Glucagon-like peptide-2 modulates the nitrergic neurotransmission in strips from the mouse gastric fundus

AIM To investigate whether glucagon-like peptide-2(GLP-2) influences the neurally-induced responses in gastric strips from mice, since no data are available. METHODS For functional experiments, gastric fundal strips were mounted in organ baths containing Krebs-Henseleit solution. Mechanical responses were recorded via forcedisplacement transducers, which were coupled to a polygraph for continuous recording of isometric tension. Electrical field stimulation(EFS) was applied via two platinum wire rings through which the preparationwas threaded. The effects of GLP-2(2 and 20 nmol/L) were evaluated on the neurally-induced contractile and relaxant responses elicited by EFS. Neuronal nitric oxide synthase(n NOS) enzyme was evaluated by immunohistochemistry.RESULTS In the functional experiments, electrical field stimulation(EFS, 4-16 Hz) induced tetrodotoxin(TTX)-sensitive contractile responses, which were reduced in amplitude by GLP-2(P < 0.05). In the presence of the nitric oxide(NO) synthesis inhibitor L-NNA, GLP-2 no longer influenced the neurally-evoked contractile responses(P > 0.05). The direct smooth muscle response to methacholine was not influenced by GLP-2(P > 0.05). In the presence of guanethidine and carbachol, the addition of GLP-2 to the bath medium evoked TTX-sensitive relaxant responses that were unaffected by L-NNA(P > 0.05). EFS induced a fast NO-mediated relaxation, whose amplitude was enhanced in the presence of the hormone(P < 0.05). Immunohistochemical experiments showed a significant increase(P < 0.05) in n NOS immunoreactivity in the nerve structures after GLP-2 exposure. CONCLUSION The results demonstrate that in gastric fundal strips, GLP-2 influences the amplitude of neurally-induced responses through the modulation of the nitrergic neurotransmission and increases n NOS expression.

What Does GABAergic Neurotransmission System Do in Acupuncture Analgesia?

As one of the essential components of traditional Chinese medicine, acupuncture has been accepted world-widely for its effectiveness in treating various disease and health conditions. Pain management is one of the least controversial therapeutic benefits of acupuncture treatment. To date, the mechanism underlying acupuncture analgesia remains poorly understood. In this review, roles of members of GABAergic neurotransmission system which has long been related to pain perception and modulation, in acupuncture analgesia are discussed.

A Calcium Paradox in the Context of Neurotransmission

The hypothesis of the calcium paradox has its origin in experiments done in neurogenically stimulated rat and mouse vas deferentia. Some old studies reported that reduction of Ca2＋ entry by mild concentrations of verapamil, diltiazem or nifedipine elicited the surprising augmentation of vas deferens contractions. Recent reports have also found that nifedipine caused a paradoxical augmentation of the exocytotic release of catecholamine elicited by paired depolarising pulses in voltage-clamped bovine chromaffin cells. Because these drugs are blocking the L-subtype of VACCs （voltage-activated calcium channels）, augmented contraction and exocytosis was an unexpected outcome. Recent experiments in neurogenically-stimulated rat vas deferens have found a more drastic potentiation of contractions with the association of verapamil and cAMP-enhancer compounds. Thus, the interaction between the signalling pathways mediated by Ca2＋ and cAMP could explain those unexpected findings and the so-called calcium paradox.

