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.

• Keywords
• Advanced biomaterials, Fluorescent probes, Fusion proteins, Molecular trafficking, Optical imaging, Retrograde transport, SNARE proteins,
• 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
• Names of Substances
• Botulinum Toxins MeSH
• Fluorescent Dyes MeSH
• Molecular Probes MeSH
• Neurotoxins * MeSH
• Tetanus Toxin * MeSH

The botulinum neurotoxin-like toxin from Weissella oryzae (BoNT/Wo) is one of the BoNT-like toxins recently identified outside of the Clostridium genus. We show that, like the canonical BoNTs, BoNT/Wo forms a complex with its non-toxic non-hemagglutinin (NTNH) partner, which in traditional BoNT serotypes protects the toxin from proteases and the acidic environment of the hosts' guts. We here report the cryo-EM structure of the 300 kDa BoNT/Wo-NTNH/Wo complex together with pH stability studies of the complex. The structure reveals molecular details of the toxin's interactions with its protective partner. The overall structural arrangement is similar to other reported BoNT-NTNH complexes, but NTNH/Wo uniquely contains two extra bacterial immunoglobulin-like (Big) domains on the C-terminus. Although the function of these Big domains is unknown, they are structurally most similar to bacterial proteins involved in adhesion to host cells. In addition, the BoNT/Wo protease domain contains an internal disulfide bond not seen in other BoNTs. Mass photometry analysis revealed that the BoNT/Wo-NTNH/Wo complex is stable under acidic conditions and may dissociate at neutral to basic pH. These findings established that BoNT/Wo-NTNH/Wo shares the general fold of canonical BoNT-NTNH complexes. The presence of unique structural features suggests that it may have an alternative mode of activation, translocation and recognition of host cells, raising interesting questions about the activity and the mechanism of action of BoNT/Wo as well as about its target environment, receptors and substrates.

• Keywords
• BoNT-NTNH complex, Weissella oryzae, botulinum neurotoxins, cryo-EM structure,
• MeSH
• Botulinum Toxins * chemistry   MeSH
• Clostridium botulinum * chemistry   metabolism   MeSH
• Cryoelectron Microscopy MeSH
• Hemagglutinins metabolism   MeSH
• Immunoglobulin Domains MeSH
• Neurotoxins metabolism   MeSH
• Weissella * MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Botulinum Toxins * MeSH
• Hemagglutinins MeSH
• Neurotoxins MeSH

In the Czech Republic, botulism is a rare life-threatening disease. A total of 155 cases have been reported since 1960; according to the ISIN (formerly EPIDAT) database, there have been only three isolated cases since 2013, with the exception of a single occurrence of familial botulism in 2013. In our work, we present the occurrence of botulism after ingestion of pâté of untraceable origin by a couple who were hospitalized for botulotoxin food poisoning in July 2022. Their neurological symptoms were dominated by dysarthria. After administration of antibotulinum serum, their condition improved significantly. Patient samples were analyzed using affinity carriers and MALDI mass spectrometry, a modern highly sensitive technique for detecting the presence of botulinum neurotoxins. Unlike traditional detection by a difficult and costly biological experiment on mice, the above analysis does not require the killing of laboratory animals.

• MeSH
• Botulism * diagnosis   epidemiology   MeSH
• Botulinum Toxins * analysis   MeSH
• Clostridium botulinum * MeSH
• Mice MeSH
• Neurotoxins MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• English Abstract MeSH
• Journal Article MeSH
• Case Reports MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Names of Substances
• Botulinum Toxins * MeSH
• Neurotoxins MeSH

Grass pea (Lathyrus sativus L.) is a rich source of protein cultivated as an insurance crop in Ethiopia, Eritrea, India, Bangladesh, and Nepal. Its resilience to both drought and flooding makes it a promising crop for ensuring food security in a changing climate. The lack of genetic resources and the crop's association with the disease neurolathyrism have limited the cultivation of grass pea. Here, we present an annotated, long read-based assembly of the 6.5 Gbp L. sativus genome. Using this genome sequence, we have elucidated the biosynthetic pathway leading to the formation of the neurotoxin, β-L-oxalyl-2,3-diaminopropionic acid (β-L-ODAP). The final reaction of the pathway depends on an interaction between L. sativus acyl-activating enzyme 3 (LsAAE3) and a BAHD-acyltransferase (LsBOS) that form a metabolon activated by CoA to produce β-L-ODAP. This provides valuable insight into the best approaches for developing varieties which produce substantially less toxin.

• MeSH
• Amino Acids, Diamino * metabolism   MeSH
• Genomics MeSH
• Lathyrus * genetics   metabolism   MeSH
• Neurotoxins metabolism   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amino Acids, Diamino * MeSH
• Neurotoxins MeSH
• oxalyldiaminopropionic acid MeSH Browser

In the rat model, 6-hydroxydopamine (6-OHDA) known as a selective catecholaminergic neurotoxin used chiefly in modeling Parkinson's disease (PD). Continuous aerobic exercise and curcumin supplementations could play a vital role in neuroprotection. This study aimed to explore the neuroprotective roles of regular aerobic exercise and curcumin during PD. For this, rats were treated as follows for 8 consecutive weeks (5 d in a week): For this, animals were orally treated with curcumin (50 ml/kg) alone or in combination with aerobic exercise. Compared with a control group, induction of PD by 6-OHDA increased the amount of alpha-synuclein protein and malondialdehyde levels and decreased the number of substantia nigra neurons, total antioxidant capacity, and glutathione peroxidase activity in brain tissue. All these changes were abolished by the administration of curcumin with aerobic exercise treatments. Activity behavioral tests also confirmed the above-mentioned results by increasing the rod test time and the number of rotations due to apomorphine injection. Histopathology assays mimic the antioxidant activity and behavioral observations. Combined curcumin with aerobic exercise treatments is potentially an effective strategy for modifying the dopaminergic neuron dysfunction in 6-OHDA-induced rats modeling PD via dual inhibiting oxidative stress indices and regulating behavioral tasks.

• MeSH
• alpha-Synuclein metabolism   MeSH
• Antioxidants metabolism   pharmacology   MeSH
• Apomorphine metabolism   pharmacology   MeSH
• Glutathione Peroxidase metabolism   MeSH
• Rats MeSH
• Curcumin * metabolism   pharmacology   MeSH
• Malondialdehyde MeSH
• Disease Models, Animal MeSH
• Neuroprotective Agents * pharmacology   MeSH
• Neurotoxicity Syndromes * MeSH
• Neurotoxins metabolism   pharmacology   MeSH
• Oxidopamine toxicity   MeSH
• Parkinson Disease * drug therapy   metabolism   MeSH
• Substantia Nigra MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• alpha-Synuclein MeSH
• Antioxidants MeSH
• Apomorphine MeSH
• Glutathione Peroxidase MeSH
• Curcumin * MeSH
• Malondialdehyde MeSH
• Neuroprotective Agents * MeSH
• Neurotoxins MeSH
• Oxidopamine MeSH

Vacuolar myelinopathy is a fatal neurological disease that was initially discovered during a mysterious mass mortality of bald eagles in Arkansas in the United States. The cause of this wildlife disease has eluded scientists for decades while its occurrence has continued to spread throughout freshwater reservoirs in the southeastern United States. Recent studies have demonstrated that vacuolar myelinopathy is induced by consumption of the epiphytic cyanobacterial species Aetokthonos hydrillicola growing on aquatic vegetation, primarily the invasive Hydrilla verticillata Here, we describe the identification, biosynthetic gene cluster, and biological activity of aetokthonotoxin, a pentabrominated biindole alkaloid that is produced by the cyanobacterium A. hydrillicola We identify this cyanobacterial neurotoxin as the causal agent of vacuolar myelinopathy and discuss environmental factors-especially bromide availability-that promote toxin production.

