dependent on the precise zone of the brain under discussion.
Figure 1.4 The free metal ion content of the cytoplasm of cells, the free metallome.
The important elements selective for particular zones are the content of theneuron vesicles themselves, ions, small or large molecules and the enzymes forproducing these small molecules, presumably in the central regions of cells. Thefree cation contents in these vesicles of special interest are those of zinc andcalcium. In the case of zinc the free ion is associated with glutamate trans-mitters, particularly in mossy fibre vesicles. This association requires that thevesicle content, probably made in the central region of the cell, is pumped intothe vesicles up to a total content of close to 10–4 M. One pump protein is aknown heavy element vesicle membrane ATP-ase. After release of its contentsthe empty vesicle may return into the synaptic vesicle of the neuron and berefilled. The zinc released is thought to modulate the action of the glutamate insome of its receptors. Apart from the free zinc in vesicles this metal has quitegeneral importance in all cells, particularly in zinc finger transcription factors.Zinc exchange is mediated by special proteins, such as the hydrolases, which arenecessary in the hydrolysis of peptides, and carriers and buffers, so that thiselement controls many functions including growth.We turn now to the small molecules other than glutamate while noting
that those carrying charge need a counter ion. A good example is adrenaline,which requires ATP3– in the ratio of one for three molecules of adrenaline,but the vesicles do not contain high Mg21, the usual counter ion of ATP3–
in enzyme reactions. The interest centres in the synthesis of adrenaline and theuptake mechanisms for both adrenaline and ATP3–. The synthesis is especiallyintriguing as it involves two steps of oxidation by iron and copper oxidases, thefirst in the cytoplasm but the second in the vesicle itself. In either casethe presence of the two in a specific zone in high concentration should berecognisable by analysis. Table 1.3 gives zones with content of the majorhydroxylated transmitters noradrenaline, adrenaline and serotonin, andTables 1.5 and 1.6 give those with high zinc and copper. The substantianigra and the locus coeruleus stand out in both tables, but there are markeddifferences and also differences of both from the distribution of non-haem iron,Table 1.7. We do not know how this selectivity is achieved but in effectthe different neurons of the brain are differentiated cells with differentDNA expression.
Before we leave the topic of adrenaline vesicles we again refer to these vesiclesin the adrenal gland. The study of the whole adrenal gland by nuclear magneticresonance (NMR) was the first such study of a whole organ. The examinationshowed that the signals from adrenaline and the ATP, known to be in vesicles,were sharp, indicating that they were freely mobile. Interestingly the studyrevealed that the vesicles also contained a functional largely unfolded protein,chromogranin A, and certain steroids were present in high amounts in thecytoplasm. Inspection of the unfolded chromogranin and of its hydrolysisrevealed that it contained short hormonal peptides. Similar studies of thevesicles of other glands have shown that for example hydroxytryptamine(serotonin) was stored with other pyrophosphates. They require synthesis byiron and copper oxidases. These studies3 imply that high resolution protonNMR of local brain regions either in situ or in slices could reveal much aboutthe vesicles and their content, but while there are also good stains for the zinccontent of cells there are only poor methods available as yet for copperimaging.Another bound metal ion is iron, but it is loosely bound relative to zinc
binding so that free Fe21 in the cytoplasm is high, 10�6 M, and it speaksdirectly to enzymes and to transcription factors. Important in the brain are thehaem-containing brain-specific neuroglobins and a special cytochrome - P450,
Table 1.6 Copper concentration in human brain zones.
Zone Cu concentration (mg/g wet weight)
Cerebellar cortex 10.4Hippocampus 6.6Substantia nigra 18.8Locus coeruleus 62.0Others o10.0
From: J. R. Prohaska, Physiol. Rev., 1987, 67, 858–901.
aThese zones are centrally placed in the regions of the midbrain and the lower part of the forebrainand above the hindbrain, where there are also Raphe Nuclei, see Figure 1.1 and Table 1.1.From: M. B. H. Youdin (ed.), Brain Iron, Taylor and Francis, London, 1988.
the non-haem, non Fe/S, hydroxylases which participate in the early steps ofoxidation to give the aromatic transmitters. Just as is the case with other metalions too much or too little iron is dangerous in the brain. The supply by carrierproteins of iron and other metal ions such as zinc and copper does not occurthrough the extracellular fluids which have so little protein. The questionremains as to whether this is a function of glial cells.Manganese is a further essential metal ion in glutamine synthetase and in
glycosylation of proteins in the endoplasmic reticulum. Excess manganese doesaffect brain function as has been observed in manganese miners. There is someevidence for the value of molybdenum in sulfite oxidase in some neurons.
