INVITED REVIEW

Proc. West. Pharmacol. Soc. 50: 8-15 (2007)

Pharmacology of Taurine
Simo S. Oja1 and Pirjo Saransaari2*
1

The Centre for Laboratory Medicine and Department of Clinical Physiology and Nuclear Medicine, Tampere University Hospital,
2
Tampere, Finland; Brain Research Center, Tampere University Medical School, Tampere, Finland
*E-mail: blpisa@uta.fi

ABSTRACT:
Taurine has a number of physiological functions, e.g.,
in cell volume regulation and inhibitory neuromodulation. Taurine and its derivatives have also
been tested as potential pharmacological agents in
many pathological states. We endeavor here to
review the present status of this investigation.
Taurine (2-aminoethanesulfonic acid) is a simple
sulfur-containing amino acid present in virtually all
cells throughout the animal kingdom. In particular, it is
enriched in electrically excitable tissues such as
brain, retina, heart and skeletal muscles. In the
central nervous system, taurine has been implicated
in two major phenomena; in cell volume regulation [13] and in inhibitory neuromodulation or neurotransmission [4-7]. Its function as a neurotransmitter
implies the existence of specific taurine receptors and
the neuromodulatory role, an interference with
functions of other transmitter systems. There is scant
evidence to corroborate the first assumption, but
ample for the latter. In other tissues taurine has also
been thought to act as an antioxidant in cell
protection and to have beneficial effects on cardiovascular functions. These taurine properties are only
partially explored so far but taurine and many of its
derivatives have been tested as potential pharmaceutical agents in a number of pathological states.
Interference with GABA and Glycine Receptors:
Taurine has been shown to compete for the binding
of GABA to the GABA-benzodiazepine receptor
complex in brain membranes [8,9] and the binding of
ligands to the benzodiazepine site on this receptor
[10,11] modulating, allosterically, flunitr-azepam
binding [12]. At low concentrations taurine inhibits
GABA-induced Cl- ion fluxes into synaptic membrane
microsacs, but at higher concentrations, apparently
due to inhibitory properties of its own, it enhances
fluxe [13]. Moreover, taurine increases Cl- ion
conductance in cerebellar Purkinje cell dendrites [14]
in the rat substantia nigra [15], and in the rat main
olfactory bulb [16,17]. Taurine also displaces glycine
from its strychnine-sensitive binding sites in the
mouse brain stem [18] and acts at glycine receptors
in Xenopus oocytes injected with mouse brain
messenger RNA [19]. Taurine and glycine act on a
strychnine-sensitive site to open the same Clchannels in the rat sacral dorsal commissural
neurons [20].

Putative Taurine Receptors: It has been difficult to

determine whether all functions of taurine are
mediated by GABA and/or glycine receptors or
whether specific taurine receptors are involved, in
particular during development and in lower animal
species. We were the first to report taurine binding to
mouse brain synaptic membranes [21], when the
membranes were subjected to freeze-thaw cycles
and detergent treatments to extract as much as
possible of the endogenous taurine attached to the
preparations tested [22]. The taurine antagonist
(TAG, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide) proved to be an effective
competitor of this binding, but it was also affected by
the glycine receptor antagonist strychnine and by
GABA antagonists. In the frog spinal cord [23] and
the olfactory organ of the lobster [24], preliminary
identification and partial character-ization of the
putative taurine receptor proteins have been made.
Frosini and co-workers [5,6] have very thoroughly
characterized [3H]taurine binding to washed and
detergent-treated synaptic membranes from the
rabbit brain. They showed that taurine binding could
be competed for by TAG, 2-amino-ethylarsonate, 2hydroxyethanesulfonate
and
()cis
-2-aminocyclohexane sulfonate. Since these agents did not
interact with GABAA and GABAB receptors, the
binding studied does not thus represent binding to
GABA receptors, but the effects of glycine agonists
and antagonists were not tested. The matter of the
independent identity of taurine receptors is thus not
yet settled.
Antinociceptic Effects of Taurine: Taurine has
been shown to be antinociceptive. It is effective in the
acetic acid test [25], reduces nociceptive behavior in
the mouse formalin test [26], in the rat tail-flick test
[27] and autonomy after neurectomy in rats [28]. It
inhibits the biting and scratching behaviors elicited by
intrathecal administration of substance P [29] and
strychnine-induced scratching and self-biting in rats,
possibly by competing for strychnine binding [30], and
intrathecal N-methyl-D-aspartate (NMDA)- and
kainate-induced nocicep-tion in mice [31]. The
analgesic effects manifest themselves at the spinal
cord level, where taurine modulates nociceptive
impulses generated by the action of substance P [32].

Abbreviations: GABA, aminobutyrate; GES, guanidine ethanesulfonate; IEM1702, 2(benzylamino)ethanesulfonic acid isopropylamide
hydrochloride, MPP+, 1methyl4phenylpyridinium; NMDA, NmethylDaspartate; MY117, taltrimide, 2phthalimidoethanesulfonN
isopropylamide;TAG,taurineantagonist,6aminomethyl3methyl4H1,2,4benzothiadiazine1,1dioxide.

