Alterations in the excitability of dorsal root ganglion (DRG) neurons are critical in the pathogenesis of acute and chronic pain. Neurotransmitter release from the terminals of DRG neurons is regulated by cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1), both activated by anandamide (AEA). In our experiments, the AEA precursor N-arachidonoylphosphatidylethanolamine (20:4-NAPE) was used to study the modulation of nociceptive DRG neurons excitability using K+-evoked Ca2+ transients. Intrathecal administration was used to evaluate in vivo effects. Application of 20:4-NAPE at lower concentrations (10 nM - 1 μM) decreased the excitability of DRG neurons, whereas the higher (10 μM) increased it. Both effects of 20:4-NAPE were blocked by the N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. Similarly, lower concentrations of externally applied AEA (1 nM - 10 nM) inhibited DRG neurons, whereas higher concentration (100 nM) did not change it. High AEA concentration (10 μM) evoked Ca2+ transients dependent on TRPV1 activation in separate experiments. Inhibition of the CB1 receptor by PF514273 (400 nM) prevented the 20:4-NAPE- and AEA-induced inhibition, whereas TRPV1 inhibition by SB366791 (1 μM) prevented the increased DRG neuron excitability. In behavioral tests, lower 20:4-NAPE concentration caused hyposensitivity, while higher evoked mechanical allodynia. Intrathecal LEI-401 prevented both in vivo effects of 20:4-NAPE. These results highlight anti- and pro-nociceptive effects of 20:4-NAPE mediated by CB1 and TRPV1 in concentration-dependent manner. Our study underscores the complexity of endocannabinoid signaling in pain transmission modulation and highlights 20:4-NAPE as a potential therapeutic target, offering new insights for developing analgesic strategies.

• MeSH
• Endocannabinoids pharmacology   metabolism   MeSH
• Phosphatidylethanolamines * pharmacology   MeSH
• Phospholipase D * metabolism   antagonists & inhibitors   MeSH
• TRPV Cation Channels metabolism   MeSH
• Rats MeSH
• Arachidonic Acids * pharmacology   MeSH
• Neurons * drug effects   metabolism   MeSH
• Polyunsaturated Alkamides pharmacology   MeSH
• Rats, Sprague-Dawley MeSH
• Receptor, Cannabinoid, CB1 metabolism   MeSH
• Ganglia, Spinal * drug effects   metabolism   cytology   MeSH
• Calcium metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Rasopathies are genetic disorders often associated with developmental delay and intellectual disability. Noonan syndrome (NS) is one of the most common Rasopathies, caused by mutations in PTPN11 in more than 50% of cases. In mammalian neurons, PTPN11 controls the trafficking of postsynaptic glutamate receptors. This process is disrupted in neurons expressing PTPN11 variants associated with Rasopathies and is thought to contribute to the cognitive impairments in Noonan syndrome. Recent work revealed presynaptic impairments upon expression of RASopathy-linked PTPN11 variants in Drosophila. However, the presynaptic role of PTPN11 has not yet been addressed in mammals. Here, we investigated membrane trafficking of synaptic vesicles in cultured mouse cortical neurons expressing Rasopathy-associated PTPN11D61Y variant. We observed a significantly smaller readily releasable and total recycling pool of synaptic vesicles. The drop in synaptic vesicle release competence was accompanied by a decreased rate of SV retrieval. Interestingly, the presynaptic phenotype was evident in mature (DIV21) but not in immature (DIV12) neurons. Thus, our data reveal importance of balanced PTPN11 activity for normal trafficking of neurotransmitter-filled synaptic vesicles in the presynaptic ending of mature neurons.

