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Background: Botulinum toxin A (BoNT-A) treatment has many uses in dermatology. Its mechanism of action and long-term effects for scar formation, rosacea, and antiaging are still being investigated., Objective: To conduct a literature review on BoNT-A to further investigate its use in scar formation, rosacea, and antiaging., Methods: A literature review was conducted using PubMed on botulinum toxin treatment for scar formation, rosacea, and antiaging. Studies discussing the toxin mechanism of action and treatment algorithm were included. The authors also provided their personal experience in BoNT-A use for these 3 conditions., Results: The mechanism of action of Botulinum toxin A in improving scar formation, rosacea, and antiaging is now better understood. While it is effective in the short term, little is still known about how frequently treatment needs to be repeated and if there are any long-term effects., Conclusion: While in vitro studies have supporting evidence on the mechanism of action of BoNT-A on scar formation, rosacea, and antiaging, further studies are needed to identify long-term treatment effects., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The author declares no conflict of interest. Yoshihiro Noda is serving as one of the Editorial Board members of this journal. We declare that Yoshihiro Noda had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Gernot Riedel.

Insomnia is the second most prevalent mental illness worldwide. Periostracum cicadae (PC), as an animal traditional Chinese medicine with rich pharmacological effects, has been documented as a treatment for children's night cries, and later extended to treat insomnia. This study aimed to investigate the effects of PC extract and N-acetyldopamine compounds in ameliorating insomnia. The UPLC-ESI-QTOF-MS analysis determined that PC extract mainly contained N-acetyldopamine components. Previously, we also isolated some acetyldopamine polymers from PC extract, among which acetyldopamine dimer A (NADA) was present in high content. Molecular docking and molecular dynamic simulations demonstrated that NADA could form stable complexes with 5-HT1A, BDNF, and D2R proteins, respectively. The effects of PC extract and NADA on insomnia were evaluated in the PCPA-induced insomnia model. The results indicated that PC extract and NADA could effectively ameliorate hypothalamic pathology of insomnia rats, increase the levels of 5-HT, GABA, and BDNF, and decrease the levels of DA, DOPAC, and HVA. Meanwhile, the PC extract and NADA also could significantly affect the expression of 5-HT1A, BDNF, and DARPP-32 proteins. This study proved that PC extract and acetyldopamine dimer A could effectively improve PCPA-induced insomnia in rats. It is speculated that the main pharmacological substances of PC were acetyldopamine components.

Recombinant interleukin-22 (rIL-22) has been reported as a protective agent in murine models of diseases driven by epithelial injury. Parasites have a circadian rhythm and their sensitivity to a certain drug may vary during the day. Therefore, this work aimed to investigate the effect of rIL-22 administration at different times of the day on the inflammation, oxidative status, and neurotransmitter release in the gut-brain axis of the Schistosoma mansoni-infected mice. Sixty male BALB/c mice aged six weeks weighing 25-30 g were divided into a control group (injected intraperitoneally with PBS), mice infected with 80 ± 10 cercariae of S. mansoni (infected group) then injected intraperitoneally with PBS, and rIL-22 treated groups. rIL-22 was administrated intraperitoneally (400 ng/kg) either at the onset or offset of the light phase for 14 days. IL-22 administration reduced the levels of IL-1β, tumor necrosis factor-alpha (TNF-α), nuclear factor kappa beta (NF-κβ), and enhanced the production of IL-22 and IL-17. The treatment with IL-22 increased glutathione (GSH) and reduced malondialdehyde (MDA) and nitric oxide (NO) levels both in the ileum and brain. The B-cell lymphoma 2 (BCL2) protein level in the ileum was diminished after IL-22 administration. Brain-derived neurotrophic factor (BDNF) and neurotransmitter release (serotonin, 5HT, norepinephrine, NE, dopamine, DA, Glutamate, Glu, and -amino butyric acid, GABA) were improved by rIL-22. In conclusion, rIL-22 showed promising immunotherapy for inflammation, oxidative damage, and neuropathological signs associated with schistosomiasis. The efficacy of IL-22 increased significantly upon its administration at the time of light offset., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A postulated role of subcortical neuromodulators is to control brain states. Mechanisms by which different neuromodulators compete or cooperate at various temporal scales remain an open question. We investigated the interaction of acetylcholine (ACh) and oxytocin (OXT) at slow and fast timescales during various brain states. Although these neuromodulators fluctuated in parallel during NREM packets, transitions from NREM to REM were characterized by a surge of ACh but a continued decrease of OXT. OXT signaling lagged behind ACh. High ACh was correlated with population synchrony and gamma oscillations during active waking, whereas minimum ACh predicts sharp-wave ripples (SPW-Rs). Optogenetic control of ACh and OXT neurons confirmed the active role of these neuromodulators in the observed correlations. Synchronous hippocampal activity consistently reduced OXT activity, whereas inactivation of the lateral septum-hypothalamus path attenuated this effect. Our findings demonstrate how cooperative actions of these neuromodulators allow target circuits to perform specific functions., Competing Interests: Declaration of interests G.B. is a member of Neuron’s advisory board., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The present work, using chromaffin cells of bovine adrenal medullae (BCCs), aims to describe what type of ionic current alterations induced by lead (Pb 2+ ) underlies its effects reported on synaptic transmission. We observed that the acute application of Pb 2+ lead to a drastic depression of neurotransmitters release in a concentration-dependent manner when the cells were stimulated with both K + or acetylcholine, with an IC 50 of 119,57 μM and of 5,19 μM, respectively. This effect was fully recovered after washout. Pb 2+ also blocked calcium channels of BCCs in a time- and concentration-dependent manner with an IC 50 of 6,87 μM. This blockade was partially reversed upon washout. This compound inhibited the calcium current at all test potentials and shows a shift of the I-V curve to more negative values of about 8 mV. The sodium current was not blocked by acute application of high Pb 2+ concentrations. Voltage-dependent potassium current was also shortly affected by high Pb 2+ . Nevertheless, the calcium- and voltage-dependent potassium current was drastically depressed in a dose-dependent manner, with an IC 50 of 24,49 μM. This blockade was related to the prevention of Ca 2+ influx through voltage-dependent calcium channels coupled to Ca 2+ -activated K + -channels (BK) instead a direct linking to these channels. Under current-clamp conditions, BCCs exhibit a resting potential of -52.7 mV, firing spontaneous APs (1-2 spikes/s) generated by the opening of Na + and Ca 2+ -channels, and terminated by the activation of K + channels. In spite of the effect on ionic channels exerted by Pb 2+ , we found that Pb 2+ didn't alter cellular excitability, no modification of the membrane potential, and no effect on action potential firing. Taken together, these results point to a neurotoxic action evoked by Pb 2+ that is associated with changes in neurotransmitter release by blocking the ionic currents responsible for the calcium influx., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jesús Miguel Hernández Guijo reports financial support was provided by Ministerio de Ciencia, Innovación y Universidades. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier B.V.)

Agmatine, a naturally occurring polyamine derived from arginine via arginine decarboxylase, has been shown to play multifaceted roles in the mammalian body, impacting a wide range of physiological and pathological processes. This comprehensive review delineates the significant insights into agmatine's pharmacological profile, emphasizing its structure and metabolism, neurotransmission and regulation, and pharmacokinetics and function. Agmatine's biosynthesis is highly conserved across species, highlighting its fundamental role in cellular functions. In the brain, comparable to established neurotransmitters, agmatine acts as a neuromodulator, influencing the regulation, metabolism, and reabsorption of neurotransmitters that are key to mood disorders, learning, cognition, and the management of anxiety and depression. Beyond its neuromodulatory functions, agmatine exhibits protective effects across various cellular and systemic contexts, including neuroprotection, nephroprotection, cardioprotection, and cytoprotection, suggesting a broad therapeutic potential. The review explores agmatine's interaction with multiple receptor systems, including NMDA, α2-adrenoceptors, and imidazoline receptors, elucidating its role in enhancing cell viability, neuronal protection, and synaptic plasticity. Such interactions underpin agmatine's potential in treating neurological diseases and mood disorders, among other conditions. Furthermore, agmatine's pharmacokinetics, including its absorption, distribution, metabolism, and excretion, are discussed, underlining the complexity of its action and the potential for therapeutic application. The safety and efficacy of agmatine supplementation, demonstrated through various animal and human studies, affirm its potential as a beneficial therapeutic agent. Conclusively, the diverse physiological and therapeutic effects of agmatine, spanning neurotransmission, protection against cellular damage, and modulation of various receptor pathways, position it as a promising candidate for further research and clinical application. This review underscores the imperative for continued exploration into agmatine's mechanisms of action and its potential in pharmacology and medicine, promising advances in the treatment of numerous conditions., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Parkinson's disease (PD) is an extrapyramidal movement disorder associated with a hypokinetic condition generated by impairment in dopaminergic neuronal viability in the nigrostriatal region of the brain. Current medications can only provide symptomatic management; to date, no permanent cure is available. To compensate for this lacuna, researchers are gaining interest in antigen-based therapy, and Bacille-Calmette-Guerin (BCG) is one of the vaccines with a high safety margin that acts by stimulating immunoreactive T-cells in the CNS and reducing expression of pro-inflammatory cytokines including interleukin (IL)-1β and tumor necrotic factor (TNF-α) to produce neuroprotection. A previous study reported that BCG exerts a neuroprotective effect against several neurodegenerative disorders, such as Alzheimer's disease., Objective: The objective of this study is to explore the neuroprotective effect of the BCG vaccine against the rotenone model of PD., Methods: Rotenone (1.5 mg/kg, s.c) for 28 days, and BCG vaccine (2 × 10 7 cfu, i.p) single dose was injected to rats, and behavioral assessments were performed on the 21st and 28th day. On the 29th day, rats were sacrificed, and brains were isolated for biochemical and neurochemical estimation., Results: BCG vaccine significantly restored rotenone-induced motor deficits (open field test, narrow beam walk, and rotarod), biochemical levels (GSH, SOD, catalase, MDA, and nitrite), neurotransmitters (dopamine, 5-hydroxy tryptamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, hemovanillic acid, and 5-hydroxy indoleacetic acid), and levels of inflammatory cytokines (IL-1β and TNF-α) in the striatum. It also prevents histopathological changes by reducing eosinophilic lesions in the striatum., Conclusion: From the results, we conclude that BCG vaccine showed neuroprotection through antioxidant and anti-inflammatory effect. Thus, in the future, it can be used as a neuroprotective agent for other neurological disorders, including PD., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Background:  Menopause is a physiological event that marks the end of a woman's reproductive stage in life. Vasomotor symptoms and changes in mood are among its most important effects. Homeopathy has been used for many years in treating menopausal complaints, though clinical and pre-clinical research in this field is limited. Homeopathy often bases its prescription on neuropsychiatric symptoms, but it is unknown if homeopathic medicines (HMs) exert a neuroendocrine effect that causes an improvement in vasomotor symptoms and mood during menopause., Objectives:  The study's objectives were to address the pathophysiological changes of menopause that could help in the understanding of the possible effect of HMs at a neuroendocrine level, to review the current evidence for two of the most frequently prescribed HMs for menopause ( Lachesis mutus and Sepia officinalis ), and to discuss the future directions of research in this field., Methods:  An extensive literature search for the pathophysiologic events of menopause and depression, as well as for the current evidence for HMs in menopause and depression, was performed., Results:  Neuroendocrine changes are involved in the pathophysiology of vasomotor symptoms and changes in mood during menopause. Gonadal hormones modulate neurotransmitter systems. Both play a role in mood disorders and temperature regulation. It has been demonstrated that Gelsemium sempervirens , Ignatia amara and Chamomilla matricaria exert anxiolytic effects in rodent models. Lachesis mutus and Sepia officinalis are frequently prescribed for important neuropsychiatric and vasomotor symptoms. Dopamine, a neurotransmitter involved in mood, is among the constituents of the ink of the common cuttlefish, Sepia officinalis ., Conclusion:  Based on all the pathophysiologic events of menopause and the improvement in menopausal complaints that certain HMs show in daily practice, these medicines might have a direct or indirect neuroendocrine effect in the body, possibly triggered via an as-yet unidentified biological mechanism. Many unanswered questions in this field require further pre-clinical and clinical research., Competing Interests: None declared., (Faculty of Homeopathy. This article is published by Thieme.)