The analgesic effects are dose-dependent and at

least opioid and GABAergic mechanisms are involved
[27].

preventing or reducing the glutamate-induced

elevation of intracellular Ca2+ [53]. Taurine also
inhibits the reverse mode of the Na+/Ca2+ exchanger
[54] and protects cultured rat astrocytes against
reperfusion injury [55]. It also inhibits the glutamateinduced release of Ca2+ from the internal pools [54],
regulates cytoplasmic and mitochondrial calcium
homeostasis [56], and inhibits the glutamate-induced
Ca2+ influx through L-, P/Q-, and N-types of voltagegated calcium channels [57]. On the other hand, it
has been shown to increase the accumulation of
45
Ca2+ in mitochondria of the rat cerebral cortex, being
thus able to attenuate the cytosolic free Ca2+
concentration, which in turn inhibits specific protein
phosphorylation and phosphoinositide turnover [58].
On the whole, taurine may have an essential role in
the modulation of intracellular calcium homeostasis
[53,59].

Role in Thermoregulation: Taurine administered by

intracerebroventricular injection has induced doserelated hypothermia in rabbits, accompanied by
depression of gross motor behavior [33], whereas the
taurine antagonist TAG increases the core
temperature [34]. It is assumed that a specific taurine
recognition site, i.e., a taurine receptor in the rabbit
brain is responsible for the taurine effects on
thermoregulation [6]. The involvement of brain
calcium metabolism in the action of taurine in
mammalian thermoregulation has also been
suggested [35].
Anticonvulsive Actions: The inhibitory nature of
taurine has led to the concept that this molecule may
function as an endogenous anti-convulsive agent.
Experiments with various animal seizure models have
proved the efficacy of taurine. Clinical trials with
human patients in general have shown that about one
third of epileptic patients benefit by administration of
taurine, at least temporarily [36-39]. In a rat model of
penicillin-induced seizures the behavior and the
frequency and amplitude of EEG was improved
markedly by taurine administration [40]. Diminishing
the brain taurine levels has markedly lowered the
threshold for seizure activity [41]. Taurine has also
inhibited the wet-dog shakes produced by [D-Ala2,
Met3]enkephalinamide [42], seizures in amygdaloidkindled rats [43], and convulsions induced by hypoxia
[44]. At variance with the investigations cited above,
Lehmann [45] saw no change in the threshold for
pentylenetetrazol seizures in kittens, and Eppler and
associates [46], no attenuation of kainate-induced
seizures in rats after dietary taurine supplementation.
However, taurine seems to be generally effective
when the administration route by-passes the bloodbrain barrier. The molecule is highly lipophobic in
nature and poorly penetrates into the brain.

The glutamate- and glutamate-receptor-agonist

evoked taurine release from neural cells might be
neuroprotective in balancing glutamate activity under
cell-damaging conditions [60-63]. It efficiently
counteracts the glutamate-induced Ca2+ uptake [6465] and forestalls cell damage evoked by overactivation of ionotropic glutamate receptors [66].
Over-activation of NMDA receptors induces
generation of free radicals, including superoxide. It is
thought that a part of the neuroprotective action of
taurine depends on its anti-oxidant properties [67].
Co-infusion of taurine with ammonia or NMDA
virtually abolishes both the ammonia- and NMDAinduced accumulation of cGMP and markedly
attenuates accumulation of hydroxyl radicals [68,69].
The effects of taurine on the accumulation of cGMP
are mediated by interactions with GABAA and glycine
receptors, since these could be blocked by coinfusion of the GABAA receptor antagonist bicuculline
and the glycine receptor antagonist strychnine [70].
Taurine prolongs rat survival and reduces striatal
damage [71] and partially protects the hippo-campus
from damage [72] caused by 3-nitro-propionic acid.
Systemic intravenous administration of taurine
protects the rabbit spinal cord against ischemia in
both normothermia and hypothermia [73]. On the
other hand, dietary depletion of brain taurine by alanine results in cerebellar [74] and retinal [75]
damage in adult cats. Taurine also protects rat
cerebellar granule cells from free radical damage
[76]. It restores the ethanol-induced depletion of
antioxidants and attenuates oxidative stress in the rat
[77] and protects brain slices against acute guanidine
ethanesulfonate (GES) neurotoxicity and blocks GESinduced cell swelling [78].

Neuroprotective Actions: Taurine has proved to be

neuroprotective in a number of situations. For
example, it is effective in a rat hypoxic model,
possibly due to its antiacidotic and membranestabilizing actions [47]. Exogenously applied taurine
alleviates neuronal damage evoked by a variety of
pathological impacts, including ischemia [48]. For
example, taurine improves the recovery of neural
functions in brain slices after hypoxic conditions [49].
Taurine could attenuate the excessive neuronal
accumulation of Ca2+ ions which predisposes cells to
damage [49-51], and protects neurons from
glutamate-induced excitotoxicity [52], this by
9

Taurine protects cultured neurons in vitro and mice in

vivo against carbon tetrachloride toxicity [79]. It also
attenuates
1-methyl-4-phenylpyridinium
(MPP+)
neurotoxicity in coronal slices from rat brain [80]. It is
likely that this effect is mediated by extracellular
mechanism(s), possibly by means of the activation of
GABAA receptors. Taurine also blocks the
neurotoxicity of -amyloid and glutamate receptor
agonists, possibly by activation of GABA receptors.
This may imply that taurine could have beneficial
effects in Alzheimer's disease and other neurological
disorders [81]. Indeed, taurine increases the levels of
acetylcholine in the brain of animals, and decreased
levels of taurine have been found in patients with
Alzheimer's disease [82]. Moreover, taurine improves
memory in rats exposed to ozone [839, but fails to do
so in healthy untreated mice [79]. However, it is
effective in attenuating the amnesia produced by
ethanol, pentobarbital, cycloheximide and sodium
nitrite [79]. Furthermore, taurine is able to facilitate
the survival of hNT neurons transplanted in the adult
rat striatum and attenuates the immune response
generated by this xenograft [84].

pharmacokinetics/pharmacodynamics after intraventricular versus peripheral administrations [95].

