This review summarizes our work in the field of syn-thesis of natural products and their derivatives. Applica-tion of modern synthetic method is discussed in the con-text of the syntheses of both enantiomers of hydromor-phone, (–)-tetrodotoxin (a marine toxin), and selaginpul-vilins C and D (natural fluorene derivatives). Further, syn-thesis of notoincisol A, selagibenzophenones A and B is described to clarify the structural aspects of the com-pounds. Last but not least, synthesis and pharmaceutical profilation of derivatives of magnolol and honokiol is dis-cussed as well.Fulltext of this article is available on the website of this Journal.
- MeSH
- Alkynes chemical synthesis chemistry MeSH
- Biological Products MeSH
- Hydromorphone chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Lignans chemical synthesis chemistry MeSH
- Polyynes chemical synthesis chemistry MeSH
- Polycyclic Compounds chemical synthesis chemistry MeSH
- Selaginellaceae chemistry MeSH
- Chemistry Techniques, Synthetic * methods MeSH
- Tetrodotoxin chemical synthesis chemistry pharmacology MeSH
- Drug Development MeSH
- Check Tag
- Humans MeSH
[Local anesthetics from the anesthesiologist perspective]
Lokální anestetika jsou léky, které blokují přenos vzruchu nervovými strukturami a způsobují anestezii nebo analgezii v oblasti zásobené daným nervem. Jediným přirozeným lokálním anestetikem je kokain, ostatní jsou syntetická. Tato je možné rozdělit na aminoestery a aminoamidy. Esterová lokální anestetika mají rychlý nástup a krátkou dobu trvání, podobně jako aminoamidová anestetika lidokainového typu. Aminoamidová lokální anestetika bupivakainového typu mají naopak delší nástup účinku a dlouhé trvání. Lokální anestetika jsou nejčastěji používána v perioperační medicíně k aplikaci na sliznici, do podkoží, k nervům i plexům nebo do epidurálního a subarachnoidálního prostoru. Stále rozšířenější je podání mezi fascie svalů k zajištění pooperační analgezie. Lidokain je podáván také nitrožilně, přičemž je využíváno jeho analgetických, protizánětlivých a imunomodulačních účinků. Nejzávažnější komplikací aplikace lokálních anestetik je jejich kardiotoxicita a neurotoxicita. Úspěšnost resuscitace se významně zvýšila po zavedení lipidové emulze jako antidota do klinické praxe. Při dlouhodobém podání lokálních anestetik do nervových blokád může dojít k tachyfylaxi, která se projeví snížením účinku. Výzkum nových molekul s lokálně anestetickým účinkem je zaměřen především na deriváty tetrodotoxinu.
Local anesthetics are drugs that block the transmission of conduction in nerve structures and cause anesthesia or analgesia in the area supplied by the given nerve. The only natural local anesthetic is cocaine, others are synthetic drugs. They can be divided into aminoesthers and aminoamides. Estheric local anesthetics have a rapid onset and short duration of action, similar to lidocaine-type aminoamide anesthetics. Aminoamide local anesthetics of the bupivacaine type have longer onset of action and longer duration. Local anesthetics are most commonly used in perioperative medicine for application to the mucosa, subcutaneous tissue, nerves and plexuses, or into the epidural and subarachnoid space. Increasingly widespread is the administration between the muscle fascias in order to provide postoperative analgesia. Lidocaine is also administered intravenously, using its analgesic, anti-inflammatory and immunomodulatory effects. The most serious complication associated with local anesthetics is their cardiotoxicity and neurotoxicity. The success rate of resuscitation increased significantly after the introduction of the lipid emulsion as an antidote into clinical practice. Long-term administration of local anesthetics to the nerves can result in tachyphylaxis, with a reduction in their effect. The research of new molecules with local anesthetic action is mainly focused on tetrodotoxin derivatives.
- MeSH
- Anesthetics, Local * adverse effects therapeutic use MeSH
- Sodium Channel Blockers pharmacology MeSH
- Bupivacaine analogs & derivatives pharmacology MeSH
- Cocaine MeSH
- Humans MeSH
- Lidocaine chemistry MeSH
- Anesthesia, Local methods MeSH
- Tachyphylaxis MeSH
- Tetrodotoxin MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review 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.