The cannabinoid system is one of the most investigated neuromodulatory systems because of its involvement in multiple pathologies such as cancer, inflammation, and psychiatric diseases. Recently, the CB2 receptor has gained increased attention considering its crucial role in modulating neuroinflammation in several pathological conditions like neurodegenerative diseases. Here we describe the rational design of pyrrole-based analogues, which led to a potent and pharmacokinetically suitable CB2 full agonist particularly effective in improving cognitive functions in a scopolamine-induced amnesia murine model. Therefore, we extended our study by investigating the interconnection between CB2 activation and neurotransmission in this experimental paradigm. To this purpose, we performed a MALDI imaging analysis on mice brains, observing that the administration of our lead compound was able to revert the effect of scopolamine on different neurotransmitter tones, such as acetylcholine, serotonin, and GABA, shedding light on important networks not fully explored, so far., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Basal electroretinogram (ERG) oscillations have shown predictive value for modifiable risk factors for type 2 diabetes. However, their origin remains unknown. Here, we seek to establish the pharmacological profile of the low delta-like (δ1) wave in the mouse because it shows light sensitivity in the form of a decreased peak frequency upon photopic exposure. Applying neuropharmacological drugs by intravitreal injection, we eliminated the δ1 wave using lidocaine or by blocking all chemical and electrical synapses. The δ1 wave was insensitive to the blockade of photoreceptor input, but was accelerated when all inhibitory or ionotropic inhibitory receptors in the retina were antagonized. The sole blockade of GABA A , GABA B , GABA C , and glycine receptors also accelerated the δ1 wave. In contrast, the gap junction blockade slowed the δ1 wave. Both GABA A receptors and gap junctions contribute to the light sensitivity of the δ1 wave. We further found that the day light-activated neuromodulators dopamine and nitric oxide donors mimicked the effect of photopic exposure on the δ1 wave. All drug effects were validated through light flash-evoked ERG responses. Our data indicate that the low δ-like intrinsic wave detected by the non-photic ERG arises from an inner retinal circuit regulated by inhibitory neurotransmission and nitric oxide/dopamine-sensitive gap junction-mediated communication., Competing Interests: Declaration of Competing interest All authors declare having no financial/personal interest or belief that could affect their objectivity in this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cholecystokinin (CCK) is a neuropeptide modulating digestion, glucose levels, neurotransmitters and memory. Recent studies suggest that CCK exhibits neuroprotective effects in Alzheimer's disease (AD) and Parkinson's disease (PD). Thus, we review the physiological function and therapeutic potential of CCK. The neuropeptide facilitates hippocampal glutamate release and gates GABAergic basket cell activity, which improves declarative memory acquisition, but inhibits consolidation. Cortical CCK alters recognition memory and enhances audio-visual processing. By stimulating CCK-1 receptors (CCK-1Rs), sulphated CCK-8 elicits dopamine release in the substantia nigra and striatum. In the mesolimbic pathway, CCK release is triggered by dopamine and terminates reward responses via CCK-2Rs. Importantly, activation of hippocampal and nigral CCK-2Rs is neuroprotective by evoking AMPK activation, expression of mitochondrial fusion modulators and autophagy. Other benefits include vagus nerve/CCK-1R-mediated expression of brain-derived neurotrophic factor, intestinal protection and suppression of inflammation. We also discuss caveats and the therapeutic combination of CCK with other peptide hormones., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

L-Glutamate (L-Glu) is an amino acid present in the diet that plays a fundamental role in the central nervous system, as the main excitatory neurotransmitter participating in learning and memory processes. In addition, the nucleoside adenosine has a crucial role in L-Glu metabolism, by regulating the liberation of this neurotransmitter through four different receptors: A 1 , A 2A , A 2B and A 3 , which activate (A 2A and A 2B ) or inhibit (A 1 and A 3 ) adenylate cyclase pathway. L-Glu at high concentrations can act as a neurotoxin and induce oxidative stress. The study of the oxidative stress correlated with an excess of L-Glu consumption during maternity is key to understand its effects on foetuses and neonates. Previous studies have shown that there is a change in the receptor levels in the brain of pregnant rats and their foetuses when mothers are administered L-Glu during gestation; however, its effect on the cerebellum is unknown. Cerebellum is known to be responsible for motor, cognitive and emotional functions, so its possible involvement after L-Glu consumption is an important issue to study. Therefore, the aim of the present work was to study the effect of L-Glu exposure during gestation and lactation on oxidative stress biomarkers and neurotransmitter receptors from the cerebellum of foetuses and neonates. After maternal L-Glu intake during gestation, oxidative stress was increased, as the ionotropic L-Glu receptors, and GluR1 AMPA subunit levels were altered in foetuses. A 1 adenosine receptor suffered changes after L-Glu treatment during gestation, lactation or both, in lactating neonate cerebellum, while adenylate cyclase activity remain unaltered. Further studies will be necessary to elucidate the importance of L-Glu intake and its possible excitotoxicity in the cerebellum of Wistar rats during the pregnancy period and their involvement in long-term neurodegeneration., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Autonomic dysreflexia (AD) is a potentially life-threatening consequence in high (above T6) spinal cord injury that involves multiple incompletely understood mechanisms. While peripheral arteriolar vasoconstriction, which controls systemic vascular resistance, is documented to be pronounced during AD, the pathophysiological neurovascular junction mechanisms of this vasoconstriction are undefined. One hypothesized mechanism is increased neuronal release of norepinephrine and co-transmitters. We tested this by examining the effects of blockade of pre-synaptic neural release of norepinephrine and co-transmitters on cutaneous vasoconstriction during AD, using a novel non-invasive technique; bretylium (BT) iontophoresis followed by skin blood flow measurements via laser doppler flowmetry (LDF)., Methods: Bretylium, a sympathetic neuronal blocking agent (blocks release of norepinephrine and co-transmitters) was applied iontophoretically to the skin of a sensate (arm) and insensate (leg) area in 8 males with motor complete tetraplegia. An nearby untreated site served as control (CON). Cutaneous vascular conductance (CVC) was measured (CVC = LDF/mean arterial pressure) at normotension before AD was elicited by bladder stimulation. The percent drop in CVC values from pre-AD vs. AD was compared among BT and CON sites in sensate and insensate areas., Results: There was a significant effect of treatment but no significant effect of limb/sensation or interaction of limb x treatment on CVC. The percent drop in CVC between BT and CON treated sites was 25.7±1.75 vs. 39.4±0.87, respectively (P = 0.004)., Conclusion: Bretylium attenuates, but does not fully abolish vasoconstriction during AD. This suggests release of norepinephrine and cotransmitters from cutaneous sympathetic nerves is involved in cutaneous vasoconstriction during AD., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Published by Elsevier B.V.)

