This review provides a comprehensive coverage of the history, biology and chemistry of tetrodotoxin (TTX). It traces the origin of this remarkable molecule all the way back to the ancient Chinese medicine records. The discovery of biological activity, isolation, and a brief overview of structure elucidation are summarized. Next, the biology of TTX is discussed, primarily in the context of its activity in the sodium channels, its anesthetic properties, and its potential use in cancer treatment or drug addiction. Biosynthesis of TTX is covered before the discussion of the total syntheses. All total, formal or partial syntheses are covered but those total syntheses that have been discussed in previous reviews are only briefly summarized. Finally, the synthesis of natural and unnatural derivatives is surveyed, and a conclusion and outlook are provided for this very extensive field of endeavor. To the best of our knowledge the literature coverage is complete up to December 2018.

• Klíčová slova
• biological activity, biosynthesis, natural products, tetrodotoxin, total synthesis,
• MeSH
• lidé MeSH
• tetrodotoxin * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• tetrodotoxin * MeSH

Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA) to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC50 concentrations in the low nanomolar range. P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels. In contrast, lidocaine and tetrodotoxin (TTX) reduce CGRP release by 53-75%, with the remaining fraction involving L-type and T-type voltage-gated calcium channels (VGCC). Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC) NaV1.9, but not NaV1.8 or NaV1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes NaV1.7 and NaV1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics.

• Klíčová slova
• P-CTX-1, TRPA1, TRPC5, TRPM8, TTX, calcitonin-gene related peptide, ciguatera, neurogenic inflammation, neuropathic pain, tetrodotoxin, voltage-gated calcium channels,
• MeSH
• ciguatera metabolismus   MeSH
• ciguatoxiny chemie   farmakologie   MeSH
• ELISA MeSH
• hyperalgezie chemicky indukované   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• lidokain farmakologie   MeSH
• membránové potenciály účinky léků   MeSH
• mořské toxiny farmakologie   MeSH
• myši transgenní MeSH
• myši MeSH
• napětím řízený sodíkový kanál, typ 1 účinky léků   MeSH
• napětově řízený sodíkový kanál typ 11 účinky léků   MeSH
• napěťově řízený sodíkový kanál, typ 9 účinky léků   MeSH
• peptid spojený s genem pro kalcitonin účinky léků   MeSH
• receptory peptidu se vztahem ke genu kalcitoninu účinky léků   MeSH
• tetrodotoxin farmakologie   MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CALCA protein, human MeSH Prohlížeč
• ciguatoxiny MeSH
• lidokain MeSH
• mořské toxiny MeSH
• napětím řízený sodíkový kanál, typ 1 MeSH
• napětově řízený sodíkový kanál typ 11 MeSH
• napěťově řízený sodíkový kanál, typ 9 MeSH
• peptid spojený s genem pro kalcitonin MeSH
• receptory peptidu se vztahem ke genu kalcitoninu MeSH
• tetrodotoxin MeSH
• vápník MeSH

The mouse Dach1 gene, involved in the development of the neocortex and the hippocampus, is expressed by neural stem cells (NSCs) during early neurogenesis, and its expression also continues in a subpopulation of cells in the dorsal part of the lateral ventricles (LV) of the adult mouse brain. In this study we aimed to elucidate the role of Dach1-expressing cells in adult neurogenesis/gliogenesis under physiological as well as post-ischemic conditions, employing transgenic mice in which the expression of green fluorescent protein (GFP) is controlled by the D6 promotor of the mouse Dach1 gene. A neurosphere-forming assay of GFP⁺ cells isolated from the dorsal part of the LV was carried out with subsequent differentiation in vitro. To elucidate the neurogenic/gliogenic potential of GFP⁺ cells in the dorsal part of the LV, in situ immunohistochemical/electrophysiological analyses of GFP⁺ cells in adult sham-operated brains (controls) and those after middle cerebral artery occlusion (MCAo) were performed. The GFP⁺ cells isolated from the dorsal part of the LV of controls formed neurospheres and differentiated solely into a glial phenotype, while those isolated after MCAo also gave rise to cells with the properties of neuronal precursors. In situ analyses revealed that GFP⁺ cells express the phenotype of adult NSCs or neuroblasts in controls as well as following ischemia. Following MCAo we found a significantly increased number of GFP⁺ cells expressing doublecortin as well as a number of GFP⁺ cells migrating through the rostral migratory stream into the olfactory bulb, where they probably differentiated into calretinin⁺ interneurons. Collectively, our results suggest the involvement of the mouse Dach1 gene in adult neurogenesis; cells expressing this gene exhibit the properties of adult NSCs or neuroblasts and respond to MCAo by enhanced neurogenesis.