1.9 Evolution of the Brain
Great interest centres on how the brain evolved,6 since it may throw light onhow it functions, but we can only make some speculative remarks as so little iscertain. We know that the nematode worm and the octopus have very primitivebrains (Table 1.8), and probably little more than corresponds to the cerebrumor cerebellum in the earliest brains in invertebrates (Figure 1.5). These zonescoordinate movement and short-term memory and are largely associated withwhat we take to be the earliest transmitters, as shown in Table 1.7. The laterdevelopments of the brain are also shown in Figure 1.5 and include theenlargement of the cerebrum and the cerebellum.Quite possibly this correspondsto the introduction of long-term memory capacity and the more complex sets ofmovements. Most novel development between the brains of the nematodeworms and the most advanced animals lies in sense organs and in control ofsleep/wake and endocrine systems. They lead to the complicated states of mind
Table 1.8 Possible evolutionary stages of chemical systems in brain.
As above plus first hydroxylations givingSerotonin and dopamine; Iron/pterinChemistry in cytoplasm; vesicle filled in centre of cellRecovery by amine oxidation (flavo-enzymes)
Jawless fish (Cambrian) As above; second hydroxylation giving noradrenaline andamidated peptides
Copper chemistry in vesiclesRecovery additionally by hydrolysisZinc enzymes
Complete vertebrates(Late Cambrian)
As above plus myelinated neurons? Use of zinc enzymes in glial cells? Free zinc
Many animals? NO/haem chemistry ? in glial cells?
n.b. Note that many transmitters are synthesised in special zones.
13An Introduction to the Brain and its Biological Inorganic Chemistry
Figure 1.5 A view of the later developments of the brain. A way to follow metal ioninvolvement during evolution is to analyse these brains, even going backto the octopus and the nematode worm.
and to its disturbances. We may suppose that their evolution was dependent onnovel transmitters and novel enzymes for their synthesis. The most obviouslikely novelty was through modification of pre-existing amino acids and pep-tides. They are the hydroxylated amino acids, tyrosine, tryptophan (adrenalineand serotonin), and the amidated peptides prepared by hydroxylation (oxida-tion) of their carboxyl-terminal glycine. The probability of these transmittersbeing a late addition is that the enzymes responsible for their production are allcopper enzymes. The small molecule transmitter nitric oxide is also prepared byoxidation of another amino acid, arginine, using haem enzymes. It is worthobserving that the content of copper is higher in the substantia nigra and locuscoeruleus, see Table 1.6. These zones are responsible for motor system connec-tions and awareness (sleep/wake balance) and appear to be a late addition.Metalanalysis of primitive brains could be very useful in the understanding of thebrain’s evolution.Another metal ion which has a strong locational differentiation in the zones
is zinc. It is high in the hippocampus (Table 1.5), which includes the somewhatpeculiar neurons, the mossy fibres, which are considered to be functionalparticularly in spatial resolution and emotional states. We may well think thatthese are recent developments in the brain. The very presence of considerablecopper and zinc in biochemical catalysis of reactions is of relatively recentorigin, after 0.75 billion years ago. Thus a consistent story could well be builton the development of brain functions, of novel organic molecules and zincused as transmitters, and the introduction of copper and zinc in quantity inbrain cells. This would suggest that, based on biochemistry, some of thetransmitters arose before a billion years ago as the source of the most primitiveactivity associated with the brain, for example coordinated body movements,while more recently the variety of transmitters has increased.
1.10 Major Functions of the Brain Zones
The general outline of brain functions is known but details are lacking.Table 1.9 lists the possible outstanding functions of brain regions but we mustremember that the brain may work as one very large integrated organ withmajor contributions of particular responses from a local region and with minorcontributions from many others. The reason for different transmitters orgroups of transmitters in particular zones of neurons appears to be unknownand maybe they are just historical accidents. This possibility is brought out ifwe look at the evolution of the brain functions from its beginning in nematodesto the sophistication shown in humans (Table 1.10). One approach is to look atbrain aberrations from those of a minor kind to those of a major kind includingthese caused by local injury. Another indication is the effect of drugs thatalleviate certain abnormalities in behaviour such as the use of adrenaline(epinephrine) in the treatment of Parkinson’s disease. These matters are thesubjects of many of the chapters in this volume and we draw attention only tothose thought to be related to inorganic elements.