- MeSH
- Ciguatera Poisoning metabolism MeSH
- Ciguatoxins chemistry pharmacology MeSH
- Enzyme-Linked Immunosorbent Assay MeSH
- Hyperalgesia chemically induced MeSH
- Rats MeSH
- Humans MeSH
- Lidocaine pharmacology MeSH
- Membrane Potentials drug effects MeSH
- Marine Toxins pharmacology MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- NAV1.1 Voltage-Gated Sodium Channel drug effects MeSH
- NAV1.9 Voltage-Gated Sodium Channel drug effects MeSH
- NAV1.7 Voltage-Gated Sodium Channel drug effects MeSH
- Calcitonin Gene-Related Peptide drug effects MeSH
- Receptors, Calcitonin Gene-Related Peptide drug effects MeSH
- Tetrodotoxin pharmacology MeSH
- Calcium metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Oceány pokrývají velkou část povrchu naší planety a jsou domovem nepřeberného množství organismů. Řada z nich teprve čeká na své objevení, podobně jako chemické látky, které syntetizují. Odvětví farmakologie označované v zahraniční literatuře termínem „marine pharmacology“ se zabývá studiem právě těchto látek a jejich využitím v medicíně. Původ v mořských organismech je pro většinu z nich jediným pojítkem a tato různorodost se promítá i do širokého spektra možného využití. Mnohé se vyznačují zcela unikátním mechanismem účinku nabízejícím nové možnosti terapeutického působení. Ačkoliv jich do klinické praxe zatím proniklo jen několik (například eribulin či cytarabin), potenciál je obrovský. V klinických studiích v současnosti sice převažují farmaka pro terapii nádorových onemocnění, zkoumány jsou ale i látky s potenciálním využitím v léčbě bolesti či Alzheimerovy choroby a mnoha dalších.
Oceans cover a large part of our planet and they are a home for an enormous amount of species. A lot of them are still waiting to be discovered by man, much like the chemicals they synthesize. Marine pharmacology concerns itself with the study of these chemicals and their potential use in medicine. Origin in marine species is for the most part the only thing this large and diverse group of substances have in common, so the spectrum of possible applications is quite wide. Many of these substances have a unique mechanism of action, offering new therapeutic possibilities. Although just a few of them are used in a clinical practice today (e.g. eribulin, cytarabine), the future looks quite promising. Current clinical trials focus mostly on the therapy of cancer, but trials for therapy of pain or Alzheimer’s disease and many others are also underway.
- Keywords
- léčiva mořského původu, zikonotid, trabectedin, eribulin mesylát, glembatumumab vedotin, DMXBA, marizomib,
- MeSH
- Alzheimer Disease drug therapy MeSH
- Analgesics therapeutic use MeSH
- Antiviral Agents MeSH
- Brentuximab Vedotin MeSH
- Bryostatins pharmacology therapeutic use MeSH
- Cytarabine pharmacology MeSH
- Depsipeptides pharmacology classification MeSH
- Clinical Studies as Topic MeSH
- Humans MeSH
- Neoplasms drug therapy MeSH
- Oceans and Seas MeSH
- Antineoplastic Agents * pharmacology classification therapeutic use MeSH
- Tetrodotoxin pharmacology MeSH
- Vidarabine pharmacology MeSH
- Aquatic Organisms * chemistry classification microbiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Geographicals
- Oceans and Seas MeSH
Toxins are produced by bacteria, plants and animals for defense or for predation. Most of the toxins specifically affect the mammalian nervous system by interfering with the transmission of nerve impulses, and such toxins have the potential for misuse by the military or terrorist organizations. This review discusses the origin, structure, toxicity and symptoms, transmission, mechanism(s) of action, symptomatic treatment of the most important toxins and venoms derived from fungi, plants, marine animals, and microorganisms, along with their potential for use in bioweapons and/or biocrime. Fungal trichothecenes and aflatoxins are potent inhibitors of protein synthesis in most eukaryotes and have been used as biological warfare agents. Ricin and abrin are plant-derived toxins that prevent the elongation of polypeptide chains. Saxitoxin, anatoxin, and tetrodotoxin are marine-derived toxins that bind to sodium channels in nerve and muscle tissue and cause muscle paralysis. Most bacterial toxins, such as botulinum and Shiga affect either the nervous system (neurotoxins) or damage cell membranes. Batrachotoxins, which are secreted by poison-dart frogs are extremely potent cardiotoxic and neurotoxic steroidal alkaloids. The aim of this review is to provide basic information to enable further understanding of these toxins and their potential military uses.