Roles of neuronal lysosomes in the etiology of Parkinson’s disease

Therapeutic progress in neurodegenerative conditions such as Parkinson’s disease has been hampered by a lack of detailed knowledge of its molecular etiology.The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease.In this respect,the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics,genomics,and pathologic indications,spanning both familial and idiopathic Parkinson’s disease.Most,if not all,genes linked to familial disease are involved,in a regulatory capacity,in lysosome function(e.g.,LRRK2,alpha-synuclein,VPS35,Parkin,and PINK1).Moreover,the majority of genomic loci associated with increased risk of idiopathic Parkinson’s cluster in lysosome biology and regulation(GBA as the prime example).Lastly,neuropathologic evidence showed alterations in lysosome markers in autoptic material that,coupled to the alpha-synuclein proteinopathy that defines the disease,strongly indicate an alteration in functionality.In this Brief Review article,I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson’s pathogenesis,aiming at a larger vision on the events underlying the onset of the disease.The attempts at targeting autophagy for therapeutic purposes in Parkinson’s have been mostly aimed at“indiscriminately”enhancing its activity to promote the degradation and elimination of aggregate protein accumulations,such as alpha-synuclein Lewy bodies.However,this approach is based on the assumption that protein pathology is the root cause of disease,while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings.In addition,it has been reported that unspecific boosting of autophagy can be detrimental.Thus,it is important to understand the mechanisms of specific autophagy forms and,even more,the adjustment of specific lysosome functionalities.Indeed,lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions.Here,I discuss hypotheses on these possible mechanisms,their links with etiologic and risk factors for Parkinson’s disease,and how they could be targeted for disease-modifying purposes.

Decoding molecular mechanisms:brain aging and Alzheimer's disease

The complex morphological,anatomical,physiological,and chemical mechanisms within the aging brain have been the hot topic of research for centuries.The aging process alters the brain structure that affects functions and cognitions,but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders,such as Alzheimer's disease.Beyond these observable,mild morphological shifts,significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain.Understanding these changes is important for maintaining cognitive health,especially given the increasing prevalence of age-related conditions that affect cognition.This review aims to explore the age-induced changes in brain plasticity and molecular processes,differentiating normal aging from the pathogenesis of Alzheimer's disease,thereby providing insights into predicting the risk of dementia,particularly Alzheimer's disease.

Progress in pathogenesis and treatment of type A hepatic encephalopathy in acute liver failure:a comprehensive review

Hepatic encephalopathy is a serious neuropsychiatric complication caused by liver failure,which is characterized by the development of cognitive and motor disorders into coma.Typically,hepatic encephalopathy can be divided into three types(A,B,and C)according to the etiology.Type A hepatic encephalopathy(AHE)caused by acute liver failure seriously affects the prognosis of patients,ranging from mild neuropsychological changes to coma,brain edema,and even death.So far,the research on the pathogenesis of AHE has focused on the toxic effects of ammonia on the central nervous system,metabolic disorders(glutamine and lactate accumulation),neurotransmission alteration,systemic inflammation,especially neuro-inflammation.All these mechanisms are not independent,but mutually have synergistic effects.In clinic,treatment of AHE based on only one mechanism is often ineffective.To clarify the pathogenesis and the interaction among the mechanisms will be beneficial to the effective treatment of AHE and reduce the mortality.The aim of this review is to provide comprehensive scientific evidence for the clinical treatment of AHE via collecting and analyzing the latest mechanism of AHE,and clarifying the relationship among these mechanisms combing the investigation of the latest research progress of drug treatment of acute liver failure.Consequently,we find that the pathogenesis of AHE is a complex neurocognitive disorder shaped by interactions among hyperammonemia,inflammation,and changes in neurotransmission,the signaling pathways thereby integrating the inflammatory and neurological inputs to impact pathophysiological or neurobehavioral outcomes.

Suppressing SNAP-25 and reversing glial glutamate transporters relieves neuropathic pain in rats by ameliorating imbalanced neurotransmission

Background Neuropathic pain results from a lesion or disease affecting the somatosensory system at either the peripheral or central level. The transmission of nociception within the central nervous system is subject to modulation by release and reuptake of neurotransmitters, which maintain a dynamic balance through the assembly and disassembly of the SNARE complex as well as a series of neurotransmitter transporters （inhibitory GABA transporters GAT and excitatory glutamate transporters GT）. Neuronal hyper-excitability or defected inhibition involved in neuropathic pain is one of the outcomes caused by imbalanced neurotransmission. SNAP-25, which is one of the SNARE complexes, can modulate the release of neurotransmitters. Glia glutamate transporter （GLT） is one of the two glutamate transporters which account for most synaptic glutamate uptake in the CNS. The role of SNAP-25 and GLT as well as GAT is not clearly understood.