However,
intraperitoneal
taurine
lengthens
pentobarbitone-induced sleep in mice [96].
Ethanol exhibits both rewarding and aversive
motivational properties, these being strongly
concentration-dependent. The ability of taurine to
modify these properties also depends on the dose of
ethanol administered [97,98]. It is likely that these
effects are mediated by pharmacological interactions
in the brain [95], even though taurine can modulate
alcohol dehydrogenase activity and oxidation to
acetaldehyde [99,100]. Acute administration of
taurine moderately reduces voluntary consumption of
ethanol in rats [101]. These effects might result from
synergistic effects of taurine and ethanol on ion
channels and neurotransmitter receptors. For
example, taurine inhibits the ethanol withdrawalinduced increase in extracellular glutamate in the
nucleus accumbens of ethanol-dependent rats [102].
Taurine Derivatives and Brain Functions:
Pharmacological actions of a large number of taurine
derivatives have already been reported in the
literature [103]. Among them, acamprosate, the
calcium salt of N-acetylhomotaurine, is already in
clinical use as an anticraving drug in alcoholism [104].
Both
homotaurine
and
acamprosate
dosedependently reduce ethanol intake and preference in
rats [101]. Our laboratory has synthesized a series of
2-acylamidoethanesulphonamides; more lipophilic
derivatives of taurine than the parent compound
[105]. Several derivatives proved to be effective
against seizures in several animal models [106,108].
The N,N-Phthaloyltaurinamides also antagonize
electrically induced seizures in rats [109]. From our
derivatives, 2-phthalimido-ethanesulfon-N-isopropylamide (taltrimide, MY-117) was subjected to phase I
clinical trials in patients with intractable epilepsy but
the good antiepileptic activity in animal models could
not be confirmed in humans [110-111]. Furthermore,
homotauryl-homo-taurine, carbobenzoxyhomotaurylhomotaurine, and -aminobutyltaurine have exhibited
anticonvulsant actions, possibly via interaction with
the GABAA binding site in the brain [34].

Other Effects: Insulin and taurine act partially in

concert. Taurine alleviates complications in patients
with type 2 diabetes, exerting beneficial effects on
nephropathy and retinopathy [85]. It may also provide
beneficial metabolic effects in advanced age [86]. A
taurine-containing drink has been reported to improve
performance in endurance athletes [87], taurine- and
caffeine-containing
drinks
stimulate
cognitive
performance and well-being [88], and a drink
containing taurine, caffeine and vitamins improves
aerobic
endurance,
anaerobic
and
mental
performance, concentration and memory [89]. In
keeping with these observations, a caffeinated taurine
beverage has been found to improve attention and
verbal reasoning, but not to affect the memory [90]. It
is not clear, however, whether caffeine alone
underlies the improvements or whether they are also
due to taurine.
Interactions of Taurine and Ethanol: Low doses of
ethanol stimulate and high doses reduce motor
activity in mice. Taurine modulates this ethanolstimulated locomotor activity; low taurine doses are
inhibitory, higher doses enhance the activity [91].
These effects are specific for ethanol. On the other
hand, taurine prolongs ethanol-induced sedation
when given intracerebroventricularly [92,93], but
attenuates the sedating effects of ethanol when given
intraperitoneally only shortly before ethanol
administration [94]. The reason for these disparate
effects is not known, but may be due to differential

Taurine shows anti-aggressive effects and several

taurine analogues with a free amino group or with a
phthalimido moiety have been synthesized and
studied in the context of aggressive behavior [112].
Taltrimide and taurinamide were more effective than
taurine itself and also all other derivatives tested were
more potent than taurine itself in inhibiting the
muricidal activity of rats. A dipeptide, -L-glutamyltaurine, reduces aversion, phobia and anxiety
10

independent, Ca2+ uptake in the retina. [125],

whereas trans-2-aminocyclohexanesulfonate, cisand trans-2-aminocyclopentanesulfonate, 3-aminotetrahydrothiophene-1,1,-dioxide,
amiomethanesulfonate, and 1,2,3,4-tetrahydroquinoline-8-sulfonate
are inhibitory in the presence of ATP [125-127]. In the
absence
of
ATP,
trans-2-aminocyclopentanesulfonate and trans-2-aminocyclohexanesulfonate are
stimulatory [128]. Similar effects have been seen in
the incorporation of phosphate into retinal proteins, 2aminoethylmethylsulfone,
3-aminotetra-hydrothiophene-1,1,-dioxide, 3-aminotetrahydro-thiopyran-1,1dioxide
and
N-methylthiomorpholine-1,1-dioxide
being equipotent inhibitors [129].

synergistically with the anxiolytic diazepam, probably

modulating excitatory aminoacidergic neurotransmission, in addition to a number of other effects on
brain functions [113].
Trimethyltaurine has been shown to bind to GABAA
receptors and to exert neuroprotective properties
similar to those of taurine [114]. Intraperitoneally
administered N-pivaloyltaurine causes significant
hypothermia and elevates the striatal dopamine
concentration in mice [96]. A series of other taurine
analogues have also been tested, including cis- and
trans-isomers of 2-aminocyclohexanesulfonate [115].
Cis-2-aminocyclohexane sulfonate, but not the transisomer, induces hypothermia, this not being mediated
by the GABA receptor but due to interaction with the
putative taurine receptor.