• MeSH
• 4-aminopyridin farmakologie   MeSH
• blokátory sodíkových kanálů farmakologie   MeSH
• buněčná diferenciace fyziologie   MeSH
• degenerace nervu etiologie   patologie   MeSH
• dospělé kmenové buňky fyziologie   MeSH
• infarkt arteria cerebri media komplikace   MeSH
• membránové potenciály účinky léků   MeSH
• metoda terčíkového zámku MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• neurogeneze fyziologie   MeSH
• neurony metabolismus   MeSH
• oční proteiny metabolismus   MeSH
• počet buněk MeSH
• proteiny nervové tkáně metabolismus   MeSH
• techniky in vitro MeSH
• tetraethylamonium farmakologie   MeSH
• tetrodotoxin farmakologie   MeSH
• ventriculi laterales patologie   MeSH
• zelené fluorescenční proteiny genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-aminopyridin MeSH
• blokátory sodíkových kanálů MeSH
• Dach1 protein, mouse MeSH Prohlížeč
• oční proteiny MeSH
• proteiny nervové tkáně MeSH
• tetraethylamonium MeSH
• tetrodotoxin MeSH
• zelené fluorescenční proteiny MeSH

The hypothalamic suprachiasmatic nuclei (SCN), the circadian master clock in mammals, releases ATP in a rhythm, but the role of extracellular ATP in the SCN is still unknown. In this study, we examined the expression and function of ATP-gated P2X receptors (P2XRs) in the SCN neurons of slices isolated from the brain of 16- to 20-day-old rats. Quantitative RT-PCR showed that the SCN contains mRNA for P2X 1-7 receptors and several G-protein-coupled P2Y receptors. Among the P2XR subunits, the P2X2 > P2X7 > P2X4 mRNAs were the most abundant. Whole-cell patch-clamp recordings from SCN neurons revealed that extracellular ATP application increased the frequency of spontaneous GABAergic IPSCs without changes in their amplitudes. The effect of ATP appears to be mediated by presynaptic P2X2Rs because ATPγS and 2MeS-ATP mimics, while the P2XR antagonist PPADS blocks, the observed enhancement of the frequency of GABA currents. There were significant differences between two SCN regions in that the effect of ATP was higher in the ventrolateral subdivision, which is densely innervated from outside the SCN. Little evidence was found for the presence of P2XR channels in somata of SCN neurons as P2X2R immunoreactivity colocalized with synapsin and ATP-induced current was observed in only 7% of cells. In fura-2 AM-loaded slices, BzATP as well as ADP stimulated intracellular Ca(2+) increase, indicating that the SCN cells express functional P2X7 and P2Y receptors. Our data suggest that ATP activates presynaptic P2X2Rs to regulate inhibitory synaptic transmission within the SCN and that this effect varies between regions.