A Fully-Decoupled RAN Architecture for 6G Inspired by Neurotransmission

While the commercial deployment and promotion of 5G is ongoing,mobile communication networks are still facing three fundamental challenges,i.e.,spectrum resource scarcity,especially for low-frequency spectrum,exacerbated by fragmented spectrum allocation,user-centric network service provision when facing billions of personalized user demands in the era of Internet of everything(IoE),and proliferating operation costs mainly due to huge energy consumption of network infrastructure.To address these issues,it is imperative to consider and develop disruptive technologies in the next generation mobile communication networks,namely 6G.In this paper,by studying brain neurons and the neurotransmission,we propose the fully-decoupled radio access network(FD-RAN).In the FD-RAN,base stations(BSs)are physically decoupled into control BSs and data BSs,and the data BSs are further physically split into uplink BSs and downlink BSs.We first review the fundamentals of neurotransmission and then propose the 6G design principles inspired by the neurotransmission.Based on the principles,we propose the FD-RAN architecture,elastic resource cooperation in FD-RAN,and improved transport service layer design.The proposed fully decoupled and flexible architecture can profoundly facilitate resource cooperation to enhance the spectrum utilization,reduce the network energy consumption and improve the quality of user experience.Future research topics in this direction are envisioned and discussed.

Involvement of genes required for synaptic function in aging control in C.elegans

Objective To identify new genes required for neurosecretory control of aging in C. elegans. Methods In view of the importance of nervous system in aging regulation, we performed the screen for genes involved in the aging regulation from genetic loci encoding synaptic proteins by lifespan assay and accumulation of lipofuscin autofluorescence. We further investigated the dauer formation phenotypes of their corresponding mutants and whether they were possibly up-regulated by the insulin-like signaling pathway. Results The genetic loci of unc-10, syd-2, hlb-1, dlk-1, mkk-4, scd- 2, snb-1, ric-4, nrx-1, unc-13, sbt-1 and unc-64 might be involved in the aging control. In addition, functions of unc-10, syd-2, hlb-1, dlk-1, mkk-4, scd-2, snb-1, ric-4 and nrx-1 in regulating aging may be opposite to those of unc-13, sbt-1 and unc-64. The intestinal autofluorescence assay further indicated that the identified long-lived and short-lived mutants were actually due to the suppressed or accelerated aging. Among the identified genes, syd-2, hlb-1, mkk-4, scd-2, snb-1, ric-4 and unc-64 were also involved in the control of dauer formation. Moreover, daf-2 mutation positively regulated the expression of syd-2 and hlb-1, and negatively regulated the expression of mkk-4, nrx-1, ric-4, sbt-1, rpm-1, unc-10, dlk- 1 and unc-13. The daf-16 mutation positively regulated the expression of syd-2 and hlb-1, and negatively regulated the expression of mkk-4, nrx-1, sbt-1, rpm-1, unc-10, dlk-1 and unc-13. Conclusion These data suggest the possibly important status of the synaptic transmission to the animal＇ s life-span control machinery, as well as the dauer formation control.

Cortical spreading depression-induced preconditioning in the brain

Cortical spreading depression is a technique used to depolarize neurons. During focal or global ischemia, cortical spreading depression-induced preconditioning can enhance tolerance of further injury. However, the underlying mechanism for this phenomenon remains relatively unclear. To date, numerous issues exist regarding the experimental model used to precondition the brain with cortical spreading depression, such as the administration route, concentration of potassium chloride, induction time, duration of the protection provided by the treatment, the regional distribution of the protective effect, and the types of neurons responsible for the greater tolerance. In this review, we focus on the mechanisms underlying cor- tical spreading depression-induced tolerance in the brain, considering excitatory neurotransmission and metabolism, nitric oxide, genomic reprogramming, inflammation, neurotropic factors, and cellular stress response. Specifically, we clarify the procedures and detailed information regarding cortical spreading depression-induced preconditioning and build a foundation for more comprehensive investigations in the field of neural regeneration and clinical application in the future.