• MeSH
• Cells, Cultured MeSH
• Mutation genetics   MeSH
• Mice MeSH
• Neurons metabolism   MeSH
• Aging genetics   metabolism   MeSH
• Synaptic Vesicles * metabolism   MeSH
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 * metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Female sexual behaviors in rodents (lordosis and appetitive or "proceptive" behaviors) are induced through a genomic mechanism by the sequential actions of estradiol (E2) and progesterone (P), or E2 and testosterone (T) at their respective receptors. However, non-steroidal agents, such as gonadotropin-releasing hormone (GnRH), Prostaglandin E2 (PGE2), noradrenaline, dopamine, oxytocin, α-melanocyte stimulating hormone, nitric oxide, leptin, apelin, and others, facilitate different aspects of female sexual behavior through their cellular and intracellular effects at the membrane and genomic levels in ovariectomized rats primed with E2. These neurotransmitters often act as intermediaries of E2 and P (or T). The classical model of steroid hormone action through intracellular receptor binding has been complemented by an alternative scenario wherein the steroid functions as a transcription factor after binding the receptor protein to DNA. Another possible mechanism occurs through the activation of second messenger systems (cyclic AMP, cyclic GMP, calcium), which subsequently initiate phosphorylation events via diverse kinase systems (protein kinases A, G, or C). These kinases target the progesterone receptor (PR) or associated effector proteins that connect the PR to the trans-activation machinery. This may also happen to the androgen receptor (AR). In addition, other cellular mechanisms could be involved since the chemical structure of these non-steroidal agents causes a change in their lipophobicity that prevents them from penetrating the cell and exerting direct transcriptional effects; however, they can exert effects on different components of the cell membrane activating a cross-talk between the cell membrane and the regulation of the transcriptional mechanisms.

• MeSH
• Rodentia MeSH
• Gonadal Steroid Hormones metabolism   pharmacology   MeSH
• Progesterone pharmacology   metabolism   MeSH
• Sexual Behavior, Animal * drug effects   physiology   MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Botulinum neurotoxins (BoNTs) and tetanus toxin (TeTX) are the deadliest biological substances that cause botulism and tetanus, respectively. Their astonishing potency and capacity to enter neurons and interfere with neurotransmitter release at presynaptic terminals have attracted much interest in experimental neurobiology and clinical research. Fused with reporter proteins or labelled with fluorophores, BoNTs and TeTX and their non-toxic fragments also offer remarkable opportunities to visualize cellular processes and functions in neurons and synaptic connections. This study presents the state-of-the-art optical probes derived from BoNTs and TeTX and discusses their applications in molecular and synaptic biology and neurodevelopmental research. It reviews the principles of the design and production of probes, revisits their applications with advantages and limitations and considers prospects for future improvements. The versatile characteristics of discussed probes and reporters make them an integral part of the expanding toolkit for molecular neuroimaging, promoting the discovery process in neurobiology and translational neurosciences.

• MeSH
• Botulinum Toxins chemistry   MeSH
• Fluorescent Dyes chemistry   MeSH
• Humans MeSH
• Molecular Probes chemistry   MeSH
• Neurons * metabolism   MeSH
• Neurotoxins * MeSH
• Neuroimaging * methods   MeSH
• Synapses * metabolism   MeSH
• Tetanus Toxin * chemistry   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

One element, potassium, can be identified as the connecting link in the research of Czech neurophysiologist Prof. František Vyskočil. It accompanied him from the first student experiments on the frog muscle (Solandt effect) via sodium-potassium pump and quantum and non-quantum release of neurotransmitters (e.g. acetylcholine) to the most appreciated work on the reversible leakage of K+ from brain neurons during the Leao ́s spreading cortical depression, often preceding migraine. He used a wide range of methods at the systemic, cellular and genetic levels. The electrophysiology and biochemistry of nerve-muscle contacts and synapses in the muscles and brain led to a range of interesting findings and discoveries on normal, denervated and hibernating laboratory mammals and in tissue cultures. Among others, he co-discovered the facilitating effects of catecholamines (adrenaline in particular) by end-plate synchronization of individual evoked quanta. This helps to understand the general effectiveness of nerve-muscle performance during actual stress. After the transition of the Czech Republic to capitalism, together with Dr. Josef Zicha from our Institute, he was an avid promoter of scientometry as an objective system of estimating a scientist ́s success in basic research (journal Vesmír, 69: 644-645, 1990 in Czech).

• MeSH
• History, 20th Century MeSH
• History, 21st Century MeSH
• Humans MeSH
• Brain * physiology   metabolism   MeSH
• Neurons * metabolism   physiology   MeSH
• Neurosciences * MeSH
• Anura MeSH
• Animals MeSH
• Check Tag
• History, 20th Century MeSH
• History, 21st Century MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Review MeSH

Možnosti léčby neuroendokrinních nádorů se v České republice v posledních letech obohatily o peptidovou receptorovou radionuklidovou terapii. Doposud je její použití omezené na tumory gastroenteropankreatického původu. Nicméně v rámci doporučení mezinárodních odborných společností ji nacházíme jako volbu i v jiných indikacích. V tomto článku je rozebíráno, jakým způsobem jsou vybíráni vhodní kandidáti k léčbě a její postavení v terapeutickém algoritmu ostatních neuroendokrinních nádorů, které ještě potřebuje oficiální potvrzení prospektivními randomizovanými studiemi.