• MeSH
• adenosintrifosfát farmakologie   MeSH
• antagonisté excitačních aminokyselin farmakologie   MeSH
• biofyzikální jevy účinky léků   MeSH
• blokátory sodíkových kanálů farmakologie   MeSH
• GABA farmakologie   MeSH
• inhibitory agregace trombocytů farmakologie   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• messenger RNA metabolismus   MeSH
• metoda terčíkového zámku MeSH
• nervový přenos účinky léků   MeSH
• nervový útlum účinky léků   MeSH
• neurony účinky léků   MeSH
• novorozená zvířata MeSH
• nucleus suprachiasmaticus cytologie   MeSH
• potkani Wistar MeSH
• purinergní látky farmakologie   MeSH
• purinergní receptory P2X genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• synaptické potenciály účinky léků   MeSH
• techniky in vitro MeSH
• tetrodotoxin farmakologie   MeSH
• vápník metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosintrifosfát MeSH
• antagonisté excitačních aminokyselin MeSH
• blokátory sodíkových kanálů MeSH
• GABA MeSH
• inhibitory agregace trombocytů MeSH
• messenger RNA MeSH
• purinergní látky MeSH
• purinergní receptory P2X MeSH
• tetrodotoxin MeSH
• vápník MeSH

The hippocampus is well known for its critical involvement in spatial memory and information processing. In this study, we examined the effect of bilateral hippocampal inactivation with tetrodotoxin (TTX) in an "enemy avoidance" task. In this paradigm, a rat foraging on a circular platform (82 cm diameter) is trained to avoid a moving robot in 20-min sessions. Whenever the rat is located within 25 cm of the robot's center, it receives a mild electrical foot shock, which may be repeated until the subject makes an escape response to a safe distance. Seventeen young male Long-Evans rats were implanted with cannulae aimed at the dorsal hippocampus 14 d before the start of the training. After 6 d of training, each rat received a bilateral intrahippocampal infusion of TTX (5 ng in 1 μL) 40 min before the training session on day 7. The inactivation severely impaired avoidance of a moving robot (n = 8). No deficit was observed in a different group of rats (n = 9) that avoided a stable robot that was only displaced once in the middle of the session, showing that the impairment was not due to a deficit in distance estimation, object-reinforcement association, or shock sensitivity. This finding suggests a specific role of the hippocampus in dynamic cognitive processes required for flexible navigation strategies such as continuous updating of information about the position of a moving stimulus.

• MeSH
• chování zvířat fyziologie   MeSH
• hipokampus anatomie a histologie   účinky léků   fyziologie   MeSH
• krysa rodu Rattus MeSH
• lokomoce fyziologie   MeSH
• potkani Long-Evans MeSH
• tetrodotoxin farmakologie   MeSH
• učení vyhýbat se fyziologie   MeSH
• vnímání pohybu fyziologie   MeSH
• vnímání prostoru fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• tetrodotoxin MeSH

The aim of this study was to determine the effect and mechanism of low concentration of lidocaine on subthreshold membrane potential oscillations (SMPO) and burst discharges in chronically compressed dorsal root ganglion (DRG) neurons. DRG neurons were isolated by enzymatic dissociation method. SMPO, burst discharges and single spike were elicited by whole cell patch-clamp technique in current clamp mode. Persistent Na(+) current (I(NaP)) and transient Na(+) current (I(NaT)) were elicited in voltage clamp mode. The results showed that SMPO was suppressed and burst discharges were eliminated by tetrodotoxin (TTX, 0.2 micromol/l) in current clamp mode, I(NaP) was blocked by 0.2 micromol/l TTX in voltage clamp mode. SMPO, burst discharges and I(NaP) were also suppressed by low concentration of lidocaine (10 micromol/l) respectively. However, single spike and I(NaT) could only be blocked by high concentration of lidocaine (5 mmol/l). From these results, it is suggested that I(NaP) mediates the generation of SMPO in injured DRG neurons. Low concentration of lidocaine (10 micromol/l) suppresses SMPO by selectively inhibiting I(NaP), but not I(NaT), in chronically compressed DRG neurons.