Background: Multiple sclerosis (MS) is a debilitating inflammatory disease characterized by demyelination, varied remyelination conservation, and partial axonal retention in central nervous system (CNS) lesions. The p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of MS. Embelin (EMB), derived from the Embelia ribes plant, possesses diverse biological activities, including anti-inflammatory properties., Objective: This study aimed to investigate the neuroprotective effects of EMB in an ethidium bromide (EB)-induced model of MS in Wistar rats., Methods: Wistar rats were randomly divided into five groups (n = 8). MS-like manifestations were induced by injecting EB (0.1 %/10 µl) into the intracerebropeduncle (ICP) region of the rat brain for seven consecutive days. EMB was administered at doses of 1.25, 2.5, and 5 mg/kg. Behavioral assessments, neuroinflammatory cytokine analysis like tumor necrosis factor-α, interleukin-1-β, interleukin-6 (TNF-α, IL-1β, IL-6), oxidative stress marker measurements malondialdehyde, reduced glutathione, superoxide dismutase (MDA, GSH, SOD), and nitrite (NO), Acetylcholinesterase enzyme (AchE), and neurotransmitter level analysis, dopamine, serotonin, and norepinephrine (DA, 5-HT, and NE) were conducted., Results: The study assessed behavioral, neurochemical, biochemical, and neuroinflammatory parameters, along with the modulation of p38 MAPK signaling. EMB administration significantly ameliorated neurological consequences induced by EB, improving motor coordination and gait abnormalities in rats. Furthermore, EMB effectively reduced neuroinflammatory cytokines (TNF-α, IL-1β, IL-6) and oxidative stress markers (AchE, SOD, MDA, GSH, nitrite). Notably, EMB exhibited a modulatory effect on neurotransmitter levels, increasing GABA, DA, and 5-HT, while reducing glutamate in EB-treated groups., Conclusion: This study demonstrates the neuroprotective potential of EMB against the EB-induced model of MS in rats. EMB administration mitigated neurological impairments, attenuated neuroinflammation, alleviated oxidative stress, and restored neurotransmitter balance. These findings highlight the promise of EMB as a therapeutic candidate for MS treatment, providing insights into its potential mechanism of action involving the modulation of p38 MAPK signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Adderall is a central nervous system stimulant while luteolin has neuroprotective activity. This study aimed to determine whether luteolin can amend neural neurotransmitters, antioxidants, and inflammatory markers in the cerebral cortex of Adderall exposed rats., Methods: Thirty-six male albino rats were divided into 6 equal groups, Control, Luteolin (1 g/kg)-treated, and Luteolin (2 g/kg)-treated groups: normal rats were orally administrated once a day with 2 ml distilled water, luteolin (1 g/kg), and luteolin (2 g/kg), respectively for 4 weeks. Adderall rats, Adderall rats + luteolin (1 g/kg)-treated, and Adderall rats + luteolin (2 g/kg)-treated groups: normal rats were orally administrated once a day with 10 mg/kg of Adderall, 3 days/week for 4 weeks, then these rats orally administrated daily once a day with 2 ml of distilled water, luteolin (1 g/kg), and luteolin (2 g/kg), respectively for another 4 weeks., Results and Conclusion: Adderall decreased superoxide dismutase, glutathione peroxidase, catalase, NADPH oxidase, interleukin-10, serotonin, dopamine, norepinephrine, γ-aminobutyric acid, and acetylcoline estrase but increased malondialdehyde, conjugated dienes, oxidative index, tumour necrosis factor-α, interleukin-1β, and interleukin-6 levels in the cerebral cortex. Adderall increased the expression of glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, and anti-calbindin in the cerebral cortex of Adderall-treated rats. In Adderall-treated rats, daily oral administration of luteolin for 4 weeks brought all these parameters back to values that were close to control where higher dose was more effective than lower dose. The importance of this research is to provide natural compound that amends Adderall-related neural disturbances and this natural compound is cheap, avaliable without any side effect and it does not interfer with Adderall efficiency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study was conducted to evaluate how sterubin affects rotenone-induced Parkinson's disease (PD) in rats. A total of 24 rats were distributed into 4 equal groups: normal saline control and rotenone control were administered saline or rotenone (ROT), respectively, orally; sterubin 10 received ROT + sterubin 10 mg/kg po; and sterubin alone was administered to the test group (10 mg/kg). Rats of the normal saline and sterubin alone groups received sunflower oil injection (sc) daily, 1 h after receiving the treatments cited above, while rats of the other groups received rotenone injection (0.5 mg/kg, sc). The treatment was continued over the course of 28 days daily. On the 29th day, catalepsy and akinesia were assessed. The rats were then euthanized, and the brain was extracted for estimation of endogenous antioxidants (MDA: malondialdehyde, GSH: reduced glutathione, CAT: catalase, SOD: superoxide dismutase), nitrative (nitrite) stress markers, neuroinflammatory cytokines, and neurotransmitter levels and their metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), norepinephrine (NE), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA)). Akinesia and catatonia caused by ROT reduced the levels of endogenous antioxidants (GSH, CAT, and SOD), elevated the MDA level, and altered the levels of nitrites, neurotransmitters, and their metabolites. Sterubin restored the neurobehavioral deficits, oxidative stress, and metabolites of altered neurotransmitters caused by ROT. Results demonstrated the anti-Parkinson's activities of sterubin in ROT-treated rats.

The Drosophila neuropeptide, DPKQDFMRFamide, was previously shown to enhance excitatory junctional potentials (EJPs) and muscle contraction by both presynaptic and postsynaptic actions. Since the peptide acts on both sides of the synaptic cleft, it has been difficult to examine postsynaptic modulatory mechanisms, particularly when contractions are elicited by nerve stimulation. Here, postsynaptic actions are examined in 3rd instar larvae by applying peptide and the excitatory neurotransmitter, l-glutamate, in the bathing solution to elicit contractions after silencing motor output by removing the central nervous system (CNS). DPKQDFMRFamide enhanced glutamate-evoked contractions at low concentrations (EC 50 1.3 nM), consistent with its role as a neurohormone, and the combined effect of both substances was supra-additive. Glutamate-evoked contractions were also enhanced when transmitter release was blocked in temperature-sensitive (Shibire) mutants, confirming the peptide's postsynaptic action. The peptide increased membrane depolarization in muscle when co-applied with glutamate, and its effects were blocked by nifedipine, an L-type channel blocker, indicating effects at the plasma membrane involving calcium influx. DPKQDFMRFamide also enhanced contractions induced by caffeine in the absence of extracellular calcium, suggesting increased calcium release from the sarcoplasmic reticulum (SR) or effects downstream of calcium release from the SR. The peptide's effects do not appear to involve calcium/calmodulin-dependent protein kinase II (CaMKII), previously shown to mediate presynaptic effects. The approach used here might be useful for examining postsynaptic effects of neurohormones and cotransmitters in other systems. NEW & NOTEWORTHY Distinguishing presynaptic and postsynaptic effects of neurohormones is a long-standing challenge in many model organisms. Here, postsynaptic actions of DPKQDFMRFamide are demonstrated by assessing its ability to potentiate contractions elicited by direct application of the neurotransmitter, glutamate, when axons are silent and when transmitter release is blocked. The peptide acts at multiple sites to increase contraction, increasing glutamate-induced depolarization at the cell membrane, acting on L-type channels, and acting downstream of calcium release from the sarcoplasmic reticulum.

Non-specifically binding of aluminum to various substances in the organism can result in toxicity. The accumulation of large amounts of aluminum can cause an imbalance in metal homeostasis and interfere with the synthesis and release of neurotransmitters. Flavonoids have strong metal chelating activity, which can reduce damage to the central nervous system. The purpose of this study was to investigate the protective effect of three representative flavonoids, rutin, puerarin and silymarin, on the brain toxicity induced by long-term exposure to aluminum trichloride (AlCl 3 ). Sixty-four Wistar rats were randomly divided into eight groups (n = 8). The rats in six intervention groups were given 100 or 200 mg/kg BW/day of three different flavonoids for four weeks after a 4-week exposure to 281.40 mg/kg BW/day AlCl 3 ·6H 2 O, while the rats in the AlCl 3 -toxicity and control groups were given the vehicle after the period of AlCl 3 exposure. The results showed that rutin, puerarin, and silymarin could increase the concentrations of magnesium, iron, and zinc in the brains of the rats. Moreover, the intake of these three flavonoids regulated the homeostasis of amino acid neurotransmitters and adjusted the concentrations of monoamine neurotransmitters to normal levels. Taken together, our data suggest that rutin, puerarin, and silymarin could ameliorate AlCl 3 -induced brain toxicity in the rats by regulating imbalance of metal elements and neurotransmitters in the brains of rats., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