The treatment options for neuroendocrine tumors in the Czech Republic have been enriched in recent years with peptide receptor radionuclide therapy. So far, its use is limited to tumors of gastroenteropancreatic origin. However, as part of the recommendations of international professional societies, we find it as an option in other indications as well. This article discusses how suitable candidates for treatment are selected and its position in the therapeutic algorithm of other neuroendocrine tumors, which still needs official confirmation by prospective randomized studies.

• Keywords
• peptidová receptorová radionuklidová terapie-PRRT, Lu-oxodotrietid, studie NETTER-1, studie NETTER-2,
• MeSH
• Clinical Trials, Phase III as Topic MeSH
• Humans MeSH
• Neuroendocrine Tumors * diagnosis   classification   radiotherapy   MeSH
• Neurotransmitter Agents MeSH
• Radioisotopes * adverse effects   therapeutic use   MeSH
• Receptors, Somatostatin MeSH
• Patient Selection MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Alzheimer's disease (AD) is a progressive, fatal, neurodegenerative disorder for which only treatments of limited efficacy are available. Despite early mentions of dementia in the ancient literature and the first patient diagnosed in 1906, the underlying causes of AD are not well understood. This study examined the possible role of dopamine, a neurotransmitter that is involved in cognitive and motor function, in AD. We treated adult zebrafish (Danio rerio) with okadaic acid (OKA) to model AD and assessed the resulting behavioral and neurochemical changes. We then employed a latent learning paradigm to assess cognitive and motor function followed by neurochemical analysis with fast-scan cyclic voltammetry (FSCV) at carbon fiber microelectrodes to measure the electrically stimulated dopamine release. The behavioral assay showed that OKA treatment caused fish to have lower motivation to reach the goal chamber, resulting in impeded learning and decreased locomotor activity compared to controls. Our voltammetric measurements revealed that the peak dopamine overflow in OKA-treated fish was about one-third of that measured in controls. These findings highlight the profound neurochemical changes that may occur in AD. Furthermore, they demonstrate that applying the latent learning paradigm and FSCV to zebrafish is a promising tool for future neurochemical studies and may be useful for screening drugs for the treatment of AD.

• MeSH
• Alzheimer Disease * MeSH
• Zebrafish MeSH
• Dopamine * MeSH
• Carbon Fiber MeSH
• Okadaic Acid MeSH
• Microelectrodes MeSH
• Neurotransmitter Agents MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously induced change in developmentally imprinted excitatory neurotransmitter phenotypes of these neurons to inhibitory has not yet been achieved. Here, we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-aminobutyric acid) synthesizing-releasing inhibitory machinery in mice with neuropathic pain. Treated animals showed a progressive and complete reversal of neuropathic pain (tactile and brush-evoked pain behavior) that persisted for a minimum of 2.5 months post-treatment. The mechanism of this treatment effect results from the switch of excitatory to preferential inhibitory neurotransmitter phenotype in dorsal horn nociceptive neurons and a resulting increase in inhibitory activity in regional spinal circuitry after peripheral nociceptive stimulation. No detectable side effects (e.g., sedation, motor weakness, loss of normal sensation) were seen between 2 and 13 months post-treatment in naive adult mice, pigs, and non-human primates. The use of this treatment approach may represent a potent and safe treatment modality in patients suffering from spinal cord or peripheral nerve injury-induced neuropathic pain.

