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Taurine is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Chronic supplementation of taurine in drinking water to mice increases brain excitability mainly through alterations in the inhibitory GABAergic system. These changes include elevated expression level of glutamic acid decarboxylase (GAD) and increased levels of GABA. Additionally we reported that GABAA receptors were down regulated with chronic administration of taurine. Here, we investigated pharmacologically the functional significance of decreased / or change in subunit composition of the GABAA receptors by determining the threshold for picrotoxin-induced seizures. Picrotoxin, an antagonist of GABAA receptors that blocks the channels while in the open state, binds within the pore of the channel between the beta2 and beta3 subunits. These are the same subunits to which GABA and presumably taurine binds. Two-month-old male FVB/NJ mice were subcutaneously injected with picrotoxin (5 mg kg-1) and observed for a) latency until seizures began, b) duration of seizures, and c) frequency of seizures. For taurine treatment, mice were either fed taurine in drinking water (0.05%) or injected (43 mg/kg) 15 min prior to picrotoxin injection. We found that taurine-fed mice are resistant to picrotoxin-induced seizures when compared to age-matched controls, as measured by increased latency to seizure, decreased occurrence of seizures and reduced mortality rate. In the picrotoxin-treated animals, latency and duration were significantly shorter than in taurine-treated animas. Injection of taurine 15 min before picrotoxin significantly delayed seizure onset, as did chronic administration of taurine in the diet. Further, taurine treatment significantly increased survival rates compared to the picrotoxin-treated mice. We suggest that the elevated threshold for picrotoxin-induced seizures in taurine-fed mice is due to the reduced binding sites available for picrotoxin binding due to the reduced expression of the beta subunits of the GABAA receptor. The delayed effects of picrotoxin after acute taurine injection may indicate that the two molecules are competing for the same binding site on the GABAA receptor. Thus, taurine-fed mice have a functional alteration in the GABAergic system. These include: increased GAD expression, increased GABA levels, and changes in subunit composition of the GABAA receptors. Such a finding is relevant in conditions where agonists of GABAA receptors, such as anesthetics, are administered.
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REVIE W Open Access
Pharmacological characterization of GABA
A
receptors in taurine-fed mice
William J LAmoreaux
1,2,3,4*
, Alexandra Marsillo
1,4
, Abdeslem El Idrissi
1,3,4
From 17
th
International Meeting of Taurine
Fort Lauderdale, FL, USA. 14-19 December 2009
Abstract
Background: Taurine is one of the most abundant free amino acids especially in excitable tissues, with wide
physiological actions. Chronic supplementation of taurine in drinking water to mice increases brain excitability
mainly through alterations in the inhibitory GABAergic system. These changes include elevated expression level of
glutamic acid decarboxylase (GAD) and increased levels of GABA. Additionally we reported that GABA
A
receptors
were down regulated with chronic administration of taurine. Here, we investigated pharmacologically the
functional significance of decreased / or change in subunit composition of the GABA
A
receptors by determining
the threshold for picrotoxin-induced seizures. Picrotoxin, an antagonist of GABA
A
receptors that blocks the
channels while in the open state, binds within the pore of the channel between the b2 and b3 subunits. These are
the same subunits to which GABA and presumably taurine binds.
Methods: Two-month-old male FVB/NJ mice were subcutaneously injected with picrotoxin (5 mg kg
-1
)andobserved
for a) latency until seizures began, b) duration of seizures, and c) frequency of seizures. For taurine treatment, mice were
either fed taurine in drinking water (0.05%) or injected (43 mg/kg) 15 min prior to picrotoxin injection.
Results: We found that taurine-fed mice are resistant to picrotoxin-induced seizures when compared to age-
matched controls, as measured by increased latency to seizure, decreased occurrence of seizures and reduced
mortality rate. In the picrotoxin-treated animals, latency and duration were significantly shorter than in taurine-
treated animas. Injection of taurine 15 min before picrotoxin significantly delayed seizure onset, as did chronic
administration of taurine in the diet. Further, taurine treatment significantly increased survival rates compared to
the picrotoxin-treated mice.
Conclusions: We suggest that the elevated threshold for picrotoxin-induced seizures in taurine-fed mice is due to
the reduced binding sites available for picrotoxin binding due to the reduced expression of the beta subunits of
the GABA
A
receptor. The delayed effects of picrotoxin after acute taurine injection may indicate that the two
molecules are competing for the same binding site on the GABA
A
receptor. Thus, taurine-fed mice have a
functional alteration in the GABAergic system. These include: increased GAD expression, increased GABA levels, and
changes in subunit composition of the GABA
A
receptors. Such a finding is relevant in conditions where agonists of
GABA
A
receptors, such as anesthetics, are administered.
Background
Maintenance of the level of excitability of neurons in the
central nervous system is essential to maintain homeo-
stasis. This balance is achieved through the regulation of
excitatory and inhibitory neurotransmitters. Any change
in this balance can lead to hyperexcitable cells and sub-
sequently to seizures. Possible mechanisms that may
contribute to hyperexcitability include changes in ion
homeostasis, ion pumps, hormones, and changes in
levels/efficiency of neurotransmitters. Of these neuro-
transmitters, the regulation of neuron excitability by
g-aminobutyric acid (GABA), the predominant
* Correspondence: William.Lamoreaux@csi.cuny.edu
1
Department of Biology, College of Staten Island, 2800 Victory Blvd., Staten
Island, NY 10314, USA
Full list of author information is available at the end of the article
LAmoreaux et al.Journal of Biomedical Science 2010, 17(Suppl 1):S14
http://www.jbiomedsci.com/content/17/S1/S14
© 2010 LAmoreaux et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attri bution License (http://creativecommons.org /licenses/by/2.0), which permits unrestricted use, distribution, and
reproductio n in any medium, provided the original work is properly cited.
inhibitory neurotransmitter, is especially required to
prevent hyperexcitability, and thus prevent seizures. Epi-
leptogenicity is characterized by chronic hypersensitivity
to sensory stimuli and thus is dependent upon the
amount of hyperexcitability expressed by neurons. In a
homeostatic brain, the GABAergic system plays an inte-
gral role in lowering the threshold required for an exci-
tatory stimulus of neurons. GABA, released from
presynaptic neurons, binds to the ionotropic GABA
A
receptor, allowing chloride influx and resulting in the
hyperpolarization of the postsynaptic neuron. Any per-
turbation of the GABAergic system, therefore, could
contribute to excitability of the neuron and seizure
induction.