Adiponectin affects the mechanical responses in strips from the mouse gastric fundus

AIM To investigate whether the adipocytes derived hormone adiponectin(ADPN) affects the mechanical responses in strips from the mouse gastric fundus. METHODS For functional experiments, gastric strips from the fundal region were cut in the direction of the longitudinal muscle layer and placed in organ baths containing KrebsHenseleit solution. Mechanical responses were recorded via force-displacement transducers, which were coupled to a polygraph for continuous recording of isometric tension. Electrical field stimulation(EFS) was applied via two platinum wire rings through which the preparation was threaded. The effects of ADPN were investigated on the neurally-induced contractile and relaxant responses elicited by EFS. The expression of ADPN receptors, Adipo-R1 and Adipo-R2, was also evaluated by touchdown-PCR analysis. RESULTS In the functional experiments, EFS(4-16 Hz) elicited tetrodotoxin(TTX)-sensitive contractile responses. Addition of ADPN to the bath medium caused a reduction in amplitude of the neurally-induced contractile responses(P < 0.05). The effects of ADPN were no longer observed in the presence of the nitric oxide(NO) synthesis inhibitor L-NG-nitro arginine(L-NNA)(P > 0.05). The direct smooth muscle response to methacholine was not influenced by ADPN(P > 0.05). In carbachol precontracted strips and in the presence of guanethidine, EFS induced relaxant responses. Addition of ADPN to the bath medium, other than causing a slight and progressive decay of the basal tension, increased the amplitude of the neurally-induced relaxant responses(P < 0.05). Touchdown-PCR analysis revealed the expression of both Adipo-R1 and Adipo-R2 in the gastric fundus.CONCLUSION The results indicate for the first time that ADPN is able to influence the mechanical responses in strips from the mouse gastric fundus.

Microglial displacement of GABAergic synapses has endogenous protective function in generation of complex febrile seizures

OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS) are the most common infantile seizures,yet its pathological progress is largely unknown.METHODS Mice pups(postnatal 8-10 d) were posted to 43℃ hyperthermia condition to develop FS,and then the latency and threshold of seizures were determined.The displacement of synapses was observed through immunofluorescence staining.We researched whether microglial displacement of GABAergic synapses will influence complex FS-induced increase in GABAergic neurotransmission and neuronal excitability with patch-clamp electrophysiology.Moreover,we used the CD11 bD TR mice to selective ablation of microglia or pharmacological inhibition of microglia to observe their effects on susceptibility to FS and synaptic stripping.RESULTS GABAergic presynaptic terminals surrounding neuronal soma and GABAergic transmissions were increased in complex FS.Meanwhile,the activated microglia ensheathe glutamatergic neuronal soma to displace,but do not phagocytize,GABAergic presynaptic terminals.Patch-clamp electrophysiology established that the microglial displacement of GABAergic synapses reduced complex FS-induced increase in GABAergic neurotransmission and neuronal excitability,while GABA exerts excitatory action in this immature stage.Moreover,pharmacological inhibition of microglial displacement of GABAergic synapses or selective ablation of microglia in CD11 bDTR mice promoted the generation of complex FS.CONCLUSION Displacement of GABAergic synapses by microglia is a protective event in the pathological progress of complex FS.

Enzymes of Earthworm as Indicators of Pesticide Pollution in Soil

The importance of the earthworms in the agricultural practices is well known. The increasing applications of pesticides and chemicals in the agricultural farms have adversely influenced the flora and fauna of the soil. Earthworms which immensely contribute in increasing the quality and fertility of agricultural soil are reported be worst hit organisms under such conditions. Recent reports have indicated growing interests among researchers to explore biochemical and molecular markers as indicators of accumulation of pollutants in the soil in general and pesticides in particular. The varying levels of several biomolecules in different parts of the earthworm have been reported which are indicative of sensitivity of the organisms to different xenobiotics. However, the existing information lacks the literature displaying stock of information regarding the impact of pesticides on the levels of some key enzymes regulating many crucial functions in the earthworm at one place. Keeping in view this issue, it was envisaged to bring out a mini review which illustrates updated information available on the impact of pesticides on the activities of certain key enzymes reported to be responsible for catalysing metabolic pathways concerning the neurotransmission system, energy metabolism, oxidative stress and amino acids metabolism in different body parts of the earthworms, a prospective bioindicators of pesticides contamination in the soil.