• MeSH
• Posterior Horn Cells MeSH
• Spinal Cord MeSH
• Mice MeSH
• Neuralgia * etiology   therapy   MeSH
• Nociceptors * MeSH
• Swine MeSH
• Gene Transfer Techniques MeSH
• Spinal Cord Dorsal Horn MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Východiska: Akupunktura je jednou z nejstarších léčebných metod. Tradiční pohled na akupunkturu ji vnímá jako ovlivnění energetických drah prostřednictvím stimulace specifických bodů. Původní meridiánová teorie, která pracuje s předpokladem normalizace proudící energie Qi v organizmu, je se vzrůstající evidencí doplňována informacemi o biologickém dopadu užití akupunktury z pohledu západní medicíny. Specifická stimulace konkrétních bodů na těle vede k aktivaci hypotalamu a hypofýzy, což má za následek široké spektrum systémových účinků. Stimulací nervů ve svalu, které pak přenášejí signál do míchy, středního mozku a hypotalamo-hypofyzárního systému, dochází k uvolňování celé řady neurotransmiterů, endogenních opioidních peptidů či hormonů. Stimulací akupunkturních bodů se mění i hladiny prozánětlivých cytokinů vč. IL-1-beta, IL-6, IL-17 a TNF-alfa. V současnosti jsou dle doporučení National Comprehensive Cancer Network (NCCN) k léčbě akupunkturou indikovány tyto symptomy: bolest vč. bolesti neuropatické, artralgie a myalgie (zvláště při léčbě inhibitory aromatázy), nevolnost a zvracení, únava, vazomotorické symptomy u žen a vazomotorické symptomy u mužů v souvislosti s androgen deprivační terapií. Akupunktura se zdá být efektivní a bezpečnou metodou terapie řady symptomů nádorových onemocnění, případně nežádoucích účinků onkologické léčby; stejně jako jakákoliv jiná léčebná metoda má však své indikace a kontraindikace. Cíl: Cílem této práce je podat ucelený přehled o využití akupunktury v definovaných indikacích, dle aktuálních mezinárodních doporučení. Lze tak rozšířit terapeutické možnosti symptomatické léčby nádorových onemocnění a léčby nežádoucích účinků onkologické terapie.

Background: Acupuncture is one of the oldest therapeutic methods. The traditional view of acupuncture is represented by influencing energy pathways through stimulation of specific points. The original meridian theory, which works with the assumption of normalization of the flowing energy Qi in the organism is, with increasing evidence, supplemented with information about the biological impact of the use of acupuncture from the perspective of Western medicine. Specific stimulation of particular points on the body leads to the activation of hypothalamus and pituitary gland through neurotransmitters, resulting in a wide range of systemic effects. Stimulation of nerves in the muscle, which then transmits a signal to the spinal cord, midbrain, and hypothalamic-pituitary system, releases neurotransmitters, endogenous opioid peptides, or hormones. Stimulation of acupuncture points changes the levels of proinflammatory cytokines, including IL-1-beta, IL-6, IL-17, and TNF-alpha. Currently, according to the National Comprehensive Cancer Network (NCCN) guidelines, the following symptoms are indicated for acupuncture treatment: pain including neuropathic pain, arthralgia, and myalgia, especially in the aromatase inhibitors therapy, nausea, and vomiting, fatigue, vasomotor symptoms in women and vasomotor symptoms in men caused by androgen deprivation therapy. Acupuncture seems to be an effective and safe treatment method for many of the cancer symptoms or the side effects of cancer treatment, but, like any other treatment method, it has its indications and contraindications. Purpose: This work aims to provide a comprehensive overview of the use of acupuncture in defined indications, according to current international guidelines. Thus, the therapeutic possibilities of symptomatic treatment of cancer and therapy of adverse events of oncological treatment can be extended.

• MeSH
• Acupuncture * MeSH
• Acupuncture Therapy methods   MeSH
• Arthralgia therapy   MeSH
• Humans MeSH
• Evidence-Based Medicine MeSH
• Myalgia therapy   MeSH
• Cancer Pain therapy   MeSH
• Neoplasms * complications   MeSH
• Practice Guidelines as Topic MeSH
• Fatigue therapy   MeSH
• Vomiting therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

In classical neuroscience, Dale ́s principle postulates that neuronal identity is conferred by the specific neurotransmitter that it releases. However, the brain might be more tractable to specific situations regardless of specific specialisation which may contradict this principle. Hence, this constrained approach of how we perceive and study the nervous system must be revisited and revised, specifically by studying the dopaminergic system. We presume a relatively flexible change in the dopaminergic system due to neuronal activity or environmental changes. While the parallel between the reward system of mammals and insects is generally well accepted, herein, we extend the idea that the insect nervous system might also possess incredible plasticity, similar to the mammalian system. In this review, we critically evaluate the available information about the reward system in vertebrates and invertebrates, emphasising the dopaminergic neuronal plasticity, a challenge to the classical Dale's principle. Thus, neurotransmitter switching significantly disrupts the static idea of neural network organisation and suggests greater possibilities for a dynamic response to the current life context of organisms.

• MeSH
• Dopamine MeSH
• Dopaminergic Neurons physiology   MeSH
• Drosophila melanogaster physiology   MeSH
• Drosophila * physiology   MeSH
• Mushroom Bodies * physiology   MeSH
• Humans MeSH
• Neurotransmitter Agents physiology   MeSH
• Mammals MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH