Dietary Chemicals and Brain Function Graham A

i i \Main" | 2003/4/21 | 18:25 | page 57 | #3 i i Journal & Proceedings of the Royal Society of New South Wales, Vol. 135, p. 57{71, 2003 ISSN 0035-9173/03/020057{15 $4.00/1 The 33rd Liversidge Lecture for the Royal Society of NSW Dietary Chemicals and Brain Function graham a. r. johnston Abstract Phytochemicals in our diet may play a vital role in maintaining the brain's chemical balance by influencing the function of receptors for the major inhibitory neurotransmitter GABA. The flavonoids apigenin and epigallocatechin gallate, found in chamomile and green tea respectively, influence the way in which GABA receptors are modulated by drugs such as diazepam. Resveratrol, a flavonoid-like polyphenol found in red wine, acts on a subtype of GABA receptors consistent with its action as a cognitive enhancer. Bilobalide from Ginkgo biloba, a herb used in cognitive therapy, also influences GABA receptors. α-Thujone, a terpenoid in the alcoholic beverage Absinthe, acts in a similar manner to bilobalide on GABA receptors. ( )-Borneol and other terpenoids from Valerian, a herb used to promote sleep, enhance the effects of GABA. The effects of these phytochemicals on GABA receptors are consistent with the overall actions of the beverages and herbal preparations that contain them, thus providing a rational basis for the use of these beverages and herbal preparations. These studies provide evidence that chemicals in our diet may influence brain function in a positive way. The chemical nature of these substances may lead to the development of new therapeutic agents for the treatment of anxiety, epilepsy, memory disorders and insomnia. Keywords: Brain function, chemicals, diet, balance, dosage THE BRAIN'S CHEMICAL over excited brain (as in Figure 1) that can be BALANCE manifested as anxiety, agitation, exhilaration, convulsions and death. On the other hand, an Two simple chemicals, glutamic acid and excess of inhibition over excitation can be man- GABA (Figure 1), are responsible for most of ifested by depression, anaesthesia, coma and the communication between nerve cells in the death. The particular manifestations of such brain. Indeed, at a very simple level, brain func- imbalances in the brain depend on what neu- tion may be thought of as a balance between ronal circuitry is involved. excitation mediated by glutamic acid and inhibition mediated by GABA. Ethanol is an example of a chemical that All nerve cells in the brain have receptors acts on both sides of the brain's chemical bal- for glutamic acid and GABA. Some 40% of ance. The CNS depression that results from in- nerve cells release glutamic acid as an excita- gestion of ethanol is due to a reduction in excitatory neurotransmitter, while a different 40% re- tion mediated by glutamic acid acting on a sub- lease GABA as an inhibitory neurotransmitter. type of glutamate receptors known as NMDA The balance between these two chemical trans- receptors and to an enhancement of inhibition mitters is vital to normal brain function. An mediated by GABA acting on GABAA recep- excess of excitation over inhibition results in an tors. i i i i i i \Main" | 2003/4/21 | 18:25 | page 58 | #4 i i 58 JOHNSTON H2N COOH H2N COOH COOH GABA Inhibition + ((( Glutamic acid ((( (((( ((( Exitation (((( (((( ¢B + ((( (((( ¢ B ¢ B Figure 1: The brain's chemical balance between excitation mediated by the major excitatory neurotransmitter, glutamic acid, and inhibition mediated by the major inhibitory neurotransmitter, GABA. GABA RECEPTORS oocytes from the South African frog, Xenopus laevis following injection of either DNA or RNA GABA (whose name is derived from the old cloned from human brain and coding for par- chemical name, γ-aminobutyric acid) acts on ticular GABA receptor protein subunits. These three main types of receptor to influence brain oocytes have the necessary cellular machinery to function. GABAA and GABAC receptors are make the human proteins and assemble them on fast acting receptors that belong to the group the surface of the oocytes as functional GABA of receptors called ligand-gated ion channels receptors. The oocytes are approximately one (LGICs) (Chebib and Johnston, 2000). GABA millimetre in diameter and readily penetrated acts as the ligand gating these receptors to by glass microelectrodes. Using 2-electrode open channels specific for chloride ions, allowing voltage clamp methodology, the effects of chem- these ions to flow rapidly into nerve cells mak- icals on the function of these GABA receptors ing them more negative and thus harder to ex- may be assessed in a convenient quantitative cite. GABAB receptors act more slowly, induc- manner. For example, using recombinant recep- ing metabolic changes in nerve cells and belong tor technology, the effects of anti-anxiety agents to the group of receptors called G-protein cou- such as diazepam (Valium) on GABA recep- pled receptors (GPCRs) (Bowery