• MeSH
• Eagles * MeSH
• Genes, Bacterial MeSH
• Bacterial Toxins biosynthesis   chemistry   isolation & purification   toxicity   MeSH
• Bromine analysis   MeSH
• Bromides metabolism   MeSH
• Caenorhabditis elegans drug effects   MeSH
• Zebrafish MeSH
• Demyelinating Diseases chemically induced   veterinary   MeSH
• Hydrocharitaceae metabolism   microbiology   MeSH
• Indole Alkaloids chemistry   isolation & purification   toxicity   MeSH
• Chickens MeSH
• Lethal Dose 50 MeSH
• Multigene Family MeSH
• Bird Diseases chemically induced   MeSH
• Neurotoxins biosynthesis   chemistry   isolation & purification   toxicity   MeSH
• Cyanobacteria * genetics   growth & development   metabolism   MeSH
• Tryptophan metabolism   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
• Research Support, U.S. Gov't, P.H.S. MeSH
• Geographicals
• Southeastern United States MeSH
• Names of Substances
• Bacterial Toxins MeSH
• Bromine MeSH
• Bromides MeSH
• Indole Alkaloids MeSH
• Neurotoxins MeSH
• Tryptophan MeSH

During the last decade, the neurotoxicity of the trichothecenes T-2 toxin and deoxynivalenol (DON) has been a major concern, and many important findings have been reported on this topic. Through a summary of relevant research reports in recent years, we discuss the potential neurotoxic mechanisms of T-2 toxin and DON. In neuronal cells, T-2 toxin induces mitochondrial dysfunction and oxidative stress through a series of signalling pathways, including Nrf2/HO-1 and p53. This toxin crosses the blood-brain barrier (BBB) by altering permeability and induces oxidative stress responses, including ROS generation, lipid peroxidation, and protein carbonyl formation. Cellular metabolites (for example, HT-2 toxin) further promote neurotoxic effects. The type B trichothecene DON induces neuronal cell apoptosis via the MAPK and mitochondrial apoptosis pathways. This molecule induces inflammation of the central nervous system, increasing the expression of proinflammatory molecules. DON directly affects brain neurons and glial cells after passing through the BBB and affects the vitality and function of astrocytes and microglia. Exposure to trichothecenes alters brain dopamine levels, decreases ganglion area, and further induces brain damage. In this review, we mainly discuss the neurotoxicity of T-2 toxin and DON. However, our main goal was to reveal the potential mechanism(s) and offer new topics, including the potential of hypoxia-inducible factors, immune evasion, and exosomes, for future research in this context. This review should help elucidate the neurotoxic mechanism of trichothecenes and provides some potential inspiration for the follow-up study of neurotoxicity of mycotoxins.

• Keywords
• Blood-brain barrier, Brain damage, Deoxynivalenol, Neurotoxicity, Oxidative stress, T-2 toxin,
• MeSH
• Apoptosis drug effects   MeSH
• Humans MeSH
• Neurons cytology   drug effects   metabolism   MeSH
• Neurotoxins toxicity   MeSH
• Oxidative Stress drug effects   MeSH
• Signal Transduction drug effects   MeSH
• T-2 Toxin toxicity   MeSH
• Trichothecenes toxicity   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• deoxynivalenol MeSH Browser
• Neurotoxins MeSH
• T-2 Toxin MeSH
• Trichothecenes MeSH

Apart from the known efficacy of Botulinum Neurotoxin Type A (BoNT/A) in hyperactive striated and smooth muscles, different pain states have become potential targets of toxin effects. This present study determined the comparative toxin effectiveness in pain reduction among those patients injected with BoNT/A in muscle-based and in non-muscle-based conditions. Randomized controlled trials (RCTs) on the effect of BoNT/A on selected pain conditions were included. The conditions were spasticity and dystonia for muscle-based pain. For non-muscle-based pain, conditions included were painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), trigeminal neuralgia (TN), complex regional pain syndrome (CRPS), and spinal cord injury (SCI). In view of possibly differing pathophysiology, myofascial pain, temporomandibular joint (TMJ), other joint or tendon pains, cervicogenic and lumbar pains, migraine and visceral pain syndromes were excluded. Standardized mean difference was used as the effect measure and computed with STATA. 25 RCTs were analyzed. Pooled estimates showed significantly lower pain score in the Treatment group (z = 5.23, p < 0.01, 95% CI = - 0.75, - 0.34). Subgroup analyses showed that BoNT/A significantly reduced both muscle-based (z = 3.78, p < 0.01, 95% CI = - 0.72, - 0.23) and non-muscle-based (z = 3.37, p = 0.001, 95% CI = - 1.00, - 0.27) pain. Meta-regression using four covariates namely dosage, route, frequency and duration was done which revealed that dosage significantly affects standardized mean differences, while the other three covariates were insignificant. The joint F-test was found to be insignificant (p value = 0.1182). The application of the model with these covariates does not significantly explain the derived heterogeneity of standardized mean differences. In conclusion, BoNT/A can be effectively used in muscle-based and non-muscle-based pain disorders. We detected no difference between the presence and magnitude of pain relief favoring muscle-based compared to non-muscle-based pain. Thus, we cannot say whether or not there might be independent mechanisms of toxin-induced pain relief for pain generated from either muscle or nerve hyperactivity.