• MeSH
• anestetika lokální farmakologie   MeSH
• blokátory sodíkových kanálů * MeSH
• elektrofyziologie MeSH
• interpretace statistických dat MeSH
• krysa rodu Rattus MeSH
• lidokain farmakologie   MeSH
• membránové potenciály účinky léků   MeSH
• metoda terčíkového zámku MeSH
• neurony účinky léků   metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• sodíkové kanály účinky léků   metabolismus   MeSH
• spinální ganglia cytologie   účinky léků   metabolismus   MeSH
• techniky in vitro MeSH
• tetrodotoxin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anestetika lokální MeSH
• blokátory sodíkových kanálů * MeSH
• lidokain MeSH
• sodíkové kanály MeSH
• tetrodotoxin MeSH

Although the gastrointestinal tract is a rich source of melatonin and possesses numerous melatonin-binding sites, the role of melatonin in this tissue has not yet been fully elucidated. In this work we focused on the role of melatonin in the modulation of ion transport in rat distal colon. Whereas melatonin had no effect on colonic secretion or caused only infrequent and small changes in the short circuit current (Isc) due to its solvent ethanol, this mediator significantly modulated the secretion elicited by some secretagogues. Out of the five substances tested (prostaglandin E(2); 5-hydroxytryptamine; bethanechol; histamine; sodium nitroprusside) melatonin inhibited the effect of prostaglandin E(2) (PGE(2)) and sodium nitroprusside (SNP). Melatonin concentration-dependently decreased PGE(2)-evoked Isc and this inhibitory effect was more obvious from the mucosal side. The basal level of cAMP in colonic mucosa was not influenced by melatonin, but this drug prevented a PGE(2)-induced increase in the level of cAMP. The neurotoxin tetrodotoxin blocked the inhibitory effect of melatonin on SNP-induced Isc. Our data suggests that melatonin takes part in the modulation of colonic ion transport. The modulatory effect of melatonin on PGE(2)-induced Isc occurs directly at the level of the epithelium, whereas the effect on SNP-induced Isc is indirect and located in tetrodotoxin-sensitive enteric neurons.

• MeSH
• AMP cyklický fyziologie   MeSH
• dinoproston farmakologie   MeSH
• iontový transport účinky léků   MeSH
• kolon účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• melatonin farmakologie   MeSH
• nitroprusid farmakologie   MeSH
• potkani Wistar MeSH
• receptor melatoninový MT1 účinky léků   fyziologie   MeSH
• tetrodotoxin farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AMP cyklický MeSH
• dinoproston MeSH
• melatonin MeSH
• nitroprusid MeSH
• receptor melatoninový MT1 MeSH
• tetrodotoxin MeSH

The effects of serosally added 5-hydroxytryptamine (5-HT, 100 microM) on the short circuit-current (Isc) across jejunum and ileum taken from fed, starved and undernourished (Gerbillus cheesmani) were investigated. The effects of the neurotoxin, tetrodotoxin (TTX, 10 microM) on the basal Isc as well as on the maximum increase in Isc induced by 5-HT were also studied. There were regional variations in the basal Isc as well as in the way by which the small intestine responds to 5-HT. The basal Isc was greater in jejunum than in ileum and such differences were TTX-sensitive. The maximum increase in Isc, which results from addition of 5-HT, was higher in jejunum than in ileum under all three feeding conditions. TTX reduced the maximum increase in Isc induced by 5-HT across stripped and intact intestine of the two regions in the three nutritional states. The 5-HT-induced Isc in the jejunum of both starved and undernourished gerbils and in the ileum of starved animals was the function of both submucosal and myenteric plexus. In jejunum and ileum taken from starved and undernourished gerbils the 5-HT-induced Isc was both chloride- and bicarbonate-dependent. Thus the results indicated that both starvation and undernourishment increase that response and such increases were TTX-sensitive and both chloride- and bicarbonate-dependent.