Other Actions of Taurine Derivatives: Taurine itself

has been claimed to be chemopreventive against the
colonic and hepatic cancers and to have beneficial
effects in acute hepatitis [130]. Tauromustine, 1-(2chloroethyl) -3- (2-dimethylaminosulfonyl) ethyl-1nitrosourea, a derivative of taurine, is in clinical use
as an anti-cancer drug [131]. Taurolidine, bis-(1,1dioxoperhydro-1,2,4-thiadiazinyl -4) methane, was
originally designed as a chemotherapeutic agent and
used as adjunctive therapy for various infections
[132,133]. Later, it was shown that taurolidine also
has antineoplastic activity and inhibits the growth of
tumor cell lines [134-136]. Taurine haloamines,
taurine chloramine and taurine bromamine exhibit
immunoregulatory [137,138], bactericidal and antiinflammatory properties [139-141]. In vivo they are
generated at a site of inflammation by the reactions
between taurine and HOCl or HOBr [142,143]. A
large number of taurine analogues have also
provided protection against erythrocyte membrane
damage induced by hydrogen peroxide, which effects
may suppress inflammatory responses [144]. Taurine
shows antihypertensive properties, lowering the blood
pressure and alleviating the complexity of
hypertension [103]. Several taurinamide derivatives
also exhibit cardioprotective activity at a lower
concentration than taurine itself [145].

Tauropyrone [2-(2,6-dimethyl-3,5-diethoxycarbonyl1,4-dihydropyridine-4-carboxamido)ethanesulfonic
acid] has been capable of protecting cerebellar
granule cells against damage induced by oxygen and
glucose deprivation [116]. It also protects cells from
glutamate-induced cell death. Tauropyrone also
attenuates 6-hydroxydopamine-induced damage to
dopaminergic cells in vivo in rats and reduces the
inflammatory agent-evoked release of NO from glial
cells in culture [117]. Intraperitoneally administered
taurepar [2-(1-phenylethylamino)ethanesulfonic acid
isopropylamide hydrochloride] has produced positive
effects on mnestic functions and exhibits antiamnestic
activity in rats after electroconvulsive shock or
intraperitoneal introduction of pentylenetrazol and
scopolamine [118]. Taurepar as well as turhythman
[2-(1-methyl-2-phenylethylamino)ethanesulfonic acid
isopropylamide hydrochloride] and IEM-1702 [2(benzylamino) ethanesulfonic acid isopropylamide
hydrochloride], have prolonged survival time of mice
and rats after acute hypoxia [119]. Taurepar did
likewise after bilateral occlusion of carotid arteries
and ameliorated neurological defects after spinal cord
compression trauma in rats [120].
Taurine Derivatives and the Retina: Retinyledin
taurine (tauret) is a water soluble taurine derivative
which is spontaneously hydrolyzed [121]. It has been
suggested that tauret is an endogenous substance in
the retina, being involved in the processes of removal
of all-trans and 11-cis retinals and rhodopsin
regeneration in darkness [122,123]. Tauret is
synthesized in pigment epithelium in frogs [124].
Sulfone
derivatives
of
taurine,
2-aminoethylmethylsulfone,thiomorpholine-1,1-dioxide,
Nmethylthiomorpholine-1,1-dioxide and cis-2-aminocyclohexanesulfonate have proved more potent than
taurine in stimulating ATP-dependent, but not ATP-

CONCLUSIONS:
Taurine participates in a great number of functions in
the organism and maintains cellular homeostasis. In
spite of this, minor alterations in taurine levels do not
generate any dramatic effects. The actions of taurine
are characteristically prolonged and slow at outset. In
the absence of potent taurine antagonists, we still do
not know exactly what taurine does and how it acts.
This hampers possibilities to develop taurine-derived
drugs. However, a variety of taurine derivatives have
already been synthesized and studied for their
taurine-like and other effects with variable success.
11

So far, it is not yet possible to relate their chemical

structures to biological activity, i.e., more basic study
on the actions taurine is still needed.
ACKNOWLEDGMENTS:
The financial support of competitive research funding from
Pirkanmaa Hospital District is acknowledged.
REFERENCES
1.

Oja, S. S. and Saransaari, P. (1992) J. Neurosci.

Res. 32, 551-561.

2.

Oja, S. S. and Saransaari, P. (1996) Metab. Brain

Dis. 11, 153-164.

3.

Pasantes-Morales, H.
Cerebellum 1, 103-109.

4.

Oja, S. S. and Kontro, P. (1983). Taurine. Pages

501-533, In Lajtha, A., editor. Handbook of
Neurochemistry, vol. 3, 2nd edn, Plenum Press, New
York.

5.

and

Franco,

R.

20.

Wang, D.-S., Xu, T.-L., Pang, Z.-P., Li, J.-S., and

Akaike, N. (1998) Brain Res. 792, 41-47.

21.

Kontro, P. and Oja, S. S. (1983) Cell. Mol. Neurobiol.

3, 183-187.

22.

Kontro, P. and Oja, S.S. (1987) Int. J. Neurosci. 32,

881-889.

23.

Kudo, Y., Akiyoshi, E., and Akagi, H. (1988) Br. J.

Pharmacol. 94, 1051-1056.

24.

Sung, D. Y., Walthall, W. W., and Derby, C. D.

(1996) Comp. Biochem. Physiol. Biochem. Mol. Biol.
115, 19-26.

