The East Asian scorpion Buthus martensii Karsch (BmK) is one of the classical traditional Chinese medicines for treating epilepsy for over a thousand years. Neurotoxins purified from BmK venom are considered as the main active ingredients, acting on membrane ion channels. Voltage-gated sodium channels (VGSCs) play a crucial role in the occurrence of epilepsy, which make them become important drug targets for epilepsy. Long chain toxins of BmK, composed of 60-70 amino acid residues, could specifically recognize VGSCs. Among them, α-like neurotoxins, binding to the receptor site-3 of VGSC, induce epilepsy in rodents and can be used to establish seizure models. The β or β-like neurotoxins, binding to the receptor site-4 of VGSC, have significant anticonvulsant effects in epileptic models. This review aims to illuminate the anticonvulsant/convulsant effects of BmK polypeptides by acting on VGSCs, and provide potential frameworks for the anti-epileptic drug-design.
Animals ; Anticonvulsants/therapeutic use* ; Neurotoxins/pharmacology* ; Scorpion Venoms/pharmacology* ; Scorpions/chemistry* ; Voltage-Gated Sodium Channels

Methylmercury is an environmental pollutant that causes neurotoxicity. Recent studies have reported that the ubiquitin-proteasome system is involved in defense against methylmercury toxicity through the degradation of proteins synthesizing the pyruvate. Mitochondrial accumulation of pyruvate can enhance methylmercury toxicity. In addition, methylmercury exposure induces several immune-related chemokines, specifically in the brain, and may cause neurotoxicity. This summary highlights several molecular mechanisms of methylmercury-induced neurotoxicity.
Animals ; Chemokines ; drug effects ; metabolism ; Humans ; Methylmercury Compounds ; toxicity ; Mice ; Neurotoxins ; toxicity ; Proteolysis ; drug effects ; Rats ; Saccharomyces cerevisiae ; drug effects

OBJECTIVE: The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant, is harmful to the nervous system, but its effects on the brain are still unclear. This study aimed to investigate the effects of TCDD on astrocytes proliferation and underlying molecular mechanism. METHODS: The cell proliferation was measured by EdU-based proliferation assay and PI staining by flow cytometry. Protein expression levels were detected by Western blotting. Immunofluorescence, cytoplasmic and nuclear fractions separation were used to assess the distribution of signal transducer and activator of transcription 3 (STAT3). RESULTS: C6 cells treated with 10 and 50 nmol/L TCDD for 24 h showed significant promotion of the proliferation of. The exposure to TCDD resulted in the upregulation in the expression levels of phosphorylated protein kinase B (p-Akt), phosphorylated STAT3, and cyclin D1 in a dose- and time-dependent manner. The inhibition of Akt expression with LY294002 or STAT3 expression with AG490 abolished the TCDD-induced cyclin D1 upregulation and cell proliferation. Furthermore, LY294002 suppressed the activation of STAT3. Finally, TCDD promoted the translocation of STAT3 from the cytoplasm to the nucleus, and LY294002 treatment blocked this effect. CONCLUSION TCDD exposure promotes the proliferation of astrocyte cells via the Akt/STAT3/cyclin D1 pathway, leading to astrogliosis.
Animals ; Animals, Newborn ; Astrocytes ; drug effects ; Cell Proliferation ; drug effects ; Cyclin D1 ; metabolism ; Environmental Pollutants ; toxicity ; Neurotoxins ; toxicity ; Polychlorinated Dibenzodioxins ; toxicity ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats, Sprague-Dawley ; STAT3 Transcription Factor ; metabolism

As a kind of neurotoxin causing muscle paralysis from Clostridium botulinum, the botulinum toxin A is currently used in different clinical aspects, especially in the facial cosmetic. Compared with the traditional surgical methods, the botulinum toxin injection is minimally invasive and safe, favored by more beauty seekers and with better efficacy. However, factors, such as injection dose, operation skills, and anatomical variation, may result in side effects during the operation, including poor injection experience and drug dispersion.
Botulinum Toxins, Type A ; Face ; Injections ; Neurotoxins

As an environmental risk factor, psychological stress may trigger the onset or accelerate the progression of Parkinson's disease (PD). Here, we evaluated the effects of acute restraint stress on striatal dopaminergic terminals and the brain metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which has been widely used for creating a mouse model of PD. Exposure to 2 h of restraint stress immediately after injection of a low dose of MPTP caused a severe loss of striatal dopaminergic terminals as indicated by decreases in the dopamine transporter protein and dopamine levels compared with MPTP administration alone. Both striatal 1-methyl-4-phenylpyridinium ion (MPP) and MPTP concentrations were significantly increased by the application of restraint stress. Striatal monoamine oxidase-B, which catalyzes the oxidation of MPTP to MPP, was not changed by the restraint stress. Our results indicate that the enhanced striatal dopaminergic terminal loss in the stressed mice is associated with an increase in the transport of neurotoxin into the brain.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; metabolism ; 1-Methyl-4-phenylpyridinium ; metabolism ; Animals ; Corpus Striatum ; drug effects ; metabolism ; Disease Models, Animal ; Dopaminergic Neurons ; drug effects ; MPTP Poisoning ; chemically induced ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neurotoxins ; metabolism ; Restraint, Physical ; Stress, Psychological ; metabolism

The aim of this study was an examination of 240 multifloral honey samples collected from Polish apiaries to determine Clostridium botulinum occurrence. Honey was collected from apiaries directly after the extraction process. Samples were inoculated by using the dilution and centrifugation method. Suspected isolates were examined by using mouse bioassay, polymerase chain reaction (PCR), and real-time PCR methods. C. botulinum type A and B strains were detected in 5 of 240 examined honey samples (2.1%). Bacterial strains were also detected that were phenotypically similar to C. botulinum but that did not exhibit the ability to produce botulinum toxins and did not show the presence of the botulinum cluster (ntnh and bont genes) or expression of the ntnh gene. The methods used in the examination, especially the expression analysis of ntnh gene, enabled specific analysis of suspected strains and could be used routinely in environmental isolate analyses of C. botulinum occurrence.
Animals ; Biological Assay ; Botulinum Toxins ; Centrifugation ; Clostridium botulinum ; Clostridium ; Honey ; Methods ; Mice ; Neurotoxins ; Polymerase Chain Reaction ; Real-Time Polymerase Chain Reaction ; Spores

There are at least three conserved protein folds shared by ion channel-targeted neurotoxins and antimicrobial defensins, including cysteine-stabilized α-helix and β-sheet fold (CSαβ), inhibitor cystine knot fold (ICK) and β-defensin fold (BDF). Based on a combined data of sequences, structures and functions, it has been proposed that these neurotoxins could originate from related ancient antimicrobial defensins by neofunctionalization. This provides an ideal system to study how a novel function emerged from a conserved structural scaffold during evolution. The elucidation of functional novelty of proteins not only has great significance in evolutionary biology but also will be helpful in guiding rational molecular design. This review describes recent progresses in origin of neurotoxins, focusing on the three conserved protein scaffolds.
Defensins ; chemistry ; Evolution, Molecular ; Neurotoxins ; chemistry ; Protein Structure, Secondary

The common marmoset (Callithrix jacchus) is a small-bodied, popular New World monkey and is used widely in reproductive biology, neuroscience, and drug development, due to its comparative ease of handling, high reproductive efficiency, and its unique behavioral characters. In this review, we discuss the marmoset models in Parkinson's disease (PD), which is a neurological movement disorder primarily resulting from a degeneration of dopaminergic neurons with clinical features of tremor, rigidity, postural instability, and akinesia. The most common PD models involve the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine to study the pathogenesis and to evaluate novel therapies. Following the systemic or local administration of these neurotoxins, the marmosets with very severe Parkinson's symptoms are recommended to be placed in an intensive care unit with artificial feeding to increase survival rate. All procedures with MPTP should be conducted in a special room with enclosed cages under negative-pressure by trained researchers with personal protection. Behavioral tests are conducted to provide an external measure of the brain pathology. Along with several biomarkers, including alpha-synuclein and DJ-1, non-invasive neuroimaging techniques such as positron emission tomography and magnetic resonance imaging are used to evaluate the functional changes associated with PD. With the recent growing interest in potential and novel therapies such as stem cell and gene therapy for PD in Korea, the marmoset can be considered as a suitable non-human primate model in PD research to bridge the gap between rodent studies and clinical applications.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; alpha-Synuclein ; Animals* ; Biomarkers ; Biology ; Brain Diseases ; Callithrix* ; Dopaminergic Neurons ; Genetic Therapy ; Humans ; Intensive Care Units ; Korea ; Magnetic Resonance Imaging ; Methods* ; Models, Animal ; Movement Disorders ; Neuroimaging ; Neurosciences ; Neurotoxins ; Nutritional Support ; Oxidopamine ; Parkinson Disease* ; Platyrrhini ; Positron-Emission Tomography ; Primates ; Rodentia ; Stem Cells ; Survival Rate ; Tremor

MicroRNAs (miRNAs) are a class of noncoding RNAs that regulates target gene expression at posttranscriptional level, leading to further biological functions. We have demonstrated that microvesicles (MVs) can deliver miRNAs into target cells as a novel way of intercellular communication. It is reported that in central nervous system, glial cells release MVs, which modulate neuronal function in normal condition. To elucidate the potential role of glial MVs in disease, we evaluated the effects of secreted astrocytic MVs on stress condition. Our results demonstrated that after Lipopolysaccharide (LPS) stimulation, astrocytes released shedding vesicles (SVs) that enhanced vulnerability of dopaminergic neurons to neurotoxin. Further investigation showed that increased astrocytic miR-34a in SVs was involved in this progress via targeting anti-apoptotic protein Bcl-2 in dopaminergic neurons. We also found that inhibition of astrocytic miR-34a after LPS stimulation can postpone dopaminergic neuron loss under neurotoxin stress. These data revealed a novel mechanism underlying astrocyte-neuron interaction in disease.
Animals ; Astrocytes ; cytology ; drug effects ; metabolism ; Cell Line, Tumor ; Cell Survival ; drug effects ; Cell-Derived Microparticles ; metabolism ; Disease Models, Animal ; Dopaminergic Neurons ; drug effects ; pathology ; Down-Regulation ; drug effects ; Humans ; Lipopolysaccharides ; pharmacology ; MicroRNAs ; metabolism ; Neurotoxins ; toxicity ; Oxidopamine ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Stress, Physiological ; drug effects

In the search for novel potent fungi-derived bioactive compounds for bioinsecticide applications, crude ethyl acetate culture filtrate extracts from 110 mangrove fungal endophytes were screened for their toxicity. Toxicity tests of all extracts against brine shrimp (Artemia salina) larvae were performed. The extracts with the highest toxicity were further examined for insecticidal activity against Spodoptera litura larvae and acetylcholinesterase (AChE) inhibition activity. The results showed that the extracts of five isolates exhibited the highest toxicity to brine shrimp at 50% lethal concentration (LC50) values of 7.45 to 10.24 ppm. These five fungal isolates that obtained from Rhizophora mucronata were identified based on sequence data analysis of the internal transcribed spacer region of rDNA as Aspergillus oryzae (strain BPPTCC 6036), Emericella nidulans (strains BPPTCC 6035 and BPPTCC 6038), A. tamarii (strain BPPTCC 6037), and A. versicolor (strain BPPTCC 6039). The mean percentage of S. litura larval mortality following topical application of the five extracts ranged from 16.7% to 43.3%. In the AChE inhibition assay, the inhibition rates of the five extracts ranged from 40.7% to 48.9%, while eserine (positive control) had an inhibition rate of 96.8%, at a concentration of 100 ppm. The extracts used were crude extracts, so their potential as sources of AChE inhibition compounds makes them likely candidates as neurotoxins. The high-performance liquid chromatography profiles of the five extracts differed, indicating variations in their chemical constituents. This study highlights the potential of culture filtrate ethyl acetate extracts of mangrove fungal endophytes as a source of new potential bioactive compounds for bioinsecticide applications.
Acetylcholinesterase ; Artemia ; Aspergillus oryzae ; Chromatography, Liquid ; Complex Mixtures ; DNA, Ribosomal ; Emericella ; Endophytes* ; Larva ; Mortality ; Neurotoxins ; Physostigmine ; Rhizophoraceae ; Spodoptera ; Statistics as Topic ; Toxicity Tests