Synthesis of GABA by glutamic acid decarboxylase
(GAD) is critical for maintenance of GABA-mediated
inhibition and regulating levels of excitability [1,2]. GAD
exists in two isoforms, GAD65 and GAD67, both
encoded by different genes [3]. Both enzymes require
the coenzyme pyridoxal phosphate, with GAD65 having
a more significant requirement [2,4] for regulation of
activity. GAD65 appears to be an apoenzyme (lacking
the coenzyme), but once the coenzyme is present, exhi-
bits a significantly higher enzymatic activity than
GAD67 [5]. GAD67 exists mainly as a holoenzyme in
the cytoplasm [5]; regulation of this enzyme appears to
be more associated with gene-level expression [2]. There
is also abundant evidence that GAD65 expression can
also be affected at the gene-level [3,6,7].
As GAD is the rate-limiting enzyme for GABA synth-
esis, perturbation of GAD activity would lead to GABA
depletion and, subsequently, to an increase in seizure
susceptibility. Isoniazid, a widely used drug to combat
tuberculosis, is also and effective GAD inhibitor, leading
to the rapid depletion of GABA [8-10]. Large doses of
isoniazid cause severe fatal seizures in experimental ani-
mals [11]. We have previously reported that the thresh-
old dose for induction of seizures in mice is 200 mg kg
-1
[12], and that doses higher than 200 mg kg
-1
induce sei-
zures of short duration and latency. Isoniazid is not
GAD-specific, but also inhibits other enzymes required
pyridoxal phosphate as a coenzyme. When mice are
administered pyridoxal phosphate 15 min prior to treat-
ment with isoniazid, we found that the threshold shifted
to 250 mg kg
-1
andthatdosesashighas350mgkg
-1
delayed seizure onset and severity [12]. The data suggest
that isoniazid likely competes for the pyridoxal phos-
phate-binding site on GAD.
Seizures can be induced by the administration of kia-
nic acid (KA), a glutamate analogue. Treatment with KA
can manifest in the GABAergic system through loss of a
subpopulation of GAD-positive neurons, leading to lim-
bic seizures [13]. Limbic seizures mostly affect the hip-
pocampus, dentate gyrus, and entorhinal cortex [14,15].
Previously, we have reported that the threshold dose for
KA is 10 mg kg
-1
[12], with doses at or above 30 mg kg
-1
inducing fatal seizures. Taken together, both isoniazid
and KA appear to negatively regulate the GABAergic
system, either directly through hyperexcitability or indir-
ectly through depletion of GABA), resulting in seizures.
We are interested, therefore, in mechanisms by which
we may positively influence the GABAergic system to
form a compensatory mechanism by which seizure
onsetandseveritymaybereduced.Tothisend,we
have found that taurine may be beneficial and may work
through the GABAergic system via the GABA
A
receptor.
We have previously reported that chronic supplementa-
tion of taurine in drinking water to mice increases brain
excitability mainly through alterations in the inhibitory
GABAergic system [12-15]. Taurine, 2-aminoethanesul-
fonic acid, concentrations are high in the CNS [16],
especially in the neonate [17-19], but drop during devel-
opment. Others and our laboratories have demonstrated
a relationship between taurine and the GABAergic sys-
tem. For example, there are brain region-specific levels
of GAD and that GAD expression (both isoforms) is ele-
vated in mice chronically fed taurine [12,18]. Taurine is
an agonist of the GABA
A
receptor [20,21] and activates
chloride influx into postsynaptic neurons via this recep-
tor [19]. Chronic administration of taurine to mice leads
to a reduction in the b2/b3 GABA
A
subunits [19]. Using
a sub-threshold dose of isoniazid coupled with sub-
threshold dose of KA, we have demonstrated that mice
undergo seizures with a short latency and duration, and
this combination was lethal in a majority of animals
[12]. In mice chronically administered taurine prior to
isoniazid/KA treatment, we demonstrated that taurine
was effective in reducing the severity of seizures as
latency was significantly increased and mortality signifi-
cantly decreased [12].
Together, our data suggest that taurine interacts
directly with the GABAergic system, likely via the
GABA
A
receptor. To further test this hypothesis, here we
used a potent GABA
A
antagonist, picrotoxin. Picrotoxin
binds to the b2/b3 subunits of the GABA
A
receptor, the
same subunits demonstrated to be reduced by chronic
exposure to taurine. Here we describe the efficacy of
taurine in decreasing picrotoxin-induced seizures.
Methods
Pharmacological agents
Picrotoxin was dissolved in isotonic saline at 3 mg/ml.
All mice used in this study were two-month-old FVB/NJ
males and all injections were subcutaneous. For taurine-
fed mice, taurine was dissolved in water at 0.05%, and
this solution was made available to the mice in place of
drinking water for 4 weeks beginning at 4 weeks of age.
For taurine-injected mice, mice were administered
LAmoreaux et al.Journal of Biomedical Science 2010, 17(Suppl 1):S14
http://www.jbiomedsci.com/content/17/S1/S14
Page 2 of 5
43 mg kg
-1
subcutaneous 15 min prior to picrotoxin
treatment. All mice were housed in groups of three in a
pathogen-free room maintained on a 12 hr light/dark
cycle and given food and water ad libitum. All proce-
dures were approved by the Institutional Animal Care
and Use Committee of the College of Staten Island/
CUNY and were in conformity with National Institutes
of Health Guidelines.
Behavioral analysis
Animals were put into individual cages the day before
the experiments. After treatment, animals were trans-
ferred to clear animal cages and videotaped for 4 h. Sei-
zures were scored by two independent observers who
were unaware of the treatment. The observers were
asked to look for the following stereotypical behaviors:
motionless stare, rearing and falling, clonic convulsions,
tonic-clonic seizures (status epilepticus) and death. The
occurrence of these behaviors, the time from injection
to initiation of the behavior (latency) and the duration
of the convulsions are measures of seizure severity. Sal-
ine-injected animals did not show any seizure behavior.
Results
Behavioral analysis
Following picrotoxin injection, control mice exhibited
a short latency period to the onset of seizures (Figure
1). The duration of these seizures were short, and in
two thirds of the control mice, seizures were fatal. In
the taurine-injected mice, the latency was significantly
longer (P<0.001) as were the durations (Figure 1).
Further, mortality rate in these mice were also signifi-
cantly less (12% p<0.001), suggesting that taurine was
protective of the effects of picrotoxin via the GABA
A
channel. Similarly, chronic administration of taurine
also significantly reduced the effects of picrotoxin, as
the latency and duration of seizures were also longer
(P<0.05) (Figure 1). Chronic administration also signif-
icantly improved survivability compared to controls.
The data suggests that taurine may act either at
the picrotoxin-binding site or at the GABA binding
site of the GABA
A
receptor. Alternatively, taurine
could mediate it protective effects against picrotoxin-
induced seizures through activation of taurine recep-
tor [22].
Figure 1 Latency to seizures Two-month-old male mice treated with 5 mg kg
-1
picrotoxin presented with short latency periods (control) that
were also of short duration. Seizures were nearly always fatal (66%). Treatment with taurine significantly increased latency and duration, whether
route of administration was injection 15 min prior to picrotoxin injection (Tau-Inj) or chronic feeding of taurine (Tau-Fed). In both cases, taurine
significantly improved survivability (P<0.05).
LAmoreaux et al.Journal of Biomedical Science 2010, 17(Suppl 1):S14
http://www.jbiomedsci.com/content/17/S1/S14
Page 3 of 5
Discussion
Picrotoxin is a potent antagonist of the GABA
A
receptor.
Binding of picrotoxin to b2/b3 subunits of the receptor
effectively blocks the chloride channel, resulting in a
post-synapticneuronthatismoreeasilyexcitableand
prone to hyperexcitability. As such, picrotoxin-induced
toxicity is epileptogenic [10,23-25]. There is compelling
evidence that taurine interacts with the GABAergic sys-
tem via the GABA
A
receptor [19,25-30]. Taurine as also
been shown to activate a taurine receptor [22], but the
molecular identity of this receptor has not been fully
characterized. Chronic taurine administration results in
improved chloride conductance while selective depres-
sion of b2/b3 subunits expression occurs [19], the same
subunits to which picrotoxin binds [31]. Taurine there-
fore maintains the integrity of the chloride channel via
binding to the receptor. The site to which taurine binds,
however, remains elusive. The data here suggests that
taurine may bind to the GABA binding site of the recep-
tor, keeping the channel open. In both taurine-fed and
injected mice, hyperexcitability was diminished, as
demonstrated by the longer latency and duration of sei-
zures. If taurine binds to the GABA binding site, the
receptorwouldremainopenaslongastaurinewaspre-
sent. This scenario could explain the acute taurine
administration data: taurine binds to the GABA
A
recep-
tor and allows the cells to become hyperpolarized and
thus resistant to picrotoxin-induced seizures. For the
chronically fed taurine animals, the taurine would most
likely be sequestered by neurons, forming intracellular
pools of taurine that would primarily be used for osmore-
gulation of the neurons [32-36]. In the taurine-fed mice,
the administration of picrotoxin could signal a release of
intracellular stores of taurine, which could bind to the
GABA binding site and open the channels. An alternative
explanation of these findings would be the activation of
the taurine receptor [22] or a synergistic effect between
the GABA
A
and the taurine receptor could explain the
selective resistance to mice to picrotoxin-induced
seizures.
Conclusions
Taurine administration may interact with the GABAer-
gic system at two points. First, taurine may interact at
the level of the enzyme GAD. Chronic administration of
taurine to mice leads to an increase in GAD levels (both
isoforms) in GABAergic neurons. This in turn leads to
anincreasedexpressioninGABAinpresynapticneu-
rons. Second, taurine interacts at the level of the
GABA
A
receptor. Binding of taurine to the receptor
increases chloride influx into the cell, hyperpolarizing
the postsynaptic neuron to reduce excitability. Chronic
administration of taurine also influences the expression
of the b2/b3 subunits of the GABA
A
receptor, which in
turn may influence the expression of GAD in the presy-
naptic neuron via a feedback mechanism. The data from
this and previous studies provide strong evidence for
the neuroprotective role of taurine in the GABAergic
system.
Acknowledgements
The authors wish to thank Alina Kogan and Elizabeth Che analyzing videos
of seizures, and the staff of the College of Staten Islands vivarium. The
authors also wish to thank the organizing committee of the 17
th
International Taurine Meeting in which preliminary data were presented.
Support for this project comes from FRAXA and PSC-CUNY to AEI.
This article has been published as part as part of Journal of Biomedical
Science Volume 17 Supplement 1, 2010: Proceedings of the 17th
International Meeting of Taurine. The full contents of the supplement are
available online at http://www.jbiomedsci.com/supplements/17/S1.
Author details
1
Department of Biology, College of Staten Island, 2800 Victory Blvd., Staten
Island, NY 10314, USA.
2
Advanced Imaging Facility, College of Staten Island,
2800 Victory Blvd., Staten Island, NY 10314, USA.
3
City University of New
York, Doctoral Program in Biology Neuroscience, 365 Fifth Avenue, New
York, NY 10016-4039, USA.
4
Center for Developmental Disabilities, College of
Staten Island, 2800 Victory Blvd., Staten Island, NY 10314, USA.
Authorscontributions
WJL participated in the design of the study, and drafted the manuscript. AEI
conceived of the study, performed the statistical analysis and participated in
its design and coordination as well as edited the manuscript. Alexandra
Marsillo video recorded seizures and helped in recording data of seizures. All
authors read and approved the final manuscript.
Competing interests
The authors have no competing interests.
Published: 24 August 2010
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doi:10.1186/1423-0127-17-S1-S14
Cite this article as: LAmoreaux et al.: Pharmacological characterization
of GABA
A
receptors in taurine-fed mice. Journal of Biomedical Science
2010 17(Suppl 1):S14.
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... It has been shown that taurine enhances GABA A receptor activity (Huidobro-Toro et al., 1987;Olive, 2002;Theile et al., 2011), a receptor demonstrated to be involved in the development of ethanol tolerance Morrow et al., 1988;Morrow et al., 1990;Montpied et al., 1991;Devaud et al., 1995). Furthermore, chronic taurine exposure alters gene expression of certain GABA A receptor subunits (L'Amoreaux et al., 2010;Shen et al., 2013) and increases gene expression and activity of both isoforms of glutamic acid decarboxylase (GAD1, GAD2), the enzyme critical for GABA synthesis (El Idrissi and Trenkner, 2004;El Idrissi and L'Amoreaux, 2008;Shen et al., 2013). ...
... Several in vitro studies performed in cell cultures have shown that long-term exposure to taurine down-regulates the mRNA expression of the TauT and decreases taurine uptake in cultured cells (Han et al., 1997;Bitoun and Tappaz, 2000;Kang et al., 2002;Voss et al., 2004). Furthermore, chronic administration of taurine has been shown to induce alterations of the GABAergic system, as demonstrated by altered mRNA expression of different GABA A receptor beta subunits and glutamate decarboxylase (El Idrissi and Trenkner, 2004;L'Amoreaux et al., 2010;Shen et al., 2013). As ethanol also has been shown to directly and indirectly modify the GABA A receptor and GABAergic neurotransmission (Mhatre and Ticku, 1993;Crews et al., 1996;Burkhardt and Adermark, 2014;Olsen and Liang, 2017) taurine could possibly alter ethanol-induced effects via influence on inhibitory neurotransmission. ...
... As ethanol also has been shown to directly and indirectly modify the GABA A receptor and GABAergic neurotransmission (Mhatre and Ticku, 1993;Crews et al., 1996;Burkhardt and Adermark, 2014;Olsen and Liang, 2017) taurine could possibly alter ethanol-induced effects via influence on inhibitory neurotransmission. Indeed, taurine treatment has been shown to increase tolerance to picrotoxin-induced seizures (L'Amoreaux et al., 2010), thus demonstrating the ability to change GABA A receptor function. However, in the present study no changes of GABA A receptor subunit or GAD mRNA expression were observed after chronic taurine, indicating that the functional GABA A -related changes previously reported might be explained by alterations at e.g. the protein level. ...
Article
Preclinical studies have shown that the amino acid taurine is of importance for the dopamine elevating properties of ethanol. Taurine intake has escalated over the last decade due to increased consumption of taurine-containing energy drinks and dietary supplements. Whether long-term intake of large amounts of taurine induces adaptations affecting ethanol-induced dopamine elevation is not clear. Thus the aim of the present studies was to explore the impact of repeated administration of large amounts of taurine on ethanol-induced behavior and dopamine neurotransmission. Repeated daily systemic administration of taurine increased taurine-induced locomotor activity and rearing. Acute administration of taurine and ethanol in naïve animals produced an additive effect on extracellular taurine but no alteration of the ethanol-induced dopamine elevation, as measured by in vivo microdialysis. Sub-chronic administration of taurine did not modify the taurine- or dopamine-elevating properties of ethanol. Daily taurine treatment also failed to change the mRNA expression of the taurine transporter and GABAA- and glycine-receptor subunits, as measured by qPCR in nucleus accumbens tissue. We conclude that systemic administration of taurine may have long lasting central effects, here displayed as behavioral sensitization. However, repeated daily exposure to taurine does not appear to influence the dopamine elevating properties of ethanol.
... However, the regulation of the GABAA receptor by taurine is complex. While acute taurine administration activates the GABAA receptor, chronic taurine feeding promotes the downregulation of the GABAA receptor (L'Amoreaux et al., 2010) and the upregulation of glutamate decarboxylase, the rate-limiting step in GABA biosynthesis (El Idrissi and L'Amoreaux, 2008). Therefore, complex interactions within the GABAeric system, as well as in the glycine and NMDA receptors, largely define the actions of taurine in the CNS. ...
... The dominant inhibitory neurotransmitter in the brain is GABA, therefore, regulation of neuroexcitability by GABA plays a prominent role in preventing neuronal hyperexcitability and seizures (L'Amoreaux et al., 2010). Taurine serves as an agonist of the GABAA receptor, an action that enhances chloride influx into postsynaptic neurons, which causes hyperpolarization that inhibits hyperexcitability. ...
... Taurine serves as an agonist of the GABAA receptor, an action that enhances chloride influx into postsynaptic neurons, which causes hyperpolarization that inhibits hyperexcitability. Suppression of kainic acid, isoniazid and picrotoxin-mediated seizures has been attributed to the actions of taurine on the GABAeric system (El Idrissi et al., 2003;El Idrissi and L'Amoreaux, 2008;Junyent et al., 2009;L'Amoreaux et al., 2010). Like GABA, glycine is a major inhibitory neurotransmitter that activates chloride conductance and hyperpolarizes neurons. ...
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Taurine is an abundant, β-amino acid with diverse cytoprotective activity. In some species, taurine is an essential nutrient but in man it is considered a semi-essential nutrient, although cells lacking taurine show major pathology. These findings have spurred interest in the potential use of taurine as a therapeutic agent. The discovery that taurine is an effective therapy against congestive heart failure led to the study of taurine as a therapeutic agent against other disease conditions. Today, taurine has been approved for the treatment of congestive heart failure in Japan and shows promise in the treatment of several other diseases. The present review summarizes studies supporting a role of taurine in the treatment of diseases of muscle, the central nervous system, and the cardiovascular system. In addition, taurine is extremely effective in the treatment of the mitochondrial disease, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and offers a new approach for the treatment of metabolic diseases, such as diabetes, and inflammatory diseases, such as arthritis. The review also addresses the functions of taurine (regulation of antioxidation, energy metabolism, gene expression, ER stress, neuromodulation, quality control and calcium homeostasis) underlying these therapeutic actions.
... In a previous study, in the hippocampus of STZ-treated diabetic mice, taurine increased the transcriptional levels of the GABAA receptor (GABAAR) α2 subunit and of the brain-derived neurotrophic factor (BDNF), thereby leading to an increased synthesis of gamma-aminobutyric acid (GABA) by glutamate decarboxylases (GAD65 and GAD67) (54). In other words, taurine has been shown to act as a GABAAR agonist in synaptic and extrasynaptic membranes, by activating the neurotransmitter system and counterbalancing the lower extracellular levels of GABA in STZ-treated mice (55). Chronic treatment with taurine has been shown to increase the expression levels of BDNF, which appear to be very low in the hippocampus of STZ-treated rats, thereby rescuing neurons from atrophy (56). ...
... In this work, taurine supplementation of pregnant rats was not used as a control because this supplementation causes hyperexcitability and motor behavior deficits in neonates [81], modifying the GABAergic [82] and glutamatergic neurotransmission [83] critical for neurodevelopment [78,84]. This deleterious taurine effect does not occur in old rats. ...
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Oxygen deprivation in newborns leads to hypoxic-ischemic encephalopathy, whose hallmarks are oxidative/nitrosative stress, energetic metabolism alterations, nutrient deficiency, and motor behavior disability. Zinc and taurine are known to protect against hypoxic-ischemic brain damage in adults and neonates. However, the combined effect of prophylactic zinc administration and therapeutic taurine treatment on intrauterine ischemia- (IUI-) induced cerebral damage remains unknown. The present work evaluated this issue in male pups subjected to transient IUI (10 min) at E17 and whose mothers received zinc from E1 to E16 and taurine from E17 to postnatal day 15 (PND15) via drinking water. We assessed motor alterations, nitrosative stress, lipid peroxidation, and the antioxidant system comprised of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Enzymes of neuronal energetic pathways, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), were also evaluated. The hierarchization score of the protective effect of pharmacological strategies (HSPEPS) was used to select the most effective treatment. Compared with the IUI group, zinc, alone or combined with taurine, improved motor behavior and reduced nitrosative stress by increasing SOD, CAT, and GPx activities and decreasing the GSSG/GSH ratio in the cerebral cortex and hippocampus. Taurine alone increased the AST/ALT, LDH/ALT, and AST/LDH ratios in the cerebral cortex, showing improvement of the neural bioenergetics system. This result suggests that taurine improves pyruvate, lactate, and glutamate metabolism, thus decreasing IUI-caused cerebral damage and relieving motor behavior impairment. Our results showed that taurine alone or in combination with zinc provides neuroprotection in the IUI rat model.
... In addition, acting specifically on GABA A , GABA B and/or the glycine receptor, it produced depressive activity [60]. The activity of taurine on GABA A receptors counters seizures mediated by a GABA A antagonist (picrotoxin) via elevating the latency of seizures [61]. Indeed, the inhibitory activity of taurine on the GABA A receptor elevates the level of GABA and enhances the production of glutamic acid decarboxylase isoforms such as GAD 65 and 67, which are connected to GABA synthesis [62]. ...
Article
Taurine is a sulfur-containing amino acid and known as semi-essential in mammals and is produced chiefly by the liver and kidney. It presents in different organs, including retina, brain, heart and placenta and demonstrates extensive physiological activities within the body. In the several disease models, it attenuates inflammation- and oxidative stress-mediated injuries. Taurine also modulates ER stress, Ca2+ homeostasis and neuronal activity at the molecular level as part of its broader roles. Different cellular processes such as energy metabolism, gene expression, osmosis and quality control of protein are regulated by taurine. In addition, taurine displays potential ameliorating effects against different neurological disorders such as neurodegenerative diseases, stroke, epilepsy and diabetic neuropathy and protects against injuries and toxicities of the nervous system. Several findings demonstrate its therapeutic role against neurodevelopmental disorders, including Angelman syndrome, Fragile X syndrome, sleep-wake disorders, neural tube defects and attention-deficit hyperactivity disorder. Considering current biopharmaceutical limitations, developing novel delivery approaches and new derivatives and precursors of taurine may be an attractive option for treating neurological disorders. Herein, we present an overview on the therapeutic potential of taurine against neurological disorders, and highlight clinical studies and its molecular mechanistic roles. This article also addresses the neuropharmacological potential of taurine analogs.
... Although sub-convulsing, our pilocarpine dose was effective in counteracting CSD propagation, as evaluated by the alteration in CSD parameters (lower propagation velocity, negative DC amplitude, and longer duration) in the pilocarpine-treated group in comparison with the controls. Pilocarpine displaces the balance between neural excitatory and inhibitory mechanisms toward a hyperexcitability state (Morimoto et al., 2004;L'amoreaux et al., 2010), which makes elicitation and propagation of CSD more difficult (Guedes and Cavalheiro, 1997). The relationship between changes in brain excitability and CSD is still a matter of controversy. ...
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Epilepsy and malnutrition constitute two worldwide health problems affecting behavior and brain function. The cholinergic agonist pilocarpine (300–380 mg/kg; single administration) reproduces the human type of temporal lobe epilepsy in rats. Pilocarpine-induced epilepsy in rodents has been associated with glycemia, learning and memory and anxiety disturbances. Cortical spreading depression (CSD) is a neural response that has been linked to brain excitability disorders and its diseases, and has been shown to be antagonized by acute pilocarpine. This study aimed to further investigate the effect of chronic pilocarpine at a sub-convulsing dose on weight gain, blood glucose levels, anxiety-like behavior and CSD. In addition, we tested whether unfavorable lactation-induced malnutrition could modulate the pilocarpine effects. Wistar rats were suckled under normal size and large size litters (litters with 9 and 15 pups; groups L9 and L15, respectively). From postnatal days (PND) 35–55, these young animals received a daily intraperitoneal injection of pilocarpine (45 mg/kg/day), or vehicle (saline), or no treatment (naïve). On PND58, the animals were behaviorally tested in an open field apparatus. This was immediately followed by 6 h fasting and blood glucose measurement. At PND60–65, CSD was recorded, and its parameters (velocity of propagation, amplitude, and duration) were calculated. Compared to the control groups, pilocarpine-treated animals presented with reduced weight gain and lower glycemia, increased anxiety-like behavior and decelerated CSD propagation. CSD velocity was higher (p < 0.001) in the L15 groups in comparison to the corresponding groups in the L9 condition. The results demonstrate an influence of chronic (21-day) administration of a sub-convulsing, very low dose (45 mg/kg) of pilocarpine on CSD propagation, anxiety-like behavior, glycemia and body weight. Furthermore, data reinforce the hypothesis of a relationship between CSD and brain excitability. The lactation condition seems to differentially modulate these effects.
... Mechanisms of learning and memory, reward, decision-making, mood, and emotionality can drive the food intake [19,33]. As a GABA A receptor modulator, taurine may affect food intake by mechanisms related with reward and mood [6,7,34,35]. Previous studies showed that taurine presents anxiolytic and antidepressant effects [7,36] and we do not discard the idea that these effects may drive the preference for more palatable food. ...
Article
Taurine, an amino acid with antioxidant and osmoregulatory properties, has been studied for its possible antidiabetic properties in type 1 and type 2 diabetic animals. In type 2 diabetic mice, taurine decreases blood glucose through increased insulin secretion and insulin receptor sensitization. However, insulin is absent in type 1 diabetic individuals. The aim of this study was to evaluate the effects of taurine on parameters related to the energy balance that could explain the metabolic action of this amino acid in type 1 diabetic rats. Control and streptozotocin-induced diabetic rats received saline or taurine (100 mg/kg/day), intraperitoneally, for 30 days. Parameters such as palatable food intake, gastrointestinal transit rate, serum glucose, insulin, leptin, and glucagon levels were measured 60 min after the last taurine administration. Liver, kidneys, heart, and retroperitoneal fat were dissected and weighted. Glycogen levels were measured in the liver and soleus muscle. Our results showed that acute taurine administration decreased glycemia. It also decreased food intake in diabetic rats, without affecting other metabolic parameters. Altogether, our results suggest that in type 1 diabetic rats, taurine decreases blood glucose by a non-insulin-dependent mechanism. Due to the safety profile of taurine, and its effect on glycemia, this amino acid may help to design new drugs to add benefit to insulin therapy in type 1 diabetic individuals.
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In this study, we examined neuronal excitability and skeletal muscle physiology and histology in homozygous knockout mice lacking cysteine sulfonic acid decarboxylase (CSAD-KO). Neuronal excitability was measured by intracerebral recording from the prefrontal cortex. Skeletal muscle response was measured through stretch reflex in the ankle muscles. Specifically, we measured the muscle tension, amplitude of electromyogram and velocity of muscle response. Stretch reflex responses were evoked using a specialized stretching device designed for mice. The triceps surae muscle was stretched at various speeds ranging from 18 to 18,000° s−1. A transducer recorded the muscle resistance at each velocity and the corresponding EMG. We also measured the same parameter in anesthetized mice. We found that at each velocity, the CSAD-KO mice generated more tension and exhibited higher EMG responses. To evaluate if the enhanced response was due to neuronal excitability or changes in the passive properties of muscles, we anesthetize mice to eliminate the central component of the reflex. Under these conditions, CSAD-KO mice still exhibited an enhanced stretch reflex response, indicating ultrastructural alterations in muscle histology. Consistent with this, we found that sarcomeres from CSAD-KO muscles were shorter and thinner when compared to control sarcomeres. Neuronal excitability was further investigated using intracerebral recordings of brain waves from the prefrontal cortex. We found that extracellular field potentials in CSAD-KO mice were characterized by reduced amplitude of low-frequency brain waves (delta, theta, alpha, beta and gamma) and increased in the high low-frequency brain waves (slow and fast ripples). Increased slow and fast ripple rates serve as a biomarker of epileptogenic brain. We have previously shown that taurine interacts with GABAA receptors and induces biochemical changes in the GABAergic system. We suggest that taurine deficiency leads to alterations in the GABAergic system that contribute to the enhanced stretch reflex in CSAD-KO mice through biochemical mechanisms that involve alterations not only at the spinal level but also at the cortical level.
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Lead (Pb2+) is a developmental neurotoxicant that causes alterations in the brain's excitation-to-inhibition (E/I) balance. By increasing chloride concentration through GABA-ARs, taurine serves as an effective inhibitory compound for maintaining appropriate levels of brain excitability. Considering this pharmacological mechanism of taurine facilitated inhibition through the GABA-AR, the present pilot study sought to explore the anxiolytic potential of taurine derivatives. Treatment groups consisted of the following developmental Pb2+-exposures: Control (0 ppm) and Perinatal (150 ppm or 1000 ppm lead acetate in the drinking water). Rats were scheduled for behavioral tests between postnatal days (PND) 36-45 with random assignments to either solutions of Saline, Taurine, or Taurine Derived compounds (i.e., TD-101, TD-102, or TD-103) to assess the rats' responsiveness to each drug in mitigating the developmental Pb2+-exposure through the GABAergic system. Long Evans Hooded rats were assessed using an Open Field (OF) test for preliminary locomotor assessment. Approximately 24-h after the OF, the same rats were exposed to the Elevated Plus Maze (EPM) and were given an i.p. injection of 43 mg/Kg of the Saline, Taurine, or TD drugs 15-min prior to testing. Each rat was tested using the random assignment method for each pharmacological condition, which was conducted using a triple-blind procedure. The OF data revealed that locomotor activity was unaffected by Pb2+-exposure with no gender differences observed. However, Pb2+-exposure induced an anxiogenic response in the EPM, which interestingly, was ameliorated in a gender-specific manner in response to taurine and TD drugs. Female rats exhibited more anxiogenic behavior than the male rats; and as such, exhibited a greater degree of anxiety that were recovered in response to Taurine and its derivatives as a drug therapy. The results from the present psychopharmacological pilot study suggests that Taurine and its derivatives could provide useful data for further exploring the pharmacological mechanisms and actions of Taurine and the associated GABAergic receptor properties by which these compounds alleviate anxiety as a potential behavioral pharmacotherapy for treating anxiety and other associated mood disorders.
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Maintenance of osmotic pressure is a primary regulatory process essential for normal cell function. The osmolarity of extracellular fluids is regulated by modifying the intake and excretion of salts and water. A major component of this regulatory process is the neuroendocrine hypothalamo-neurohypophysial system, which consists of neurons located in the paraventricular and supraoptic nuclei. These neurons synthesize the neurohormones vasopressin and oxytocin and release them in the blood circulation. We here review the mechanisms responsible for the osmoregulation of the activity of these neurons. Notably, the osmosensitivity of the supraoptic nucleus is described including the recent data that suggests an important participation of taurine in the transmission of the osmotic information. Taurine is an amino acid mainly known for its involvement in cell volume regulation, as it is one of the major inorganic osmolytes used by cells to compensate for changes in extracellular osmolarity. In the supraoptic nucleus, taurine is highly concentrated in astrocytes, and released in an osmodependent manner through volume-sensitive anion channels. Via its agonist action on neuronal glycine receptors, taurine is likely to contribute to the inhibition of neuronal activity induced by hypotonic stimuli. This inhibitory influence would complement the intrinsic osmosensitivity of supraoptic neurons, mediated by excitatory mechanoreceptors activated under hypertonic conditions. These observations extend the role of taurine from the regulation of cell volume to that of the whole body fluid balance. They also point to a new role of supraoptic glial cells as active components in a neuroendocrine regulatory loop.
Article
We present data that summarize our findings on the role of taurine in the central nervous system and in particular taurine's interaction with the inhibitory and excitatory systems. In taurine‐fed mice, the expression level of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, is elevated. Increased expression of GAD was accompanied by increased levels of GABA. We also found in vitro, that taurine regulates neuronal calcium homeostasis and calcium‐dependent processes, such as protein kinase C (PKC) activity. This calcium‐dependent kinase was regulated by taurine, whereas the activity of protein kinase A (PKA), a cAMP‐dependent, calcium‐independent kinase, was not affected. Furthermore, as a consequence of calcium regulation, taurine counteracted glutamate‐induced mitochondrial damage and cell death.
Article
Taurine is a ubiquitous dietary constituent of most mammals and is present in especially high concentrations in the tissues of developing mammals. Research to date indicates that taurine plays an important role in the development of the nervous system and the process of migration in particular. It is speculated that taurine uptake and release, in conjunction with glutamate uptake and release, may represent one form of communication between neurons and glial cells. The need of taurine by the body is emphasized by the ability of the kidney to curtail taurine excretion to conserve taurine in the face of a low dietary taurine intake. The evidence for a special role of taurine in development is considered and discussed.
Article
: γ-Aminobutyric acid (GABA) is synthesized in brain in at least two compartments, commonly called the transmitter and metabolic compartments, and because reglatory processes must serve the physiologic function of each compartment, the regulation of GABA synthesis presents a complex problem. Brain contains at least two molecular forms of glutamate decarboxylase (GAD), the principal synthetic enzyme for GABA. Two forms, termed GAD65 and GAD67, are the products of two genes and differ in sequence, molecular weight, interaction with the cofactor, pyridoxal 5′-phosphate (pyridoxal-P), and level of expression among brain regions. GAD65 appears to be localized in nerve terminals to a greater degree than GAD67, which appears to be more uniformly distributed throughout the cell. The interaction of GAD with pyridoxal-P is a major factor in the short-term regulation of GAD activity. At least 50% of GAD is present in brain as apoenzyme (GAD without bound cofactor; apoGAD), which serves as a reservoir of inactive GAD that can be drawn on when additional GABA synthesis is needed. A substantial majority of apoGAD in brain is accounted for by GAD65, but GAD67 also contributes to the pool of apoGAD. The apparent localization of GAD65 in nerve terminals and the large reserve of apo-GAD65 suggest that GAD65 is specialized to respond to short-term changes in demand for transmitter GABA. The levels of apoGAD and the holoenzyme of GAD (holoGAD) are controlled by a cycle of reactions that is regulated by physiologically relevant concentrations of ATP and other polyanions and by inorganic phosphate, and it appears possible that GAD activity is linked to neuronal activity through energy metabolism. GAD is not saturated by glutamate in synaptosomes or cortical slices, but there is no evidence that GABA synthesis in vivo is regulated physiologically by the availability of glutamate. GABA competitively inhibits GAD and converts holo- to apoGAD, but it is not clear if intracellular GABA levels are high enough to regulate GAD. There is no evidence of short-term regulation by second messengers. The syntheses of GAD65 and GAD67 proteins are regulated separately. GAD67 regulation is complex; it not only is present as apoGAD67, but the expression of GAD67 protein is regulated by two mechanisms: (a) by control of mRNA levels and (b) at the level of translation or protein stability. The latter mechanism appears to be mediated by intracellular GABA levels.
Article
We recently reported that the mammalian brain has two forms of the GABA synthetic enzyme glutamate decarboxylase (GAD, E.C. 4.1.1.15), which are the products of two genes. The two forms, which we call GAD65 and GAD67, differ from each other in sequence, molecular size, subcellular distribution, and interactions with the cofactor pyridoxal phosphate (PLP), with GAD65 activity more dependent than that of GAD67 on the continued presence of exogenous PLP. The existence of two GAD genes suggests that individual GABA neurons may be subject to differential regulation of GABA production. We have examined the expression of these two forms of GAD during postnatal development of the rat striatum to determine whether different classes of GABA neurons selectively express different amounts of the two GAD mRNAs. Here we present evidence for a dramatic developmental difference in the expression of the two mRNAs during postnatal development of the rat striatum. Using in situ hybridization to the two GAD mRNAs, we observed a selective increase in GAD65 mRNA during the second postnatal week, at the time when striatal matrix neurons innervate the substantia nigra (SN). PLP-dependent enzyme activity in the midbrain increases in parallel with increased expression of GAD65 mRNA in the striatum. We hypothesize that the innervation of the SN by striatal neurons triggers an increase in GAD65. The changing ratios of GAD65 and GAD67 in the striatum may contribute to the well-documented changes in seizure susceptibility that occur in early life.
1.1. The administration of isonicotinic acid hydrazide (INH) produced seizures in the mouse, rat, guinea pig and chick, the mouse being considerably more susceptible than the other species.2.2. INH-induced inhibition of glutamic acid decarboxylase was greatest in mouse brain whereas the inhibition of GABA-α-oxoglutarate aminotransferase was greatest in chick brain.3.3. A consequence of this species difference in enzyme sensitivity was the different concentration of γ-amino-butyric acid (GABA) present 6 hr after INH treatment in chick brain and rat brain respectively. The GABA level in rat brain was not significantly different from that in untreated animals whereas the concentration of the amino acid in chick brain was almost three times normal.
Article
Age-related impairment of central functions is though to result from alterations of neurochemical indices of synaptic function. These neurochemical modifications involve structural proteins, neurotransmitters, neuropeptides and related receptors. Several studies demonstrated that GABA receptors, glutamic acid decarboxylase (GAD65&67), and different subpopulations of GABAergic neurons are markedly decreased in experimental animal brains during aging. Thus, the age-related decline in cognitive functions could be attributable, at least in part, to decrements in the function of the GABAergic inhibitory neurotransmitter system. In this study we show that chronic supplementation of taurine to aged mice significantly ameliorated the age-dependent decline in memory acquisition and retention, and caused alterations in the GABAergic system. These changes include increased levels of the neurotransmitters GABA and glutamate, increased expression of glutamic acid decarboxylase and the neuropeptide somatostatin and increased in the number of somatostatin-positive neurons. These specific alterations of the inhibitory system caused by taurine treatment oppose those naturally-occurring during aging, and suggest a protective role of taurine in this process. Increased understanding of age-related neurochemical changes in the GABAergic system will be important in elucidating the underpinnings of the functional changes of aging. Taurine might help forestall the age-related decline in cognitive functions through interaction with the GABAergic system.
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Taurine, 2-aminoethanesulfonic acid, is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. We have previously reported that in mice, supplementation of the drinking water with taurine induces alterations in the inhibitory GABAergic system. In taurine-fed mice we found that the expression level of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, is elevated. Increased expression of GAD was accompanied by increased levels of GABA. Here, we investigated pharmacologically the functional significance of taurine-induced increase in GAD expression by determining the threshold for kainic acid-induced seizures after partial inhibition of GAD activity with isoniazide. We found that taurine-fed mice have elevated GAD expression and showed a higher threshold for seizure onset when compared with age-matched controls. Thus, taurine-fed mice have a functional increase in GAD activity which offers some protection in this seizure model. Furthermore, this pharmacological manipulation can be used to determine the level of GAD activity in other model systems that show alterations in GAD expression.