25.

Serrano, J. S., Serrano, M. I., Guerrero, M. R., Ruiz,

R., and Polo, J. (1990) Gen. Pharmacol. 21, 333336.

26.

Silva, M. A., Cunha, G. M., Viana, G. S., and Rao, V.

S. (1993) Braz. J. Med. Biol. Res. 26, 1319-1324.

27.

Serrano, M. I., Serrano, J. S., Guerrero, M. R., and

Fernndez, A. (1994) Gen. Pharmacol. 24, 11231129.

28.

Belfer, I., Davidson, E., Ratner, A., Beery, E., Shir,

Y., and Selzer, Z. (1998) Neuroreport 13, 3103-3107.

(2002)

Frosini, M., Sesti, C., Dragoni, S., Valoti, M., Palmi,

M., Dixon, H. B. F., Machetti, F., and Sgaragli, G.
(2003) Br. J. Pharmacol. 138, 1163-1171.

6.

Frosini, M., Sesti, C., Saponara, S., Ricci, L., Valoti,

M., Palmi, M., Machetti, F., and Sgaragli, G. (2003)
Br. J. Pharmacol. 139, 487-494.

29.

Smullin, D. H., Schamber, C. D., Skilling, S. R., and

Larson, A. A. (1990) Prog. Clin. Biol. Res. 351, 129132.

7.

El Idrissi, A. and Trenkner, E. (2004) Neurochem.

Res. 29, 189-197.

30.

Beyer, C., Banas, C., Gomora, P., and Komisurak, B.

R. (1988) Pharmacol. Biochem. Behav. 29, 73-78.

8.

Malminen, O. and Kontro, P. (1986) Neurochem.

Res. 11, 85-94.

31.

9.

Malminen, O. and Kontro, P. (1987) Neurochem. Int.

11, 113-117.

Hornfeldt, C. S., Smullin, D. H., Schamber, C. D.,

Sun, X., and Larson, A. A. (1992) Life Sci. 50, 19251934.

32.

10.

Iwata, H., Nakayama, K., Matsuda, T., and Baba, A.

(1984) Neurochem. Res. 9, 535-544.

Beyer, C., Banas, C., Gonzalez-Flores, O., and

Komisaruk, B. R. (1989) Pharmacol. Biochem.
Behav. 34, 491-495.

11.

Medina, J. H. and De Robertis, E. (1984) J.

Neurochem. 42, 1212-1217.

33.

Sgaragli, G. P., Carl, V., Magnani, M., and Galli, A.

(1981) J. Pharmacol. Exp. Ther. 219, 778-785.

12.

Quinn, M. R. and Miller, C. I. (1992) J. Neurosci.

Res. 33, 136-141.

34.

13.

Oja, S. S., Korpi, E. R., and Saransaari, P. (1990)

Neurochem. Res. 15, 797-804.

Sgaragli, G. P., Frosini, M., Palmi, M., Bianchi, L.,

and Della Corte, L. (1994) Adv. Exp. Med. Biol. 359,
299-308.

35.

14.

Okamoto, K., Kimura, H., and Sakai, Y. (1983) Brain

Res. 259, 319-323.

Palmi, M., Frosini, M., and Sgaragli, G. P. (1987)

Adv. Exp. Med. Biol. 217, 237-244.

36.

15.

Ye, G.-I., Tse, A. C. O., and Yung, W.-H. (1997)

Brain Res. 749, 175-179.

Airaksinen, E. M., Oja, S. S., Marnela, K.-M., Leino,

E., and Pkknen, L. (1980) Prog. Clin. Biol. Res.
3, 157-166.

16.

Puopolo, M., Kratskin, I., and Belluzzi, O. (1998)

Neuroreport 9, 2319-2322.

37.

Oja, S. S. and Kontro, P. (1983) Acta Neurol. Scand.

67 (Suppl. 93), 5-20.

17.

Belluzzi, D., Puopolo, M., Benedusi, M., and

Kratskin, I. (2004) Neuroscience 124, 929-944.

38.

Anyanwu, E. and Harding, G. F. (1993) Acta Physiol.

Pharmacol. Ther. Latinoamer. 43, 20-27.

18.

Kontro, P. and Oja, S. S. (1987) Int. J. Devl.

Neurosci. 5, 461-470.

39.

El Idrissi, A., Messing, H., Scalia, J., and Trenkner,

E. (2003) Adv. Exp. Med. Biol. 526, 515-525.

19.

Horikoshi, T., Asanuma, A., Yanagisawa, K., Anzai,

K., and Goto, S. (1988) Brain Res. 464, 97-105.

40.

Yang, R., Li, Q., Guo, J.-C., Jin, H.-B., Liu, J., Wang,
B.-E., and Cheng, J.-S. (2006) Adv. Exp. Med. Biol.
583, 389-394.

12

41.

Pasantes-Morales, H., Arzate, M. E., Quesada, O.,

and Huxtable, R. J. (1987) Neuropharmacology 26,
1721-1725.

42.

Yoshida, M., Izumi, K., Koja, T., Fukuda, T.,

Munekata,
E.,
and
Nakanishi,
T.
(1986)
Neuropharmacology 25, 1373-1378.

43.
44.

62.

Saransaari, P. and Oja, S. S. (1997) Neuroscience

79, 847-854.

63.

Saransaari, P. and Oja, S. S. (1999) Neuroscience

94, 949-954.

64.

El Idrissi, A., Harris, C., and Trenkner, E. (1998) Adv.