α2-Adrenoreceptors (ARs) are main G i -protein coupled autoreceptors in sympathetic nerve terminals and targets for dexmedetomidine (DEX), a widely used sedative. We hypothesize that α2-ARs are also potent regulators of neuromuscular transmission via G protein-gated inwardly rectifying potassium (GIRK) channels. Using extracellular microelectrode recording of postsynaptic potentials, we found DEX-induced inhibition of spontaneous and evoked neurotransmitter release as well as desynchronization of evoked exocytotic events in the mouse diaphragm neuromuscular junction. These effects were suppressed by SKF-86,466, a selective α2-AR antagonist. An activator of GIRK channels ML297 had the same effects on neurotransmitter release as DEX. By contrast, inhibition of GIRK channels with tertiapin-Q prevented the action of DEX on evoked neurotransmitter release, but not on spontaneous exocytosis. The synaptic vesicle exocytosis is strongly dependent on Ca 2+ influx through voltage-gated Ca 2+ channels (VGCCs), which can be negatively regulated via α2-AR - GIRK channel axis. Indeed, inhibition of P/Q-, L-, N- or R-type VGCCs prevented the inhibitory action of DEX on evoked neurotransmitter release; antagonists of P/Q- and N-type channels also suppressed the DEX-mediated desynchronization of evoked exocytotic events. Furthermore, inhibition of P/Q-, L- or N-type VGCCs precluded the frequency decrease of spontaneous exocytosis upon DEX application. Thus, α2-ARs acting via GIRK channels and VGCCs (mainly, P/Q- and N-types) exert inhibitory effect on the neuromuscular communication by attenuating and desynchronizing evoked exocytosis. In addition, α2-ARs can suppress spontaneous exocytosis through GIRK channel-independent, but VGCC-dependent pathway., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite affecting over 1.5 billion people globally, hearing loss (HL) has been referred to as an "invisible disability", with noise exposure being a major causative factor. Accumulating evidence suggests that HL can induce cognitive impairment. However, relatively little is known about the effects of noise-induced hearing loss (NIHL) on social memory. This study aimed to further investigate the effect of NIHL on social behaviours in mice. We established a rodent model of NIHL using 4-week-old C57BL/6J mice who experienced narrow noise exposure at 116 dB for 3 h per day over two consecutive days. Hearing ability was subsequently evaluated through auditory brainstem response (ABR) testing, and potential changes in the morphology of cochlear hair cells were assessed using immunofluorescence. The sociability and social memory of the mice were evaluated using the three-chamber social interaction test. Noise exposure resulted in complete and persistent HL in C57BL/6J mice, accompanied by severe loss of cochlear hair cells. More importantly, social memory was impaired in adult NIHL mice, whereas their sociability remained intact, these changes were accompanied by a decrease in the protein levels of the inhibitory neuron marker glutamic acid decarboxylase 67 (GAD67) in the ventral hippocampus. This study is the first to confirm that long-term auditory deprivation from HL induced by noise exposure results in social memory deficits in mice without altering their sociability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Neuromodulation lends flexibility to neural circuit operation but the general notion that different neuromodulators sculpt neural circuit activity into distinct and characteristic patterns is complicated by interindividual variability. In addition, some neuromodulators converge onto the same signaling pathways, with similar effects on neurons and synapses. We compared the effects of three neuropeptides on the rhythmic pyloric circuit in the stomatogastric ganglion of male crabs, Cancer borealis Proctolin (PROC), crustacean cardioactive peptide (CCAP), and red pigment concentrating hormone (RPCH) activate the same modulatory inward current, I MI , and have convergent actions on synapses. However, while PROC targets all four neuron types in the core pyloric circuit, CCAP and RPCH target the same subset of only two neurons. After removal of spontaneous neuromodulator release, none of the neuropeptides restored the control cycle frequency, but all restored the relative timing between neuron types. Consequently, differences between neuropeptide effects were mainly found in the spiking activity of different neuron types. We performed statistical comparisons using the Euclidean distance in the multidimensional space of normalized output attributes to obtain a single measure of difference between modulatory states. Across preparations, the circuit output in PROC was distinguishable from CCAP and RPCH, but CCAP and RPCH were not distinguishable from each other. However, we argue that even between PROC and the other two neuropeptides, population data overlapped enough to prevent reliable identification of individual output patterns as characteristic for a specific neuropeptide. We confirmed this notion by showing that blind classifications by machine learning algorithms were only moderately successful. Significance Statement It is commonly assumed that distinct behaviors or circuit activities can be elicited by different neuromodulators. Yet it is unknown to what extent these characteristic actions remain distinct across individuals. We use a well-studied circuit model of neuromodulation to examine the effects of three neuropeptides, each known to produce a distinct activity pattern in controlled studies. We find that, when compared across individuals, the three peptides elicit activity patterns that are either statistically indistinguishable or show too much overlap to be labeled characteristic. We ascribe this to interindividual variability and overlapping subcellular actions of the modulators. Because both factors are common in all neural circuits, these findings have broad significance for understanding chemical neuromodulatory actions while considering interindividual variability., (Copyright © 2023 the authors.)

Animal models indicate that motor behaviour is shaped by monoamine neuromodulators released diffusely throughout the brain and spinal cord. As an alternative to conducting a single study to explore the effects of neuromodulators on the human motor system, we have identified and collated human experiments investigating motor effects of well-characterised drugs that act on serotonergic and noradrenergic networks. In doing so, we present strong neuropharmacology evidence that human motor pathways are affected by neuromodulators across both healthy and clinical populations, insight that cannot be determined from a single reductionist experiment. We have focused our review on the effects that monoaminergic drugs have on muscle responses to non-invasive stimulation of the motor cortex and peripheral nerves, and other closely related tests of motoneuron excitability, and discuss how these measurement techniques elucidate the effects of neuromodulators at motor cortical and spinal motoneuronal levels. Although there is some heterogeneity in study methods, we find drugs acting to enhance extracellular concentrations of serotonin tend to reduce the excitability of the human motor cortex, and enhanced extracellular concentrations of noradrenaline increases motor cortical excitability by enhancing intracortical facilitation and reducing inhibition. Both monoamines tend to enhance the excitability of spinal motoneurons. Overall, this review details the importance of neuromodulators for the output of human motor pathways and suggests that commonly prescribed monoaminergic drugs target the motor system in addition to their typical psychiatric/neurological indications., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Hypothesis: Schizophrenia (SCZ) is associated with complex crosstalk between the gut microbiota and host metabolism, but the underlying mechanism remains elusive. Investigating the aberrant neurotransmitter processes reflected by alterations identified using multiomics analysis is valuable to fully explain the pathogenesis of SCZ., Study Design: We conducted an integrative analysis of multiomics data, including the serum metabolome, fecal metagenome, single nucleotide polymorphism data, and neuroimaging data obtained from a cohort of 127 drug-naïve, first-episode SCZ patients and 92 healthy controls to characterize the microbiome-gut-brain axis in SCZ patients. We used pathway-based polygenic risk score (PRS) analyses to determine the biological pathways contributing to genetic risk and mediation effect analyses to determine the important neuroimaging features. Additionally, a random forest model was generated for effective SCZ diagnosis., Study Results: We found that the altered metabolome and dysregulated microbiome were associated with neuroactive metabolites, including gamma-aminobutyric acid (GABA), tryptophan, and short-chain fatty acids. Further structural and functional magnetic resonance imaging analyses highlighted that gray matter volume and functional connectivity disturbances mediate the relationships between Ruminococcus_torgues and Collinsella_aerofaciens and symptom severity and the relationships between species Lactobacillus_ruminis and differential metabolites l-2,4-diaminobutyric acid and N-acetylserotonin and cognitive function. Moreover, analyses of the Polygenic Risk Score (PRS) support that alterations in GABA and tryptophan neurotransmitter pathways are associated with SCZ risk, and GABA might be a more dominant contributor., Conclusions: This study provides new insights into systematic relationships among genes, metabolism, and the gut microbiota that affect brain functional connectivity, thereby affecting SCZ pathogenesis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The copper hydroxide [Cu(OH) 2 ] nanopesticide is an emerging agricultural chemical that can negatively impact aquatic organisms. This study evaluated the behavioral changes of zebrafish larvae exposed to the Cu(OH) 2 nanopesticide and assessed its potential to induce neurotoxicity. Metabolomic and transcriptomic profiling was also conducted to uncover the molecular mechanisms related to potential neurotoxicity. The Cu(OH) 2 nanopesticide at 100 μg/L induced zebrafish hypoactivity, dark avoidance, and response to the light stimulus, suggestive of neurotoxic effects. Altered neurotransmitter-related pathways (serotoninergic, dopaminergic, glutamatergic, GABAergic) and reduction of serotonin (5-HT), dopamine (DA), glutamate (GLU), γ-aminobutyric acid (GABA), and several of their precursors and metabolites were noted following metabolomic and transcriptomic analyses. Differentially expressed genes (DEGs) were associated with the synthesis, transport, receptor binding, and metabolism of 5-HT, DA, GLU, and GABA. Transcripts (or protein levels) related to neurotransmitter receptors for 5-HT, DA, GLU, and GABA and enzymes for the synthesis of GLU and GABA were downregulated. Effects on both the glutamatergic and GABAergic pathways in zebrafish were specific to the nanopesticide and differed from those in fish exposed to copper ions. Taken together, the Cu(OH) 2 nanopesticide induced developmental neurotoxicity in zebrafish by inhibiting several neurotransmitter-related pathways. This study presented a model for Cu(OH) 2 nanopesticide-induced neurotoxicity in developing zebrafish that can inform ecological risk assessments.

Objective: To investigate the effect of sleep deprivation on the metabolism of the hippocampal region in mice., Methods: The mice were randomly assigned to three groups, a control group, a 24-h sleep deprivation (SD) group, and a 48-h SD group. Each group had 10 mice. The sleep deprivation model was induced by the modified multiple platform method. The mice's anxiety-like behaviors were assessed with the open field test (OFT) and their depression-like behaviors were assessed with the sucrose preference test (SPT), the forced swimming test (FST), and tail suspension test (TST). High performance liquid chromatography (HPLC) was performed to determine the levels of 6 monoamine neurotransmitters, including 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), gamma-aminobutyric acid (GABA), 5-dihydroxyphenylacetic acid (5-DOPAC), and homovanillic acid (HVA), and 4 amino acids, including glutamic acid (Glu), aspartic acid (Asp), serine (Ser), and taurine (Tau), in the hippocampal region. Immunofluorescence staining was performed to examine the expression of glial cells in the hippocampal region of the mice. The main indicators measured were the levels of monoamine neurotransmitters and amino acids., Results: According to the results of the behavioral analysis, in comparison with the findings for the control group, the 24-h SD mice exhibited increased consumption of sucrose in SFT, significantly decreased total immobility time in FST and TST, and increased total distance covered in OFT, while the 48-h SD mice showed decreased consumption of sucrose in SFT, prolonged total immobility time in FST and TST, and decreased total distance covered in OFT. The results of the HPLC analysis of the monoamine neurotransmitter showed that 24-h SD mice had in their hippocampal region increased levels of DA ( P <0.001) and NE ( P <0.01) and decreased levels of GABA ( P <0.05) in comparison with those of the control mice, while their 5-HT, 5-DOPAC, and HVA levels were not significantly different from those of the control mice. In comparison with those of the control mice, the 48-h SD mice had, in their hippocampal region, decreased levels of 5-HT and NE (all P <0.05), decreased DA ( P <0.01), and increased level of GABA ( P <0.01), while the levels of 5-DOPAC and HAV were not significantly different. The 48-h SD group showed a significant decrease in the levels of Tau and Glu in comparison with those of the 24-h SD group (all P <0.05). According to the results of immunofluorescence assay, there was no significant difference between the control group and the 24-h SD group in the cell count of glial fibrillary acidic protein (GFAP)-positive cells, while a decline in GFAP-positive cells in comparison with that of the control group was observed in the 48-h SD group., Conclusion: SD of 24 hours may induce anxiety-like behavioral changes in mice by activating their hippocampal glial cells, upregulating the levels of 5-HT, DA, and NE, and increasing the levels of Glu and Tau in the hippocampal region. SD of 48 hours may induce depression-like behavioral changes in mice by inhibiting the activation of glial cells in the hippocampal region and regulating in the opposite direction the levels of the above-mentioned monoamine neurotransmitters and amino acids in the hippocampal region., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2023《四川大学学报（医学版）》编辑部 版权所有Copyright ©2023 Editorial Board of Journal of Sichuan University (Medical Sciences).)

At the vertebrate neuromuscular junction (NMJ), presynaptic homeostatic potentiation (PHP) refers to an increase in neurotransmitter release that restores the strength of synaptic transmission following a blockade of nicotinic acetylcholine receptors (nAChRs). Mechanisms informing the presynaptic terminal of the loss of postsynaptic receptivity remain poorly understood. Previous research at the mouse NMJ suggests that extracellular protons may function as a retrograde signal that triggers an upregulation of neurotransmitter output (measured by quantal content, QC) through the activation of acid-sensing ion channels (ASICs). We further investigated the pH-dependency of PHP in an ex-vivo mouse muscle preparation. We observed that increasing the buffering capacity of the perfusion saline with HEPES abolishes PHP and that acidifying the saline from pH 7.4 to pH 7.2-7.1 increases QC, demonstrating the necessity and sufficiency of extracellular acidification for PHP. We then sought to uncover how the blockade of nAChRs leads to the pH decrease. Plasma-membrane calcium ATPase (PMCA), a calcium-proton antiporter, is known to alkalize the synaptic cleft following neurotransmission in a calcium-dependent manner. We hypothesize that since nAChR blockade reduces postsynaptic calcium entry, it also reduces the alkalizing activity of the PMCA, thereby causing acidosis, ASIC activation, and QC upregulation. In line with this hypothesis, we found that pharmacological inhibition of the PMCA with carboxyeosin induces QC upregulation and that this effect requires functional ASICs. We also demonstrated that muscles pre-treated with carboxyeosin fail to generate PHP. These findings suggest that reduced PMCA activity causes presynaptic homeostatic potentiation by activating ASICs at the mouse NMJ., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Membrane cholesterol oxidation is a hallmark of redox and metabolic imbalance, and it may accompany neurodegenerative disorders. Using microelectrode recordings of postsynaptic responses as well as fluorescent dyes for monitoring synaptic vesicle cycling and membrane properties, the action of enzymatic cholesterol oxidation on neuromuscular transmission was studied in the mice diaphragms. Cholesterol oxidase (ChO) at low concentration disturbed lipid-ordering specifically in the synaptic membranes, but it did not change markedly spontaneous exocytosis and evoked release in response to single stimuli. At low external Ca 2+ conditions, analysis of single exocytotic events revealed a decrease in minimal synaptic delay and the probability of exocytosis upon plasmalemmal cholesterol oxidation. At moderate- and high-frequency activity, ChO treatment enhanced both neurotransmitter and FM-dye release. Furthermore, it precluded a change in exocytotic mode from full-fusion to kiss-and-run during high-frequency stimulation. Accumulation of extracellular acetylcholine (without stimulation) dependent on vesamicol-sensitive transporters was suppressed by ChO. The effects of plasmalemmal cholesterol oxidation on both neurotransmitter/dye release at intense activity and external acetylcholine levels were reversed when synaptic vesicle membranes were also exposed to ChO (i.e., the enzyme treatment was combined with induction of exo-endocytotic cycling). Thus, we suggest that plasmalemmal cholesterol oxidation affects exocytotic machinery functioning, enhances synaptic vesicle recruitment to the exocytosis and decreases extracellular neurotransmitter levels at rest, whereas ChO acting on synaptic vesicle membranes suppresses the participation of the vesicles in the subsequent exocytosis and increases the neurotransmitter leakage. The mechanisms underlying ChO action can be related to the lipid raft disruption., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: General anesthesia has long been used in clinical practice, but its precise pharmacological effects on neural circuits are not fully understood. Recent investigations suggest that the sleep-wake system may play a role in the reversible loss of consciousness induced by general anesthetics. Studies in mice have shown that microinjection of dopamine receptor 1 (D1R) agonists into the nucleus accumbens (NAc) promotes recovery from isoflurane anesthesia, while microinjection of D1R antagonists has the opposite effect. Furthermore, during the induction and maintenance of sevoflurane anesthesia, there is a significant decrease in extracellular dopamine levels in the NAc, which subsequently increases during the recovery period. These findings suggest the involvement of the NAc in the regulation of general anesthesia. However, the specific role of D1R-expressing neurons in the NAc during general anesthesia and the downstream effect pathways are still not well understood., Methods: In order to analyze the impact of sevoflurane anesthesia on NAc D1R  neurons and the NAc D1R -VP pathway, this study employed calcium fiber photometry to investigate alterations in the fluorescence intensity of calcium signals in dopamine D1-receptor-expressing neurons located in the nucleus accumbens (NAc D1R  neurons) and the NAc D1R -VP pathway during sevoflurane anesthesia. Subsequently, optogenetic techniques were utilized to activate or inhibit NAc D1R  neurons and their synaptic terminals in the ventral pallidum (VP), aiming to elucidate the role of NAc D1R  neurons and the NAc D1R -VP pathway in sevoflurane anesthesia. These experiments were supplemented with electroencephalogram (EEG) recordings and behavioral tests. Lastly, a genetically-encoded fluorescent sensor was employed to observe changes in extracellular GABA neurotransmitters in the VP during sevoflurane anesthesia., Results: Our findings revealed that sevoflurane administration led to the inhibition of NAc D1R neuron population activity, as well as their connections within the ventral pallidum (VP). We also observed a reversible reduction in extracellular GABA levels in the VP during both the induction and emergence phases of sevoflurane anesthesia. Additionally, the optogenetic activation of NAc D1R  neurons and their synaptic terminals in the VP resulted in a promotion of wakefulness during sevoflurane anesthesia, accompanied by a decrease in EEG slow wave activity and burst suppression rate. Conversely, the optogenetic inhibition of the NAc D1R -VP pathway exerted opposite effects., Conclusion: The NAc D1R -VP pathway serves as a crucial downstream pathway of NAc D1R neurons, playing a significant role in regulating arousal during sevoflurane anesthesia. Importantly, this pathway appears to be associated with the release of GABA neurotransmitters from VP cells., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Spinal motoneuron firing depends greatly on persistent inward currents (PICs), which in turn are facilitated by the neuromodulators serotonin and noradrenaline. The aim of this study was to determine whether jaw clenching (JC) and mental stress (MS), which may increase neuromodulator release, facilitate PICs in human motoneurons. The paired motor unit (MU) technique was used to estimate PIC contribution to motoneuron firing. Surface electromyograms were collected using a 32-channel matrix on gastrocnemius medialis (GM) during voluntary, ramp, plantar flexor contractions. MU discharges were identified, and delta frequency (ΔF), a measure of recruitment-derecruitment hysteresis, was calculated. Additionally, another technique was used (VibStim) that evokes involuntary contractions that persist after cessation of combined Achilles tendon vibration and triceps surae neuromuscular electrical stimulation. VibStim measures of plantar flexor torque and soleus activity may reflect PIC activation. ΔF was not significantly altered by JC (p = .679, n = 18, 9 females) or MS (p = .147, n = 14, 5 females). However, all VibStim variables quantifying involuntary torque and muscle activity during and after vibration cessation were significantly increased in JC (p < .011, n = 20, 10 females) and some, but not all, increased in MS (p = .017-.05, n = 19, 10 females). JC and MS significantly increased the magnitude of involuntary contractions (VibStim) but had no effect on GM ΔF during voluntary contractions. Effects of increased neuromodulator release on PIC contribution to motoneuron firing might differ between synergists or be context dependent. Based on these data, the background level of voluntary contraction and, hence, both neuromodulation and ionotropic inputs could influence neuromodulatory PIC enhancement., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood 1 . Dysfunction of monoaminergic circuits has been implicated in various neurodegenerative and neuropsychiatric disorders 2 . Vesicular monoamine transporters (VMATs) pack monoamines into vesicles for synaptic release and are essential to neurotransmission 3-5 . VMATs are also therapeutic drug targets for a number of different conditions 6-9 . Despite the importance of these transporters, the mechanisms of substrate transport and drug inhibition of VMATs have remained elusive. Here we report cryo-electron microscopy structures of the human vesicular monoamine transporter VMAT2 in complex with the antichorea drug tetrabenazine, the antihypertensive drug reserpine or the substrate serotonin. Remarkably, the two drugs use completely distinct inhibition mechanisms. Tetrabenazine binds VMAT2 in a lumen-facing conformation, locking the luminal gating lid in an occluded state to arrest the transport cycle. By contrast, reserpine binds in a cytoplasm-facing conformation, expanding the vestibule and blocking substrate access. Structural analyses of VMAT2 also reveal the conformational changes following transporter isomerization that drive substrate transport into the vesicle. These findings provide a structural framework for understanding the physiology and pharmacology of neurotransmitter packaging by synaptic vesicular transporters., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In the human brain, neurophysiological activity is modulated by the movement of neurotransmitters and neurosteroids. To date, the similarity between cerebral organoids and actual human brains has been evaluated using comprehensive multiomics approaches. However, a systematic analysis of both neurotransmitters and neurosteroids from cerebral organoids has not yet been reported. Here, we performed quantitative and qualitative assessments of neurotransmitters and neurosteroids over the course of cerebral organoid differentiation. Our multiomics approaches revealed that the expression levels of neurotransmitter-related proteins and RNA, including neurosteroids, increase as cerebral organoids mature. We also found that the electrophysiological activity of human cerebral organoids increases in tandem with the expression levels of both neurotransmitters and neurosteroids. Our study demonstrates that the expression levels of neurotransmitters and neurosteroids can serve as key factors in evaluating the maturity and functionality of human cerebral organoids.

Background: Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and self-injury. Some pharmacological interventions might help treat some behaviours of concern, but can also have adverse effects (AEs)., Objectives: To assess the effectiveness and AEs of pharmacological interventions for managing the behaviours of irritability, aggression, and self-injury in ASD., Search Methods: We searched CENTRAL, MEDLINE, Embase, 11 other databases and two trials registers up to June 2022. We also searched reference lists of relevant studies, and contacted study authors, experts and pharmaceutical companies., Selection Criteria: We included randomised controlled trials of participants of any age with a clinical diagnosis of ASD, that compared any pharmacological intervention to an alternative drug, standard care, placebo, or wait-list control., Data Collection and Analysis: We used standard Cochrane methods. Primary outcomes were behaviours of concern in ASD, (irritability, aggression and self-injury); and AEs. Secondary outcomes were quality of life, and tolerability and acceptability. Two review authors independently assessed each study for risk of bias, and used GRADE to judge the certainty of the evidence for each outcome., Main Results: We included 131 studies involving 7014 participants in this review. We identified 26 studies as awaiting classification and 25 as ongoing. Most studies involved children (53 studies involved only children under 13 years), children and adolescents (37 studies), adolescents only (2 studies) children and adults (16 studies), or adults only (23 studies). All included studies compared a pharmacological intervention to a placebo or to another pharmacological intervention. Atypical antipsychotics versus placebo At short-term follow-up (up to 6 months), atypical antipsychotics probably reduce irritability compared to placebo (standardised mean difference (SMD) -0.90, 95% confidence interval (CI) -1.25 to -0.55, 12 studies, 973 participants; moderate-certainty evidence), which may indicate a large effect. However, there was no clear evidence of a difference in aggression between groups (SMD -0.44, 95% CI -0.89 to 0.01; 1 study, 77 participants; very low-certainty evidence). Atypical antipsychotics may also reduce self-injury (SMD -1.43, 95% CI -2.24 to -0.61; 1 study, 30 participants; low-certainty evidence), possibly indicating a large effect. There may be higher rates of neurological AEs (dizziness, fatigue, sedation, somnolence, and tremor) in the intervention group (low-certainty evidence), but there was no clear evidence of an effect on other neurological AEs. Increased appetite may be higher in the intervention group (low-certainty evidence), but we found no clear evidence of an effect on other metabolic AEs. There was no clear evidence of differences between groups in musculoskeletal or psychological AEs. Neurohormones versus placebo At short-term follow-up, neurohormones may have minimal to no clear effect on irritability when compared to placebo (SMD -0.18, 95% CI -0.37 to -0.00; 8 studies; 466 participants; very low-certainty evidence), although the evidence is very uncertain. No data were reported for aggression or self -injury. Neurohormones may reduce the risk of headaches slightly in the intervention group, although the evidence is very uncertain. There was no clear evidence of an effect of neurohormones on any other neurological AEs, nor on any psychological, metabolic, or musculoskeletal AEs (low- and very low-certainty evidence). Attention-deficit hyperactivity disorder (ADHD)-related medications versus placebo At short-term follow-up, ADHD-related medications may reduce irritability slightly (SMD -0.20, 95% CI -0.40 to -0.01; 10 studies, 400 participants; low-certainty evidence), which may indicate a small effect. However, there was no clear evidence that ADHD-related medications have an effect on self-injury (SMD -0.62, 95% CI -1.63 to 0.39; 1 study, 16 participants; very low-certainty evidence). No data were reported for aggression. Rates of neurological AEs (drowsiness, emotional AEs, fatigue, headache, insomnia, and irritability), metabolic AEs (decreased appetite) and psychological AEs (depression) may be higher in the intervention group, although the evidence is very uncertain (very low-certainty evidence). There was no evidence of a difference between groups for any other metabolic, neurological, or psychological AEs (very low-certainty evidence). No data were reported for musculoskeletal AEs. Antidepressants versus placebo At short-term follow-up, there was no clear evidence that antidepressants have an effect on irritability (SMD -0.06, 95% CI -0.30 to 0.18; 3 studies, 267 participants; low-certainty evidence). No data for aggression or self-injury were reported or could be included in the analysis. Rates of metabolic AEs (decreased energy) may be higher in participants receiving antidepressants (very low-certainty evidence), although no other metabolic AEs showed clear evidence of a difference. Rates of neurological AEs (decreased attention) and psychological AEs (impulsive behaviour and stereotypy) may also be higher in the intervention group (very low-certainty evidence) although the evidence is very uncertain. There was no clear evidence of any difference in the other metabolic, neurological, or psychological AEs (very low-certainty evidence), nor between groups in musculoskeletal AEs (very low-certainty evidence). Risk of bias We rated most of the studies across the four comparisons at unclear overall risk of bias due to having multiple domains rated as unclear, very few rated as low across all domains, and most having at least one domain rated as high risk of bias., Authors' Conclusions: Evidence suggests that atypical antipsychotics probably reduce irritability, ADHD-related medications may reduce irritability slightly, and neurohormones may have little to no effect on irritability in the short term in people with ASD. There was some evidence that atypical antipsychotics may reduce self-injury in the short term, although the evidence is uncertain. There was no clear evidence that antidepressants had an effect on irritability. There was also little to no difference in aggression between atypical antipsychotics and placebo, or self-injury between ADHD-related medications and placebo. However, there was some evidence that atypical antipsychotics may result in a large reduction in self-injury, although the evidence is uncertain. No data were reported (or could be used) for self-injury or aggression for neurohormones versus placebo. Studies reported a wide range of potential AEs. Atypical antipsychotics and ADHD-related medications in particular were associated with an increased risk of metabolic and neurological AEs, although the evidence is uncertain for atypical antipsychotics and very uncertain for ADHD-related medications. The other drug classes had minimal or no associated AEs., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Despite considerable unmet medical needs, effective pharmacological treatments that promote functional recovery after spinal cord injury remain limited. Although multiple pathological events are implicated in spinal cord injuries, the development of a microinvasive pharmacological approach that simultaneously targets the different mechanisms involved in spinal cord injury remains a formidable challenge. Here we report the development of a microinvasive nanodrug delivery system that consists of amphiphilic copolymers responsive to reactive oxygen species and an encapsulated neurotransmitter-conjugated KCC2 agonist. Upon intravenous administration, the nanodrugs enter the injured spinal cord due to a disruption in the blood-spinal cord barrier and disassembly due to damage-triggered reactive oxygen species. The nanodrugs exhibit dual functions in the injured spinal cord: scavenging accumulated reactive oxygen species in the lesion, thereby protecting spared tissues, and facilitating the integration of spared circuits into the host spinal cord through targeted modulation of inhibitory neurons. This microinvasive treatment leads to notable functional recovery in rats with contusive spinal cord injury., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Neurotransmitter release from sympathetic terminals is a key avenue for heart regulation. Herein, presynaptic exocytotic activity was monitored in mice atrial tissue using a false fluorescent neurotransmitter FFN511, a substrate for monoamine transporters. FFN511 labeling had similarity with tyrosine hydroxylase immunostaining. High [K + ] o depolarization caused FFN511 release, which was augmented by reserpine, an inhibitor of neurotransmitter uptake. However, reserpine lost the ability to increase depolarization-induced FFN511 unloading after depletion of ready releasable pool with hyperosmotic sucrose. Cholesterol oxidase and sphingomyelinase modified atrial membranes, changing in opposite manner fluorescence of lipid ordering-sensitive probe. Plasmalemmal cholesterol oxidation increased FFN511 release upon K + -depolarization and more markedly potentiated FFN511 unloading in the presence of reserpine. Hydrolysis of plasmalemmal sphingomyelin profoundly enhanced the rate of FFN511 loss due to K + -depolarization, but completely prevented potentiating action of reserpine on FFN511 unloading. If cholesterol oxidase or sphingomyelinase got access to membranes of recycling synaptic vesicles, then the enzyme effects were suppressed. Hence, a fast neurotransmitter reuptake dependent on exocytosis of vesicles from ready releasable pool occurs during presynaptic activity. This reuptake can be enhanced or inhibited by plasmalemmal cholesterol oxidation or sphingomyelin hydrolysis, respectively. These modifications of plasmalemmal (but not vesicular) lipids increase the evoked neurotransmitter release., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors consent to publish the article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Previous studies have indicated that neurotransmitters play important roles in the occurrence and development of gastric cancer. MAOA is an important catecholamine neurotransmitter-degrading enzyme involved in the degradation of norepinephrine, epinephrine and serotonin. To find a potential therapeutic target for the treatment of gastric cancer, the biological functions of MAOA and the underlying mechanism in gastric cancer need to be explored., Methods: The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) datasets, Kaplan‒Meier (KM) plotter were used to identify the differentially expressed genes, which mainly involved the degradation and synthesis enzymes of neurotransmitters in gastric cancer. We also investigated the expression pattern of MAOA in human and mouse tissues and cell lines by immunohistochemistry and Western blotting analysis. Western blotting, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and a Seahorse experiment were used to identify the molecular mechanism of cancer cell glycolysis. MAOA expression and patient survival were analysed in the Ren Ji cohort, and univariate and multivariate analyses were performed based on the clinicopathological characteristics of the above samples., Results: MAOA expression was significantly downregulated in gastric cancer tissue and associated with poor patient prognosis. Moreover, the expression level of MAOA in gastric cancer tissue had a close negative correlation with the SUXmax value of PET-CT in patients. MAOA suppressed tumour growth and glycolysis and promoted cancer cell apoptosis. We also reported that MAOA can interact with NDRG1 and regulate glycolysis through suppression of the PI3K/Akt/mTOR pathway. MAOA expression may serve as an independent prognostic factor in gastric cancer patients., Conclusions: MAOA attenuated glycolysis and inhibited the progression of gastric cancer through the PI3K/Akt/mTOR pathway. Loss of function or downregulation of MAOA can facilitate gastric cancer progression. Overexpression of MAOA and inhibition of the PI3K/Akt/mTOR pathway may provide a potential method for gastric cancer treatment in clinical therapeutic regimens., (© 2023. Springer Nature Switzerland AG.)