• Keywords
• BoNT/A, Botulinum neurotoxin, Muscle-based pain, Non-muscle-based pain, Pain,
• MeSH
• Botulinum Toxins, Type A * therapeutic use   MeSH
• Dystonia * MeSH
• Humans MeSH
• Neuromuscular Agents * therapeutic use   MeSH
• Neuralgia * drug therapy   MeSH
• Neurotoxins MeSH
• Muscles MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Botulinum Toxins, Type A * MeSH
• Neuromuscular Agents * MeSH
• Neurotoxins MeSH

OBJECTIVE: To determine electrical changes in the heart in a chronic, nonstatus model of epilepsy. METHODS: Electrocorticography (ECoG) and electrocardiography (ECG) of nine animals (five made epileptic by intrahippocampal injection of tetanus neurotoxin (TeNT) and four controls), are monitored continuously by radiotelemetry for up to 7 weeks. RESULTS: Epileptic animals develop a median of 168 seizures, with postictal tachycardias reaching a mean of 487 beats/min and lasting a mean of 661 seconds. Ictal changes in heart rate include tachycardia and in the case of convulsive seizures, bradyarrhythmias resembling Mobitz type 1 second-degree atrioventricular block; notably the P-R interval increased before block. Postictally, the amplitude of T wave increases. Interictally, QT dependence on RR is modest and conventional QT corrections prove ineffective. Interictal QT intervals, measured at a heart rate of 400 bpm, increased from 65 to 75 ms, an increase dependent on seizure incidence over the preceding 10-14 days. SIGNIFICANCE: Repeated seizures induce a sustained tachycardia and increase in QT interval of the ECG and evoke arrhythmias including periods of atrioventricular block during Racine type 4 and 5 seizures. These changes in cardiac function may predispose to development in fatal arrhythmias and sudden death in humans with epilepsy.

• Keywords
• QT correction, QT prolongation, cardiac dysfunction, epilepsy,
• MeSH
• Bradycardia etiology   MeSH
• Electrocardiography MeSH
• Electrocorticography MeSH
• Rats MeSH
• Sudden Unexpected Death in Epilepsy etiology   MeSH
• Neurotoxins toxicity   MeSH
• Rats, Wistar MeSH
• Tachycardia etiology   MeSH
• Tetanus Toxin toxicity   MeSH
• Seizures chemically induced   complications   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Neurotoxins MeSH
• Tetanus Toxin MeSH

The neuromuscular junction (NMJ) is the principal site for the translation of motor neurochemical signals to muscle activity. Therefore, the release and sensing machinery of acetylcholine (ACh) along with muscle contraction are two of the main targets of natural toxins and pathogens, causing paralysis. Given pharmacology and medical advances, the active ingredients of toxins that target postsynaptic mechanisms have become of major interest, showing promise as drug leads. Herein, we review key facets of prevalent toxins modulating the mechanisms of ACh sensing and generation of the postsynaptic response, with muscle contraction. We consider the correlation between their outstanding selectivity and potency plus effects on motor function, and discuss emerging data advocating their usage for the development of therapies alleviating neuromuscular dysfunction.

• MeSH
• Humans MeSH
• Models, Neurological MeSH
• Neuromuscular Junction physiology   MeSH
• Synaptic Transmission physiology   MeSH
• Neurotoxins pharmacology   therapeutic use   MeSH
• Post-Synaptic Density drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Neurotoxins MeSH