Exp. Med. Biol. 442, 385-396.

Uemura, S., Ienaga, K., Higashiura, K., and Kimura,

H. (1991) Jap. J. Psychiatry Neurol. 45, 383-385.

65.

Trenkner, E., El Idrissi, A., Dumas, R., and Rabe, A.

(1998) Adv. Exp. Med. Biol. 442, 277-284.

Malcangio, M., Bartolini, A., Ghelardini, C.,

Bennardini, F., Malmberg-Aiello, P., Franconi, F.,
and Giotti, A. (1989) Psychopharmacology 98, 316320.

66.

Zieliska, M., Law, R. O., and Albrecht, J. (2003)

Neurochem. Int. 43, 299-303.

67.

Schaffer, S. W., Azuma, J., Takahashi, K., and

Mozaffari, M. (2003) Adv. Exp. Med. Biol. 526, 307321.

68.

Hilgier, W., Anderzhanova, E., Oja, S. S.,

Saransaari, P., and Albrecht, J. (2003) Eur. J.
Pharmacol. 468, 21-25.

69.

Anderzhanova, E., Saransaari, P., and Oja, S. S.

(2006) Adv. Exp. Med. Biol. 583, 377-387.

70.

Hilgier, W., Oja, S. S., Saransaari, P., and Albrecht,

J. (2005) Brain Res. 1043, 242-246.

71.

Rivas-Arancibia, S., Rodrguez, A. I., Zigova, T.,

Willing, A. E., Brown, W. D., Cahill, D. W., and
Sanberg, P. R. (2001) Int. J. Neurosci. 108, 55-67.

72.

Rodrguez-Martnez,
E.,
Rugerio-Vargas,
C.,
Rodrguez, A. I., Borgonio-Prez, G., and RivasArancibia, S. (2004) Int. J. Neurosci. 114, 11331145.

45.

Lehmann, A. (1987) Acta Physiol. Scand. 131, 453458.

46.

Eppler, B., Patterson, T. A., Zhou, W., Millard, W. J.,

and Dawson, R., Jr. (1999) Amino Acids 16, 133147.

47.

Mankovskaya, I. N., Serebrovskaya, T. V., Swanson,

R. J., Vavilova, G. L., and Kharlamova, O. N. (2000)
High Alt. Med. Biol. 1, 105-110.

48.

Kingston, R., Kelly, C. J., and Murray, P. (2004) Curr.

Pharm. Des. 10, 2401-2410.

49.

Schurr, A., Tseng, M. T., West, C. A., and Rigor, B.

M. (1987) Life Sci. 40: 2059-2066.

50.

Lehmann, A., Hagberg. H., and Hamberger, A.

(1984) Neurosci. Lett. 52, 341-346.

51.

Kontro, P. and Oja, S. S. (1988) Int. J. Neurosci. 38,

103-109.

73.

52.

Tang, X. W., Deupree, D. L., Sun, Y., and Wu, J.-Y.

(1996) Adv. Exp. Med. Biol. 403, 499-505.

Miyamoto, K. J., Miyamoto, M. R., and Miyamoto, T.

A. (2006) Adv. Exp. Med. Biol. 583, 323-351.

74.

53.

Chen, W. Q., Jin, H., Nguyen, M., Carr, J., Lee, Y. J.,
Hsu, C. C., Faiman, M. D., Schloss, J. V., and Wu,
J.-Y. (2001) J. Neurosci. Res. 66, 612-619.

Lu, P., Xu, W., and Sturman, J. A. (1996) J.

Neurosci. Res. 43, 112-119.

75.

Sturman, J. A., Lu, P., Messing, J. M., and Imaki, H.

(1996) Adv. Exp. Med. Biol. 403, 19-36.

54.

Wu, J.-Y., Chen, W., Tang, X. W., Jin, H., Foos, T.,
Schloss, J. V., Davis, K., Faiman, M. D., and Hsu,
C.-C. (2000) Adv. Exp. Med. Biol. 483, 35-44.

76.

Boldyrev, A. A., Johnson, P., Wei, Y., Tan, Y., and

Carpenter, D. O. (1999) Neurosci. Lett. 263, 169172.

55.

Matsuda, T., Takuma, K., Kishida, Y., Azuma, J., and

Baba, A. (1996) Adv. Exp. Med. Biol. 403, 491-497.

77.

Pushpakiran, G., Mahalakshmi K., and Anuradha C.

V. (2004) Amino Acids 27, 91-96.

56.

El Idrissi, A. and Trenkner, E. (2003) Adv. Exp. Med.

Biol. 526, 527-536.

78.

Law, R. O. (2006) Adv. Exp. Med. Biol. 583, 359-364

57.

Wu, H., Jin, Y., Wei, J., Jin, H., Sha, D., and Wu, J.Y. (2005) Brain Res. 1038, 123-131.

79.

Vohra, B. P. and Hui X. (2000) Neural Plast. 7, 245259.

58.

Li, Y. P. and Lombardini, J. B. (1991) Brain Res. 553,

89-96.

80.

OByrne, M. B. and Tipton, K. F. (2000) J.

Neurochem. 74, 2087-2093.

59.

Foos, T. M. and Wu, J.-Y. (2002) Neurochem. Res.

27, 21-26.

81.

Louzada, P. R., Lima, A. C. P., Mendona-Silva, D.

L., Nol, F., De Mello, F. G., and Ferreira, S. T.
(2004) FASEB J. 18, 511-518.

60.