There is need for novel fast acting treatment options in affective disorders. 3α-reduced neurosteroids such as allopregnanolone are powerful positive allosteric modulators of GABA A receptors and target also extrasynaptic receptors. Their synthesis is mediated by the translocator protein 18 kDa (TSPO). TSPO ligands not only promote endogenous neurosteroidogenesis, but also exert a broad spectrum of functions involving modulation of mitochondrial activity and acting as anti-inflammatory and neuroregenerative agents. Besides affective symptoms, in depression cognitive impairment can be frequently observed, which may be ameliorated through targeting of extrasynaptic GABA A receptors either via TSPO ligands or exogenously administered 3α-reduced neurosteroids. Interestingly, recent findings indicate an enhanced activation of the complement system, e.g., enhanced expression of C1q, both in depression and dementia. It is of note that benzodiazepines have been shown to reduce long-term potentiation and to cause cognitive decline. Intriguingly, TSPO may be crucial in mediating the effects of benzodiazepines on synaptic pruning. Here, we discuss how benzodiazepines and TSPO may interfere with synaptic pruning. Moreover, we highlight recent developments of TSPO ligands and 3α-reduced neurosteroids as therapeutic agents. Etifoxine is the only clinically available TSPO ligand so far and has been studied in anxiety disorders. Regarding 3α-reduced neurosteroids, brexanolone, an intravenous formulation of allopregnanolone, has been approved for the treatment of postpartum depression and zuranolone, an orally available 3α-reduced neurosteroid, is currently being studied in major depressive disorder and postpartum depression. As such, 3α-reduced neurosteroids and TSPO ligands may constitute promising treatment approaches for affective disorders., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Depression is a severe mental illness that endangers human health. Depressed individuals are prone to sleep less and to the loss of appetite for food; their thinking and cognition processes, as well as mood, may even be affected. Danzhi Xiaoyao San (DXS), documented in the Internal Medicine Summary, has been used for hundreds of years in China and is widely applied traditionally to treat liver qi stagnation, liver and spleen blood deficiency, menstrual disorders, and spontaneous and night sweating. DXS can also clear heat and drain the liver. Presently, it is used frequently in the treatment of depression based on its ability to clear the liver and alleviate depression., Purpose: To summarize clinical and preclinical studies on the antidepressant-like effects of DXS, understand the material basis and mechanisms of these effects, and offer new suggestions and methods for the clinical treatment of depression., Methods: "Danzhi Xiaoyao", "Danzhixiaoyao", "Xiaoyao", "depression" and active ingredients were entered as keywords in PubMed, Google Scholar, CNKI and WANFANG DATA databases in the search for material on DXS and its active ingredients. The PRISMA guidelines were followed in this review process., Results: Per clinical reports, DXS has a therapeutic effect on patients with depression but few side effects. DXS and its active ingredients allegedly produce their neuroprotective antidepressant-like effects by modulating monoamine neurotransmitter levels, inhibiting the hypothalamic-pituitary-adrenal (HPA) axis hyperfunction, reducing neuroinflammation and increasing neurotrophic factors., Conclusion: Overall, DXS influences multiple potential mechanisms to exert its antidepressant-like effects thanks to its multicomponent character. Because depression is not caused by a single mechanism, probing the antidepressant-like effects of DXS could further help understand the pathogenesis of depression and discover new antidepressant drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Glucose accesses the brain primarily via the astrocyte cell compartment, where it passes through the glycogen shunt before catabolism to the oxidizable fuel L-lactate. Glycogen phosphorylase (GP) isoenzymes GPbb and GPmm impose distinctive control of ventromedial hypothalamic nucleus (VMN) glucose-regulatory neurotransmission during hypoglycemia, but lactate and/or gliotransmitter involvement in those actions is unknown. Lactate or the octadecaneuropeptide receptor antagonist cyclo(1-8)[DLeu 5 ] OP (LV-1075) did not affect gene product down-regulation caused by GPbb or GPmm siRNA, but suppressed non-targeted GP variant expression in a VMN region-specific manner. Hypoglycemic up-regulation of neuronal nitric oxide synthase was enhanced in rostral and caudal VMN by GPbb knockdown, yet attenuated by GPMM siRNA in the middle VMN; lactate or LV-1075 reversed these silencing effects. Hypoglycemic inhibition of glutamate decarboxylase65/67 was magnified by GPbb (middle and caudal VMN) or GPmm (middle VMN) knockdown, responses that were negated by lactate or LV-1075. GPbb or GPmm siRNA enlarged hypoglycemic VMN glycogen profiles in rostral and middle VMN. Lactate and LV-1075 elicited progressive rostral VMN glycogen augmentation in GPbb knockdown rats, but stepwise-diminution of rostral and middle VMN glycogen after GPmm silencing. GPbb, not GPmm, knockdown caused lactate or LV-1075 - reversible amplification of hypoglycemic hyperglucagonemia and hypercorticosteronemia. Results show that lactate and octadecaneuropeptide exert opposing control of GPbb protein in distinct VMN regions, while the latter stimulates GPmm. During hypoglycemia, GPbb and GPmm may respectively diminish (rostral, caudal VMN) or enhance (middle VMN) nitrergic transmission and each oppose GABAergic signaling (middle VMN) by lactate- and octadecaneuropeptide-dependent mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. The pathogenesis of PD includes oxidative stress, mitochondrial dysfunction, neuroinflammation, and neurotransmitter dysregulation. L-theanine is found in green tea and has antioxidant, anti-inflammatory, and neuroprotective effects with a high blood brain barrier permeability., Objective: The objective of this study was to investigate the possible neuroprotective effect of L-theanine in lipopolysaccharide (LPS) induced motor deficits and striatal neurotoxicity in a rat model of PD., Methods: LPS was infused at a dose of 5 μg/5 μl PBS stereotaxically into SNpc of rats. Treatment with L-theanine (50 and 100 mg/kg; po) and Sinemet (36 mg/kg; po) was given from day 7 to 21 in of LPS injected rat. On a weekly basis all behavioral parameters were assessed, and animals were sacrificed on day 22. The striatum tissue of brain was isolated for biochemicals (Nitrite, GSH, catalase, SOD, mitochondrial complexes I and IV), neuroinflammatory markers, and neurotransmitters (serotonin, dopamine, norepinephrine, GABA, and glutamate) estimations., Results: Results revealed that L-theanine dose-dependently and significantly reversed motor deficits, assessed through locomotor and rotarod activity. Moreover, L-theanine attenuated biochemical markers, reduced oxidative stress, and neurotransmitters dysbalance in the brain. L-theanine treatment at 100 mg/kg; po substantially reduced these pathogenic events by increasing mitochondrial activity, restoring neurotransmitter levels, and inhibiting neuroinflammation., Conclusions: These data suggest that the positive effects of L-theanine on motor coordination may be mediated by the suppression of NF-κB induced by LPS. Therefore, L-theanine would have a new therapeutic potential for PD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Epilepsy is one of the most serious worldwide neurological disorders that lead to the cognitive-psychosocial insults in recurrent seizures. About one third of the patients are drug-resistant, so innovative drugs are needed to manage seizures to improve the quality of life. Ceftriaxone is a cephalosporin antibiotic that increases the expression of glutamate transporters-1 and improves the neurobehavioral effects caused by increased glutamate level in the CNS. Selenium is well known antioxidant. The present study aimed to investigate ceftriaxone and selenium therapeutic effects against epilepsy in rats. Epilepsy was induced by PTZ given at a dose (50 mg/kg I.P) on alternative days for 13 days. Eighty rats were randomly divided into 8 groups: Group1-2; normal and vehicle control, Group 3; PTZ group, Group 4-8; kindled rats received selenium, ceftriaxone100, ceftriaxone200, selenium + ceftriaxone100 and selenium + ceftriaxone200 mg/kg/day respectively for a week. At the end of the study, behavioral tests were performed. Oxidative stress, inflammatory markers, neurotransmitters and GLT-1 were measured in brain tissue homogenate. Brain histopathological investigation was also done. PTZ-kindled rats exhibited increased Racine score, besides behavioral tests and histopathological changes, significant elevation in oxidative stress and inflammatory markers, with decrease in serotonin, dopamine, GABA levels and GLT-1 expressions. Selenium and Ceftriaxone alone or combined treatment decreased Racine score with remarkable improvement in behavioral and histopathological changes. The antioxidant enzymes, neurotransmitters and GLT-1 expressions were increased, along with reduced TNF-α, IL-1 levels. Current study showed that selenium + ceftriaxone100 group represents a possible approach to improve epilepsy particularly through inhibiting oxidative stress and inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The presence of a renal GABA/glutamate system has previously been described; however, its functional significance in the kidney remains undefined. We hypothesized, given its extensive presence in the kidney, that activation of this GABA/glutamate system would elicit a vasoactive response from the renal microvessels. The functional data here demonstrate, for the first time, that activation of endogenous GABA and glutamate receptors in the kidney significantly alters microvessel diameter with important implications for influencing renal blood flow. Renal blood flow is regulated in both the renal cortical and medullary microcirculatory beds via diverse signaling pathways. GABA- and glutamate-mediated effects on renal capillaries are strikingly similar to those central to the regulation of central nervous system capillaries, that is, exposing renal tissue to physiological concentrations of GABA, glutamate, and glycine led to alterations in the way that contractile cells, pericytes, and smooth muscle cells, regulate microvessel diameter in the kidney. Since dysregulated renal blood flow is linked to chronic renal disease, alterations in the renal GABA/glutamate system, possibly through prescription drugs, could significantly impact long-term kidney function. NEW & NOTEWORTHY Functional data here offer novel insight into the vasoactive activity of the renal GABA/glutamate system. These data show that activation of endogenous GABA and glutamate receptors in the kidney significantly alters microvessel diameter. Furthermore, the results show that these antiepileptic drugs are as potentially challenging to the kidney as nonsteroidal anti-inflammatory drugs.