- MeSH
- Abrin chemistry poisoning adverse effects MeSH
- Aflatoxins chemistry poisoning adverse effects MeSH
- Bacterial Toxins poisoning MeSH
- Batrachotoxins chemistry poisoning adverse effects MeSH
- Biological Warfare Agents * MeSH
- Toxins, Biological * poisoning adverse effects MeSH
- Botulinum Toxins chemistry poisoning adverse effects MeSH
- Humans MeSH
- Marine Toxins poisoning MeSH
- Mycotoxins poisoning adverse effects MeSH
- Poisoning * prevention & control therapy MeSH
- Ricin chemistry poisoning adverse effects MeSH
- Saxitoxin chemistry poisoning adverse effects MeSH
- Shiga Toxins chemistry poisoning adverse effects MeSH
- T-2 Toxin chemistry poisoning adverse effects MeSH
- Tetrodotoxin chemistry poisoning adverse effects MeSH
- Toxoids poisoning adverse effects MeSH
- Venoms poisoning adverse effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review 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
- Adenosine Triphosphate pharmacology MeSH
- Excitatory Amino Acid Antagonists pharmacology MeSH
- Biophysical Phenomena drug effects MeSH
- Sodium Channel Blockers pharmacology MeSH
- gamma-Aminobutyric Acid pharmacology MeSH
- Platelet Aggregation Inhibitors pharmacology MeSH
- Rats MeSH
- Cells, Cultured MeSH
- RNA, Messenger metabolism MeSH
- Patch-Clamp Techniques MeSH
- Synaptic Transmission drug effects MeSH
- Neural Inhibition drug effects MeSH
- Neurons drug effects MeSH
- Animals, Newborn MeSH
- Suprachiasmatic Nucleus cytology MeSH
- Rats, Wistar MeSH
- Purinergic Agents pharmacology MeSH
- Receptors, Purinergic P2X genetics metabolism MeSH
- Gene Expression Regulation drug effects MeSH
- Synaptic Potentials drug effects MeSH
- In Vitro Techniques MeSH
- Tetrodotoxin pharmacology MeSH
- Calcium metabolism MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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-Aminopyridine pharmacology MeSH
- Sodium Channel Blockers pharmacology MeSH
- Cell Differentiation physiology MeSH
- Nerve Degeneration etiology pathology MeSH
- Adult Stem Cells physiology MeSH
- Infarction, Middle Cerebral Artery complications MeSH
- Membrane Potentials drug effects MeSH
- Patch-Clamp Techniques MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Neurogenesis physiology MeSH
- Neurons metabolism MeSH
- Eye Proteins metabolism MeSH
- Cell Count MeSH
- Nerve Tissue Proteins metabolism MeSH
- In Vitro Techniques MeSH
- Tetraethylammonium pharmacology MeSH
- Tetrodotoxin pharmacology MeSH
- Lateral Ventricles pathology MeSH
- Green Fluorescent Proteins genetics MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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
- Behavior, Animal physiology MeSH
- Hippocampus anatomy & histology drug effects physiology MeSH
- Rats MeSH
- Locomotion physiology MeSH
- Rats, Long-Evans MeSH
- Tetrodotoxin pharmacology MeSH
- Avoidance Learning physiology MeSH
- Motion Perception physiology MeSH
- Space Perception physiology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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 patchclamp technique in current clamp mode. Persistent Na+ current (INaP) and transient Na+ current (INaT) were elicited in voltage clamp mode. The results showed that SMPO was suppressed and burst discharges were eliminated by tetrodotoxin (TTX, 0.2 µmol/l) in current clamp mode, INaP was blocked by 0.2 µmol/l TTX in voltage clamp mode. SMPO, burst discharges and INaP were also suppressed by low concentration of lidocaine (10 µmol/l) respectively. However, single spike and INaT could only be blocked by high concentration of lidocaine (5 mmol/l). From these results, it is suggested that INaP mediates the generation of SMPO in injured DRG neurons. Low concentration of lidocaine (10 µmol/l) suppresses SMPO by selectively inhibiting INaP, but not INaT, in chronically compressed DRG neurons.
- Keywords
- Lidocaine, Neuropathic pain, Dorsal root ganglion, Ectopic discharges, Subthreshold membrane potential oscillations, Persistent Na+ current,
- MeSH
- Anesthetics, Local pharmacology MeSH
- Sodium Channel Blockers MeSH
- Electrophysiology MeSH
- Financing, Organized MeSH
- Data Interpretation, Statistical MeSH
- Rats MeSH
- Lidocaine pharmacology MeSH
- Membrane Potentials drug effects MeSH
- Patch-Clamp Techniques MeSH
- Neurons metabolism drug effects MeSH
- Rats, Sprague-Dawley MeSH
- Sodium Channels metabolism drug effects MeSH
- Ganglia, Spinal cytology metabolism drug effects MeSH
- Tetrodotoxin pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Female MeSH
- Animals 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
- Cyclic AMP physiology MeSH
- Dinoprostone pharmacology MeSH
- Financing, Organized MeSH
- Ion Transport drug effects MeSH
- Colon secretion drug effects MeSH
- Rats MeSH
- Melatonin pharmacology MeSH
- Nitroprusside pharmacology MeSH
- Rats, Wistar MeSH
- Receptor, Melatonin, MT1 physiology drug effects MeSH
- Tetrodotoxin pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