Trenkner, E., El Idrissi, A., and Harris, C. (1996) Adv.

Exp. Med. Biol. 403, 507-517.

82.

Birdsall, T. C., (1998) Altern. Med. Rev. 3, 128-136.

61.

Katoh, H., Sima, K., Nawashiro, H., Wada, K., and

Chigasaki, H. (1997) Brain Res. 758, 153-162.

83.

Rivas-Arancibia, S., Dorado-Martnez, C., BorgonioPrez G., Hiriart-Urdanivia, M., Verdugo-Daz, L.,
Durn-Vzquez, A., Colin-Baranque, L., and AvilaCosta, M. R. (2000) Environ. Res. 82, 7-17.

13

84.

Rivas-Arancibia, S., Willing, A. E., Zigova, T.,

Rodrguez, A. I., Cahill, D. W., and Sanberg, P. R.
(2000) Cell Transplant. 9, 751-758.

85.

Chauncey, K. B., Tenner, T. E., Lombardini, J. B.,

Jones, B. G., Brooks, M. L., Warner, R. D., Davis, R.
L., and Ragain, R. M. (2003). Adv. Exp. Med. Biol.
526, 91-96.

86.

Dawson, R., Jr. (2003) Adv. Exp. Med. Biol. 23, 537545.

87.

Geiss, K.-R., Jester, I., Falke, W., Hamm, M., and

Waag, K. L. (1994) Amino Acids 7, 45-56.

88.

Seidl, R., Peyrl, A., Nicham, R., and Hauser, E.

(2000) Amino Acids 19, 635-642.

89.

Alford, C., Cox, H., and Wescott, R. (2001) Amino

Acids 21, 139-150.

90.

Warburton, D. M., Bersellini, E., and Sweeney, E.

(2001) Psychopharmacology 158, 322-328.

91.

Aragn, C. M., Trudeau, L. E., and Amit, Z. (1992)

Psychopharmacology 107, 337-340.

92.

Ferko, A. P. (1987) Pharmacol. Biochem. Behav. 27,

235-238.

93.

Ferko, A. P. and Bobyock, E. (1988) Pharmacol.

Biochem. Behav. 31, 667-673.

94.

McBroom, M. J., Elkhawad, A. O., and Dlouha, H.

(1986) Gen. Pharmacol. 17, 97-100.

95.

Olive, M. F. (2002) Amino Acids 23, 345-357.

96.

Ahtee, L., Auvinen, H., Menp, A.-R., Vahala, M.L., Lehtinen, M., and Halmekoski, J. (1985) Acta
Pharmacol. Toxicol. 57, 96-105.

97.

Aragn, C. M. and Amit, Z. (1993) Pharmacol.

Biochem. Behav. 44, 236-263.

98.

Quartemont, E., Goffaux, V., Vlaminck, A.-M., Wolff,

C., and De Witte, P. (1998b) Alcohol 16, 201-206.

99.

Theofanopoulos, V. and Lau-Cam, C. A. (1988) Adv.

Exp. Med. Biol. 442, 309-318.

107. Oja, S. S., Kontro, P., Lindn, I.-B., and Gothni, G.

(1983) Eur. J. Pharmacol. 87, 191-198.
108. Nakagawa, K. and Huxtable,
Neurochem. Int. 7, 819-824.

R.

J.

(1985)

109. Usifoh, C. O., Lambert, D. M., Woulters, J., and

Scriba, G. K. E. (2001) Arch. Pharm. Pharmacol.
Med. Chem. 234, 323-331.
110. Koivisto, K., Sivenius, J., Kernen, T., Partanen, J.,
Riekkinen, P., Gothni, G., Tokola, O., and
Neuvonen, P. J. (1986) Epilepsia 27, 87-90.
111. Airaksinen, E. M., Koivisto, K., Kernen, T.,
Pitknen, A., Riekkinen, P. J., Oja, S. S., Marnela,
K.-M., Partanen, J. V., Tokola, O., Gothni, G.,
Neuvonen, P. J., and Airaksinen, M. M. (1987)
Epilepsy Res. 1, 308-311.
112. Mandel, P., Gupta, R. C., Bourguignon, J. J.,
Wermuth, C. G., Molina,V., Gobaille, S., Ciesielski,
L., and Simler, S. (1985) Prog. Clin. Biol. Res. 179,
449-458.
113. Bittner, S., Win, T., and Gupta, R. (2005). Amino
Acids 28: 343-356.
114. Marangolo, M., Zisterer, D., Williams, D. C., Tipton,
K. F., and Della Corte, L. (1997) Pages 959-962. In
Teelken, A. and Korf, J., editors. Neurochemistry:
Cellular, Molecular and Clinical Aspects, Plenum
Press, New York.
115. Frosini, M., Sesti, C., Saponara, S., Donati, A.,
Palmi, M., Valoti, M., Machetti, F., and Sgaragli, G.
(2000) Adv. Exp. Med. Biol. 483, 273-282.
116. Klua, V., Klimaviciusa, L., Duburs, G., Poikans, J.,
and Zharkovsky, A. (2006) Adv. Exp. Med. Biol. 583,
499-508.
117. Ward, R., Cirkovic-Vellichovia, T., Ledeque, F.,
Tirizitis, G., Dubars, G., Datla, K., Dexter, D.,
Heushling, P., and Crichton, R. (2006) Adv. Exp.
Med. Biol. 583, 299-306.
118. Sapronov, N. S. and Gavrovskaya, L. K. (2006) Adv.
Exp. Med. Biol. 583, 509-514.