Physiological significance of nitrergic transmission in human penile erection

Aim: Epididymal proteins are known to play an important role in the maturation of spermatozoa, we ought to deter-mine if there are regional differences in androgen-dependent epididymal proteins. Methods: A group of adult rats wascastrated and epididymides were removed three days following castration. The epididymides were dissected into caput,corpus and cauda segments, homogenized, and proteins were fractionated by anion exchange HPLC. Proteins in select-ed fractions were resolved by SDS-PAGE and visualized by silver staining. Results: It was observed that the levels ofmultiple proteins drastically reduced in the various regions of epididymis of the orchiectomized rats. Conclusion: Theepididymal proteins appear to be useful markers to study androgenic action in the epididymis.

Importance of being Nernst: Synaptic activity and functional relevance in stem cell-derived neurons

Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagationof neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron(SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments.

The adjustment of γ-aminobutyric acid_A tonic subunits in Huntington＇s disease：from transcription to translation to synaptic levels into the neostriatum

γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as GABAA and GABAB,the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6,β3,δ,or ρ1-3 subunits,they are located at perisynaptic and/or in extrasynaptic regions.The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation.On this basis,GABAA tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington＇s disease.Huntington＇s disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein.For experimental studies of Huntington＇s disease mouse models have been developed,such as R6/1,R6/2,Hdh Q92,Hdh Q150,as well as YAC128.In all of them,some key experimental reports are focused on neostriatum.The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures,its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively,they display strong expression of many types of GABAA receptors,including tonic subunits.The studies about of GABAA tonic subunits and Huntington＇s disease into the neostriatum are rising in recent years,suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition,a hallmark of Huntington＇s disease.

Changes in the levels of CAM kinase II and synapsin I caused by oxidative stress in the rat brain, and its prevention by vitamin E

To define whether oxidative stress and aging induce abnormal dissociation of neurotransmitter-enclosing synaptic vesicles in rat brain nerve terminals, we assessed the activation of Ca+/calmodulin dependent protein kinase II (CAM kinase II) and changes in the levels of synapsin I, which is a synaptic vesicle-associated protein involved in the modulation of neurotransmitter release. Assessment of young rats subjected to hyperoxia-induced oxidative stress and normal aged rats revealed that synaptic CAM kinase II in the rat brain was markedly activated through oxidative stress and aging. In accordance with the activation of CAM kinase II, the levels of phosphorylated synapsin I increased significantly in nerve terminals. Furthermore, it was found that vitamin E prevents these oxidative stress-induced abnormal processes in rat nerve terminals. These results suggest that oxidative stress and aging facilitate the mobilization of neurotransmitter-enclosing synaptic vesicles from the reserve pool in the nerve terminal, thereby inducing abnormal accumulation of synaptic vesicles in the synapse, and that vitamin E inhibits this process in the brain through its antioxidative action.

Menopause, cessation of menses, vs. “menopause”, a primary brain disorder?

The “menopause” (not menopause, the cessation of menses) mechanism responsible for its symptom complex (Menopausal Symptom Complex) (or, Climacteric Syndrome) including chronic fatigue, fibromyalgia, depression, tension headache, cervical vertigo, sleep disturbances, irritability, anxiety/panic attacks, cognitive changes (decreased concentration to obsessional/delusional thought), decreased libido, and vasomotor dysfunction remains elusive. And MSC, other than vasomotor dysfunction, is not significantly altered by treatment with sex hormones (estrogen/progesterone), which have major neoplastic and vascular side effects. Thus at present, there are minimal indications for treatment with these compounds. Confusion between menopause and “menopause” (MSC) as well as research money made available by pharma advocating ERT/HRT (estrogen replacement therapy/hormone replacement therapy) has produced both therapeutic and research inertia. Presently, there would appear to be mismanagement of a symptom complex which infers primary brainlimbic system dysfunction and for which there is no correlation with falling sex hormone levels. Pharmacological modification of the proposed aberrant limbic circuitry responsible for the MSC has been successfully accomplished using specific NT/MMs (neurotransmission/modulation modifiers) i.e. a combination of alpha-1 and norepinephrine reuptake blockers, and thus providing initial elucidation of this particular brain pathophysiology as well as an efficient treatment of a problem affecting up to 60% of women ages 35 to 55. Specific NT/MMs capable of affecting a number of neurotransmitter/receptor types within limbic circuitry appear to reverse the MSC which includes chronic fatigue and fibromyalgia, pointing to aberrant limbic circuitry as their etiology as well.