15An Introduction to the Brain and its Biological Inorganic Chemistry
Many chapters of this book are devoted to injury to the brain and drugs used tocombat brain damage. We can only draw attention to the frequent con-centration on the oxidised transmitters and related drugs and on the problemscaused by the presence of excesses of metal ions such as Mn, Cu, Fe and Zn. Weare still at some distance from understanding the bioinorganic chemistry ofthe brain, although excessive or aberrant oxidation is thought to be a majorproblem. Of major interest are Parkinson’s disease, related in some way toadrenaline (epinephrine), and Alzheimer’s disease, associated with the
Cerebellum Movement coordinationTectum (pineal) Light and auditory responsesHypothalamus Controls autonomic nervous and endocrine systems:
internal milieuRed nucleus and substantianigra
Motor system connections
Locus coeruleus Vigilance, sleep/wake cycleMedulla Control of heart and skeletal muscle
aZones are interconnected but the very fact that they differ in chemical composition, physicalappearance and that damage to them causes differential disturbance indicates that they have majorfunctional roles in addition to general cooperative ones.Taken in part from: J. D. Fix, High-yield Neuroanatomy, Lippincott, Williams and Wilkins, Phi-ladelphia, 2nd edn, 2000.
Table 1.10 Possible evolution of the properties of the brain.
Species Brain Characteristics
(1) Nematode(4500 � 106 years)
Simple nerve net from body to head regionNo senses except touch and general chemotaxis. Ring (ofnerve cells) brain.
(2) Amphioxus(B500 � 106 years)
As for (1) with an eye spot. Some coordination of sightwith the body. No evidence of olfactory or hearingsenses. Little or no telencephalox or cerebral cortex.
Has forebrain, pineal and hypothalamus-like systems.(3) Jawless fish(450 � 106 years)
As for (2) with olfactory system and a cerebellum formaintaining posture while viewing.
Very small cortex and telencephalox.(4) Vertebrates with jaws(400� 106 years)
As for (3) with ever more complex states of awareness.Development of myelin and of mid-brain. Enlargedcortex.
(5) Warm-blooded animals(350 � 106 years)
As for (4) with temperature controls. Enlarged cortexand states resembling emotions and consciousness.
Taken in part from: J. M. Allman, Evolving Brains, Scientific American Library, New York, 2000.
formation of b-amyloid protein plaques, which can bind both copper and zinc.4
Is the problem of the plaque not just its presence but its ability to collect metalions and become an active enzyme?
1.12 Conclusions
This introduction to the role of metal ions in the brain has required a pre-sentation of many general features of this complex organ. Against this com-plexity it is clear that much detail is lacking so that any definite conclusions asto the exact roles of the metal ions are not yet available. We have thereforeattempted no more than an approach showing the problems. Subsequentchapters describe the present state of our knowledge of various normal andabnormal conditions of the brain in the context of this general outline. It isshown that, as elsewhere in the body of organisms, several metal ions havemajor roles both as free ions and in combination with proteins.
References
Note. Much of the material of this chapter is taken from previous articles andbooks. We draw attention especially to references 1 and 2. Other major refer-ences are included in the Tables where they are most relevant.There have been several publications recently on brain chemistry related
to this chapter. In particular the article by M. J. Pushie, I. J. Pickering,G. R. Morton, S. Tsutsui, F. R. Jink and G. N. George, Prion proteinexpression levels atters regional copper, iron and zinc content in the mousebrain, Metallomics, 2010, 3, 206–214.1. R. J. P. Williams, J. Inorg. Chim. Acta, 2003, 356, 27–40.2. J. J. R. Frausto da Silva and J. Armando L. da Silva, The Inorganic
Chemistry of the Brain (in Portuguese), Gradiva, Lisbon, 2008.3. A. Daniels, R. J. P. Williams and P. E. Wright, Nature, 1976, 261, 321–323.4. A. Kretzel and W. Maret, J. Amer. Chem. Soc., 2007, 129, 10911–10921.5. R. J. P. Williams, Endeavour, 1984, 8, 65–70.6. J. J. R. Frausto da Silva and R. J. P. Williams, The Biological Chemistry of
the Elements, Oxford University Press, Oxford, 2001.
17An Introduction to the Brain and its Biological Inorganic Chemistry
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