et al. 1997). tors can be easily shown to be restricted to a specific sub-group of GABAA receptors. The The study of GABA receptors has been rev- technology is not restricted to the study of pure olutionised by the introduction of recombinant chemicals { relatively crude mixtures of chem- receptor technology whereby receptors cloned icals can be studied, for example to follow the from human brain are expressed in cells that do purification of chemicals acting on GABA re- not normally express such receptors (Barnard et ceptors from extracts of herbal products. al. 1998). The recombinant receptors so formed may be studied in relative isolation using stan- dard electrophysiological methodology. Since FLAVONOIDS AND TERPENOIDS all GABA receptors are made up of protein subunits, recombinant receptors of known subunit Flavonoids are polyphenolic chemicals widely composition may be studied. distributed in the plant kingdom particularly The most common way to study recombi- in flowering plants. Flavonoids are responsi- nant GABA receptors is to express them in ble for many of the brilliant colours of fruits i i i i i i \Main" | 2003/4/21 | 18:25 | page 59 | #5 i i DIETARY CHEMICALS AND BRAIN FUNCTION 59 and vegetables and are important constituents van, epigallocatechin gallate (Figure 2). of red wine, green tea and many herbal prepa- Terpenoids are also widespread in plants, es- rations (Aherne and O'Brien, 2002). Chemi- pecially in what are known as essential oils that cally, flavonoids are C15 compounds based on can be extracted from plants and have a wide the chromane ring structure. Flavonoids have range of uses from perfume constituents to paint been studied extensively as anti-oxidants and thinners. Terpenoids are oxygenated products oestrogens (Collins-Burow et al. 2000). Many formally derived from C5 isoprene units and are of them show anti-cancer and anti-viral proper- classified by the number of C5 units in their ties (Le Marchand, 2002). structure. Thus monoterpenoids have 2xC5 There is an extensive literature on the effects units, sesquiterpenoids 3xC5 units, diterpenoids of flavonoids on GABA receptors (for a recent 4xC5 units and triterpenoids 6xC5 units. In review see Marder and Paladini (2002), dating the present context of actions on GABA recep- from the discovery of some plant derived isofla- tors, the following terpenoids are of interest: vans in bovine urine that inhibited the bind- α-thujone, ( )-borneol, bilobalide and picrotox- ing of diazepam to brain membranes (Luk et inin (Figure 3). Picrotoxinin is widely used ex- al. 1983). In the present context of actions on perimentally as a non-competitive antagonist of GABA receptors, the following flavonoids are GABAA and GABAC receptors, however, its of interest: the flavone apigenin; the isoflavone convulsant action restricts its therapeutic use genistein; the flavanone naringenin; and the fla- (Chebib and Johnston, 2000). OH HO O HO O OH O OH OH O Genistein, an isoflavone found in soy products, including tofu. Apigenin, a flavone found in chamomile tea and related beverages. OH OH OH HO O OH HO O O OH OH O OH O OH Naringenin, a flavone found in grapefruit. OH (-)-Epigallocatechin Gallate, a flavan found in green tea. Figure 2: Some representative flavonoids i i i i i i \Main" | 2003/4/21 | 18:25 | page 60 | #6 i i 60 JOHNSTON CH H C 3 CH3 3 H3C CH3 CH3 O OH α-Thujone, a monoterpene ( )-Borneol, a monoterpene from Artemisia absinthium from Valerian officinalis O O O O H H OH HO O O O OH O O O O H Bilobalide, a sesquiterpenoid Picrotoxinin, a sesquiterpenoid from from Ginkgo biloba Anamirta cocculus Figure 3: Some terpenoids that influence GABA receptors i i i i i i \Main" | 2003/4/21 | 18:25 | page 61 | #7 i i DIETARY CHEMICALS AND BRAIN FUNCTION 61 APIGENIN FROM CHAMOMILE bell in our research group investigated the ac- TEA tion of apigenin on recombinant GABA receptors. She used electrophysiological recordings The lead compound for our investigations was from Xenopus laevis oocytes injected with re- apigenin (Figure 2), a flavonoid with a known combinant human RNA for the most common anti-anxiety action found in chamomile tea. subtype of GABAA receptor (α1β2γ2L) in the Chamomile tea is used widely to treat anxi- brain. The actions of GABA at these receptors ety and insomnia. Current therapeutic drugs are enhanced by a variety of modulators includ- used for the treatment of anxiety and insom- ing barbiturates, benzodiazepines, ethanol, and nia such as the benzodiazepines Valium and neuroactive steroids. Serepax act at GABAA receptors in the brain, She showed the action of apigenin on the increasing chloride flow into neurones, result- GABAA receptor is more complex than sug- ing in decreased neural activity. There were gested by earlier studies. The effects of api- divergent reports of the effects of apigenin on genin were biphasic dependent on the dose used.

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