100. Ward, R. J., Kest, W., Bruyeer, P., Lallemand, F.,

and De Witte, P. (2001) Alcohol Alcohol. 36, 39-43.

119. Gavrovskaya, L. K., Krlova, I. B., Selina, E. N.,

Safonova, A. F., Petrova, N. N., and Sapronov, N. S.
(2006) Adv. Exp. Med. Biol. 583, 523-528.

101. Olive, M. F., Nannini, M. A., Ou, C. J., Koenig, H. N.,

and Hodge, C. W. (2002) Eur. J. Pharmacol. 437, 5561.
102. Dahchour, A. and De Witte, P. (2000) Pharmacol.
Biochem. Behav. 65, 345-350.

120. Krylova, I. B., Bulion, V. V., Gavrovskaya, L. K.,

Selina, E. N., Kuznetzova, N. N., and Sapronov, N.
S. (2006) Adv. Exp. Med. Biol. 583, 543-550.

103. Gupta, R. C. (2006) Adv. Exp. Med. Biol. 583, 449467.

121. Petrosian, A. M. and Haroutounian, J. E. (1990)

Prog. Clin. Biol. Res. 351, 471-475.

104. Ward, R. J., Martinez, J., Ball, D., Marshall, E. J.,

and De Witte, P. (2000) Adv. Exp. Med. Biol. 483,
375-381.

122. Petrosian, A. M., Haroutounian, J. E., and Zueva, L.

V. (1996) Adv. Exp. Med. Biol. 403, 333-342.
123. Petrosian, A. M., Haroutounian, J. E., Gundersen, T.
E., Blomhoff, R., Fugelli, K., and Kanli, H. (2000)
Adv. Exp. Med. Biol. 483, 453-460.

105. Andersen, L., Sundman. L.-O., Lindn, I.-B., Kontro,

P., and Oja, S. S. (1984) J. Pharm. Sci. 73, 106-108.
106. Lindn, I. - B., Gothni, G., Kontro, P., and Oja, S. S.
(1983) Neurochem. Int. 5, 319-324.

14

124. Petrosian, A. M., Haroutounian, J. E., Fugelli, K., and

Kanli, H. (2000) Adv. Exp. Med. Biol. 483, 441-451.

136. Nici, L., Monfils, B., and Calabresi, P. (2004) Clin.

Cancer Res. 10, 7655-7661.

125. Liebowitz, S. M., Lombardini, J. B., and Salva, P. S.

(1987) Biochem. Pharmacol. 36, 2109-2114.

137. Marcinkiewicz, J., Grabowska, A., Bereta, J., and

Stelmaszynska, T. (1995) J. Leukoc. Biol. 58, 667674.

126. Liebowitz, S. M., Lombardini, J. B., and Allen, C. I.

(1988) Biochem. Pharmacol. 37, 1303-1309.

138. Schuller-Levis, G. B. and Park, E., 2003. FEMS

Microbiol. Lett. 226, 195-202.

127. Lombardini, J. B. and Liebowitz, S. M. (1990) Prog.

Clin. Biol. Res. 351, 197-206.

139. Nagl, M., Hess, M. W., Pfaller, K., Hengster, P., and
Gottardi, W. (2000) Antimicrob. Agents Chemother.
44, 2507-2513.

128. Lombardini, J. B. and Liebowitz, S. M. (1990) Curr.

Eye Res. 9, 1147-1156.

140. Marcinkiewicz, J., Mak, M., Bobek, M., Biedron, R.,

Bialecka, A., Koprowski, M., Kontny, E., and
Maslinski, W. (2005) Inflamm. Res. 54, 42-49.

129. Liebowitz, S. M., Lombardini, J. B., and Allen, C. I.

(1989) Biochem. Pharmacol. 38, 399-406.
130. Reddy, B. S., Raoi, C. V., Rivenson, A., and Kelloff,
G. (1993) Cancer Res. 35, 3493-3498.

141. Marcinkiewicz, J., Kurnyta, M., Biedro, R., Bobek,

M., Kontny E., and Maliski, W. (2006) Adv. Exp.
Med. Biol. 583, 482-491.

131. Molineux, H., Schofield, R., and Testa, N. G. (1987)

Cancer Treat. Rep. 71, 837-841.

142. Klebanoff, S. J. and Hamon, C. B. (1972) J.

Reticuloendothel. Soc. 12, 170-196.

132. Browne, M. K., Leslie, G. B., and Pfirrmann, R. W.

(1976) J. Appl. Bacteriol. 41, 363- 368.
133. Traub, W. H., Leonhard, B., and Bauer, D. (1993)
Chemotherapy 39, 322-330.

143. Thomas, E. L., Bozeman, P. M., Jefferson, M. M.,

and King, C. C. (1995) J. Biol. Chem. 270, 29062913.

134. McCourt, M., Wang, J. H., Sookhai, S., and

Redmond, H. P. (2000) Ann. Surg. Oncol. 7, 685691.

144. Pokhrel, P. K. and Lau-Cam, C .A. (2000) Adv. Exp.

Med. Biol. 483, 503-522.
145. Molaparast-Saless, F., Nellis, S. H., and Liedkte, A.
S. (1988) J. Mol. Cell. Cardiol. 20, 63-74.

135. Darnowski, J. W., Goulette, F. A., Cousens, L. P.,

Chatterjee, D., and Calabresi, P. (2004) Cancer
Chemother. Pharmacol. 54, 249-258.

15