Orexin-A and -B (identical to hypocretin-1 and -2) are neuropeptides synthesized in the lateral hypothalamus and perifornical area, and orexin neurons project their axon terminals broadly throughout the entire central nervous system (CNS). The activity of orexins is mediated by two specific G protein-coupled receptors (GPCRs), termed orexin type1 receptor (OX1R) and orexin type2 receptor (OX2R). The orexin system plays a relevant role in various physiological functions, including arousal, feeding, reward, and thermogenesis, and is key to human health. Orexin neurons receive various signals related to environmental, physiological, and emotional stimuli. Previous studies have reported that several neurotransmitters and neuromodulators influence the activation or inhibition of orexin neuron activity. In this review, we summarize the modulating factors of orexin neurons in the sleep/wake rhythm and feeding behavior, particularly in the context of the modulation of appetite, body fluids, and circadian signaling. We also describe the effects of life activity, behavior, and diet on the orexin system. Some studies have observed phenomena that have been verified in animal experiments, revealing the detailed mechanism and neural pathway, while their applications to humans is expected in future research., Competing Interests: Conflicts of interest The authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine are known to be abundant in the substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc). Thus, it has been recognized as an initial synaptic site for regulating orofacial nociceptive stimuli. Honokiol, a principal active ingredient derived from the bark of Magnolia officinalis, has been exploited in traditional remedies with multiple biological effects, including anti-nociception on humans. However, the anti-nociceptive mechanism of honokiol on SG neurons of the Vc remains fully elusive. In this study, effects of honokiol on SG neurons of the Vc in mice were investigated using the whole-cell patch-clamp method. In a concentration-dependent manner, honokiol significantly enhanced frequencies of spontaneous postsynaptic currents (sPSCs) that were independent of action potential generation. Notably, honokiol-induced increase in the frequency of sPSCs was attributed to the release of inhibitory neurotransmitters through both glycinergic and GABAergic pre-synaptic terminals. Furthermore, higher concentration of honokiol induced inward currents that were noticeably attenuated in the presence of picrotoxin (a GABA A receptor antagonist) or strychnine (a glycine receptor antagonist). Honokiol also exhibited potentiation effect on glycine- and GABA A receptor-mediated responses. In inflammatory pain model, the increase in frequency of spontaneous firing on SG neurons induced by formalin was significantly inhibited by the application of honokiol. Altogether, these findings indicate that honokiol might directly affect SG neurons of the Vc to facilitate glycinergic and GABAergic neurotransmissions and modulate nociceptive synaptic transmission against pain. Consequently, the inhibitory effect of honokiol in the central nociceptive system contributes to orofacial pain management., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Phytopharmaceuticals have attracted a lot of attention due to their multicomponent and multiple targets. The natural phenolic chemicals known as flavonoids are found in a wide variety of plants, fruits, vegetables, and herbs. Recently, they have been found to have modulatory effects on anxiety disorders, with current research focusing on the modulation of neurotransmitters. There has not yet been a review of the various natural flavonoid monomer compounds and total plant flavonoids that have been found to have anxiolytic effects. The study on the anti-anxiety effects of plant-derived flavonoids on neurotransmitters was reviewed in this paper. We, therefore, anticipate that further study on the conformational interaction underlying flavonoids' anti-anxiety effects will offer a theoretical framework for the creation of pertinent treatments., (© 2023 Wiley Periodicals LLC.)

Alzheimer's disease (AD) is a most common and prevalent age related insidious neurological condition characterised by formation of Aβ (1-42) plaques and NFT in the hippocampus. Major symptoms of AD include memory and cognitive loss caused by neuroinflammation, Aβ (1-42) plaques, and NFT accumulation in the brain. Intracerebroventricular administration of STZ up-regulates the level of Aβ (1-42) plaques, and NFT by activating NF-kB pathway. All animals were trained for behaviour analysis before infusion of ICV-STZ bilaterally, at a dose of 3 mg/kg; icv. The stereotaxic surgery was performed in target region with coordinates -2 mm [AP], 1.6 mm [MR], and1.5 mm [DV]. On day 1 and day 3 after surgery HS (hamilton syringe) was used to infuse STZ at the target region of brain. Morris Water Maze (MWM), and Elevated Plus Maze (EPM) tests were performed to check spatial and learning memory in all groups. ICV-STZ infusion produced memory impairment by increasing the activity of AchE, oxidative markers (LPO, GSH, and nitrite), neurotransmitters levels (AchE, GABA, and glutamate), and release of neuroinflammatory markers (NF-kB, IL-6, and IL-1β). The treatment with Honokiol (Bioactive polyphenolic compound) significantly ameliorated the behavioural changes at a dose of 5, and 10 mg/kg; i.p on day 7, 14, and 21. After behavioural analysis rats were sacrificed on day 22, and the hippocampus tissue was collected to investigate the biochemical, neuroinflammatory, neurotransmitters, histopathological, and immunohistopathological changes. Here, we have found Honokiol significantly down regulates the Aβ plaques via NF-kB inhibition and also reduced neuroinflammation in the brain of rats. Further inhibits the NF-kB expression confirmed for immunohistochemistry analysis. It was observed that Honokiol (5, and 10 mg/kg; i.p) dose-dependently ameliorated AchE level restored neurotransmitters concentrations in hippocampal region, and prevented neuronal loss confirmed from histopathology studies. We concluded that Honokiol drastically produced protective effect in AD model via antioxidant, reducing inflammation, AchE level, restoration of neurofibrillary tangles and preventing NF-kB as well as histopathological changes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Control of cutaneous circulation is critically important to maintain thermoregulation, especially in individuals with cervical spinal cord injury (CSCI) who have no or less central thermoregulatory drive. However, the peripheral vasoconstrictor mechanism and capability have not been fully investigated after CSCI. Post- and presynaptic sensitivities of the cutaneous vasoconstrictor system were investigated in 8 CSCI and 7 sedentary able-bodied (AB) men using an intradermal microdialysis technique. Eight doses of norepinephrine (NE, 10 -8 to 10 -1 M) and five doses of tyramine (TY, 10 -8 , 10 -5 to 10 -2 M) were administered into the anterior right and left thigh, respectively. Endogenous catecholamines, noradrenaline, and dopamine, collected at the TY site, were determined by high-performance liquid chromatography with electrochemical detection. Regardless of vasoconstrictor agents, cutaneous vascular conductance decreased dose-dependently and responsiveness was similar between the groups (NE: Group P = 0.255, Dose P = 0.014; TY: Group P = 0.468, Dose P < 0.001), whereas the highest dose of each drug induced cutaneous vasodilation. Administration of TY promoted the release of noradrenaline and dopamine in both groups. Notably, the amount of noradrenaline released was similar between the groups ( P = 0.819), although the concentration of dopamine was significantly greater in individuals with CSCI than in AB individuals ( P = 0.004). These results suggest that both vasoconstrictor responsiveness and neural functions are maintained after CSCI, and dopamine in the skin is likely to induce cutaneous vasodilation.

Alzheimer's disease (AD) is the most frequent cause of cognitive impairment in middle-aged and older populations. There is a lack of drugs that demonstrate significant efficacy in AD, so the study of the pathogenesis of AD is of great importance. More efficacious interventions are needed, as reflected by our population's fast aging. Synaptic plasticity is the capacity of neurons to adjust their connections, and it is strongly tied to learning and memory, cognitive function, and brain injury recovery. Changes in synaptic strength, such as long-term potentiation (LTP) or inhibition (LTD), are thought to represent the biological foundation of the early stages of learning and memory. The results of numerous studies confirm that neurotransmitters and their receptors play an important role in the regulation of synaptic plasticity. However, so far, there is no definite correlation between the function of neurotransmitters in aberrant neural oscillation and AD-related cognitive impairment. We summarized the AD process to understand the impact of neurotransmitters in the progression and pathogenesis of AD, including the current status of neurotransmitter target drugs, and the latest evidence of neurotransmitters' function and changes in the AD process.

Hydrogen sulfide (H 2 S) is a unique signaling molecule that, along with carbon monoxide and nitric oxide, belongs to the gasotransmitters family. H 2 S is endogenously synthesized by enzymatic and non-enzymatic pathways. Three enzymatic pathways involving cystathionine-γ-lyase, cystathionine-β-synthetase, and 3-mercaptopyruvate sulfurtransferase are known as endogenous sources of H 2 S. This gaseous molecule has recently emerged as a regulator of many systems and physiological functions, including the cardiovascular system where it controls the vascular tone of small arteries. In this context, H 2 S leads to vasorelaxation by regulating the activity of vascular smooth muscle cells, endothelial cells, and perivascular nerves. Specifically, H 2 S modulates the functionality of different ion channels to inhibit the autonomic sympathetic outflow-by either central or peripheral mechanisms-or to stimulate perivascular sensory nerves. These mechanisms are particularly relevant for those pathological conditions associated with impaired neuromodulation of vascular tone. In this regard, exogenous H 2 S administration efficiently attenuates the increased activity of the sympathetic nervous system often seen in patients with certain pathologies. These effects of H 2 S on the autonomic sympathetic outflow will be the primary focus of this review. Thereafter, we will discuss the central and peripheral regulatory effects of H 2 S on vascular tone. Finally, we will provide the audience with a detailed summary of the current pathological implications of H 2 S modulation on the neural regulation of vascular tone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us., (Copyright © 2022 Elsevier B.V. All rights reserved.)