• MeSH
• chloridy metabolismus   MeSH
• fyziologie výživy zvířat * MeSH
• Gerbillinae MeSH
• glukonáty metabolismus   MeSH
• hladovění metabolismus   patofyziologie   MeSH
• hydrogenuhličitany metabolismus   MeSH
• ileum účinky léků   metabolismus   patofyziologie   MeSH
• jejunum účinky léků   metabolismus   patofyziologie   MeSH
• membránové potenciály MeSH
• modely nemocí na zvířatech MeSH
• neurotoxiny farmakologie   MeSH
• podvýživa metabolismus   patofyziologie   MeSH
• serotonin metabolismus   MeSH
• tetrodotoxin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• chloridy MeSH
• glukonáty MeSH
• hydrogenuhličitany MeSH
• neurotoxiny MeSH
• serotonin MeSH
• tetrodotoxin MeSH

Spatial navigation is used as a popular animal model of higher cognitive functions in people. The data suggest that the hippocampus is important for both storing spatial memories and for performing spatial computations necessary for navigation. Animals use multiple behavioral strategies to solve spatial tasks often using multiple memory systems. We investigated how inactivation of the rat hippocampus affects performance in a place avoidance task to determine if the role of the hippocampus in this task could be attributed to memory storage/retrieval or to the computations needed for navigation. Injecting tetrodotoxin (TTX) into both hippocampi impaired conditioned place avoidance, but after injecting only one hippocampus, the rats learned the place avoidance as well as without any injections. Retention of the place avoidance learned with one hippocampus was not impaired when the injection was switched to the hippocampus that had not been injected during learning. The result suggests that during learning, the hippocampus did not store the place avoidance memory.

• MeSH
• anestetika lokální farmakologie   MeSH
• elektrický šok MeSH
• hipokampus fyziologie   MeSH
• krysa rodu Rattus MeSH
• paměť účinky léků   fyziologie   MeSH
• potkani Long-Evans MeSH
• stravovací zvyklosti účinky léků   fyziologie   MeSH
• tetrodotoxin farmakologie   MeSH
• učení vyhýbat se účinky léků   fyziologie   MeSH
• vnímání prostoru účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anestetika lokální MeSH
• tetrodotoxin MeSH

Cognitive coordination refers to processes that organize the timing of activity among neurons without altering individual discharge properties. Coordinating processes allow neural networks to coactivate related representations and prevent the coactivation of unrelated representations. Impaired cognitive coordination, also called cognitive disorganization, is hypothesized to be the core deficit in the disorganized syndrome of schizophrenia (Phillips and Silverstein, 2003), a condition characterized by hallucinations, disorganization, and thought disorder. This disorganization hypothesis is based on the observation that schizophrenic subjects are impaired at segregating relevant and irrelevant stimuli and selectively using associations between relevant cues. We report that injecting the neural activity blocker tetrodotoxin (TTX) into one hippocampus persistently coactivated pyramidal cells in the uninjected hippocampus that initially discharged independently. In accord with the definition of cognitive disorganization, pyramidal cell firing rates only changed for 15 min and did not accompany the coactivation. The TTX-induced coactivity was maximal at gamma periods, consistent with altered gamma oscillations and disorganization in schizophrenia. A network model confirmed that increasing the coupling of weakly associated cells impairs the selective activation and inhibition of stored spatial representations. This TTX-induced cognitive disorganization correctly predicted that the same TTX injection selectively impaired the ability of rats to segregate relevant associations among distal spatial stimuli from irrelevant local stimuli (Wesierska et al., 2005). The TTX-induced coactivity of hippocampal pyramidal cell discharge has construct and predictive validity as a physiological model of psychosis-related disorganization.

• MeSH
• akční potenciály účinky léků   fyziologie   MeSH
• hipokampus fyziologie   MeSH
• kognitivní poruchy chemicky indukované   patofyziologie   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech * MeSH
• psychotické poruchy patofyziologie   MeSH
• tetrodotoxin toxicita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• tetrodotoxin MeSH