Neural regulation of sexual function in men

Male sexual response is controlled by a series of neurally mediated phenomena regulating libido, motivation, arousal and genital responses such as penile erection and ejaculation. These neural events that occur in a hormonally defined milieu involve different neurophysiological, neurochemical, and neuropsychological parameters controlled by central mechanisms, spinal reflexes and peripheral nervous system. Epidemiologic studies have suggested the high prevalence of male sexual dysfunction worldwide with significant impact on the quality of life of patients suffering from this problem. The incidence of sexual dysfunction is particularly high among men with neurologic disorders. Sexual dysfunction in men, such as loss of sexual desire, erectile dysfunction(ED), changes in arousal, and disturbances in orgasm and ejaculation may involve organic causes, psychological problems, or both. Organic male sexual disorders include a wide variety of neurologic, vasculogenic, neurovascular or hormonal factors that interfere with libido,erection, ejaculation and orgasm. Neurogenic sexual dysfunction may result from a specific neurologic problem or it could be the presenting symptom of a developing neurologic disease. Neurologic ED could result from complications of chronic neurologic disorders, trauma, surgical injury or iatrogenic causes. These etiologic factors and the underlying pathophysiologic conditions could overlap, which should be considered when making a diagnosis and selecting a treatment. A detailed history of physical examination, neurologic disorders, as well as any past history of psychological and psychiatric disturbances, and a thorough neurological examination will provide better understanding of the underlying causes of neurogenic sexual dysfunction. In patients with spinal cord injury, the location of the lesion and the time of onset of injury should be determined. Therapeutic strategies against erectile dysfunction are initiated with the least invasive options using the phosphodiesterase inhibitors. When oral medication options are exhausted, intraurethral and intracavernosal therapies and ultimately vacuum constriction devices and penile implants are considered. Recent basic research has suggested the potential role of stem cell-based therapeutic strategies to protect penile neural integrity and reverse cavernosal neurodegeneration in experimental models. Further insight into the central, spinal and peripheral neural mechanisms of male sexual response may help precise diagnosis and better management of neurogenic sexual dysfunction in men.

神经损伤是轮胎橡胶衍生污染物6PPDQ引起虹鳟急性毒性的重要原因

N-(1,3-dimethylbutyl)-N’-phenyl-p-phenylenediamine quinone(6PPDQ)has attracted significant attention due to its highly acute lethality to sensitive salmonids.However,studies investigating the mechanisms underlying its acute toxicity have been lacking.In this work,we demonstrated the sensitivity of rainbow trout to 6PPDQ-induced mortality.Moribund trout exhibited significantly higher brain concentrations of 6PPDQ compared to surviving trout.In an in vitro model using human brain microvascular endothelial cells,6PPDQ can penetrate the blood–brain barrier and enhance blood–brain barrier permeability without compromising cell viability.The time spent in the top of the tank increased with rising6PPDQ concentrations,as indicated by locomotion behavior tests.Furthermore,6PPDQ influenced neurotransmitter levels and m RNA expression of neurotransmission-related genes in the brain and exhibited strong binding affinity to target neurotransmission-related proteins using computational simulations.The integrated biomarker response value associated with neurotoxicity showed a positive linear correlation with trout mortality.These findings significantly contribute to filling the knowledge gap between neurological impairments and apical outcomes,including behavioral effects and mortality,induced by6PPDQ.