Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies.

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression.

Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia-neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.

The Alterations in the Brain Corresponding to Low Back Pain: Recent Insights and Advances.

Low back pain (LBP) is a leading cause of global disabilities. Numerous molecular, cellular, and anatomical factors are implicated in LBP. Current issues regarding neurologic alterations in LBP have focused on the reorganization of peripheral nerve and spinal cord, but neural mechanisms of exactly what LBP impacts on the brain required further researches. Based on existing clinical studies that chronic pain problems were accompanying alterations in brain structures and functions, researchers proposed logical conjectures that similar alterations occur in LBP patients as well. With recent extensive studies carried out using noninvasive neuroimaging technique, increasing number of abnormalities and alterations has been identified. Here, we reviewed brain alterations including white matters, grey matters, and neural circuits between brain areas, which are involved in chronic LBP. Moreover, brain structural and functional connectivity abnormalities are correlated to the happening and transition of LBP. The negative emotions related to back pain indicate possible alterations in emotional brain regions. Thus, the aim of this review is to summarize current findings on the alterations corresponding to LBP in the brain. It will not only further our understanding of etiology of LBP and understanding of negative emotions accompanying with back pain but also provide ideas and basis for new accesses to the diagnosis, treatment, and rehabilitation afterward based on integral medicine.

High-efficiency recovery of valuable metals from spent lithium-ion batteries: Optimization of SO2 pressure leaching and selective extraction of trace impurities.

The recovery of valuable metals from spent lithium-ion batteries (LIBs) is crucial for environmental protection and resource optimization. In the traditional recovery process of spent LIBs, the leaching of high-valence metals has the problems of high cost and limited reagent utilization, and some valuable metals are lost in the subsequent purification process of the leaching solution. To reduce the cost of reagents, this study proposes the use of low-cost SO2 as a reagent combined with pressure leaching to efficiently recover high-valence metals from delithiated materials of spent LIBs, while selective solvent extraction is used to remove trace impurities in the leaching solution to avoid the loss of valuable metals. Experimental results demonstrated that by optimizing the conditions to 0.25 MPa SO2 partial pressure and 60 min reaction time at 70 °C, the leaching efficiencies for Ni, Co, and Mn reached 99.6%, 99.3%, and 99.6%, respectively. The kinetic study indicated that the leaching process was diffusion-controlled. Furthermore, the delithiated materials were used to completely utilize the residual SO2 in the solution to obtain a high concentration Ni-Co-Mn rich solution. Subsequently, Fe and Al impurities were deeply removed through a synergistic extraction of Di-2-ethylhexyl phosphoric acid (D2EHPA) and tributyl phosphate (TBP) without loss of valuable metals, achieving a high-purity Ni-Co-Mn solution. The process developed based on this work has the characteristics of environmental friendliness, high valuable metal recovery, and high product purity, providing a reference technical method for the synergistic treatment of waste SO2 flue gas with spent LIBs and the deep purification of impurities in spent LIBs.

Taurine Alleviates Chronic Social Defeat Stress-Induced Depression by Protecting Cortical Neurons from Dendritic Spine Loss.

Abnormal amino acid metabolism in neural cells is involved in the occurrence and development of major depressive disorder. Taurine is an important amino acid required for brain development. Here, microdialysis combined with metabonomic analysis revealed that the level of taurine in the extracellular fluid of the cerebral medial prefrontal cortex (mPFC) was significantly reduced in mice with chronic social defeat stress (CSDS)-induced depression. Therefore, taurine supplementation may be usable an intervention for depression. We found that taurine supplementation effectively rescued immobility time during a tail suspension assay and improved social avoidance behaviors in CSDS mice. Moreover, taurine treatment protected CSDS mice from impairments in dendritic complexity, spine density, and the proportions of different types of spines. The expression of N-methyl D-aspartate receptor subunit 2A, an important synaptic receptor, was largely restored in the mPFC of these mice after taurine supplementation. These results demonstrated that taurine exerted an antidepressive effect by protecting cortical neurons from dendritic spine loss and synaptic protein deficits.

Microfluidic Biosensor Based on Molybdenum Disulfide (MoS2) Modified Thin-Core Microfiber for Immune Detection of Toxoplasma gondii.

Toxoplasma gondii (T. gondii) is a zoonotic parasite that is widely distributed and seriously endangers public health and human health. Therefore, accurate and effective detection of T. gondii is crucial. This study proposes a microfluidic biosensor using a thin-core microfiber (TCMF) coated with molybdenum disulfide (MoS2) for immune detection of T. gondii. The single-mode fiber was fused with the thin-core fiber, and the TCMF was obtained by arc discharging and flame heating. In order to avoid interference and protect the sensing structure, the TCMF was encapsulated in the microfluidic chip. MoS2 and T. gondii antigen were modified on the surface of TCMF for the immune detection of T. gondii. Experimental results showed that the detection range of the proposed biosensor for T. gondii monoclonal antibody solutions was 1 pg/mL to 10 ng/mL with sensitivity of 3.358 nm/log(mg/mL); the detection of limit was calculated to be 87 fg/mL through the Langmuir model; the dissociation constant and the affinity constant were calculated to be about 5.79 × 10-13 M and 1.727 × 1014 M-1, respectively. The specificity and clinical characteristics of the biosensor was explored. The rabies virus, pseudorabies virus, and T. gondii serum were used to confirm the excellent specificity and clinical characteristics of the biosensor, indicating that the proposed biosensor has great application potential in the biomedical field.

Eco-friendly extraction of arsenic and tungsten from hazardous tungsten residue waste by pressure oxidation leaching in alkaline solutions: Mechanism and kinetic model.

Tungsten residue waste (TRW), considered an environmental burden due to high content and excessive leaching toxicity of arsenic (As), are also secondary tungsten (W) resources. A novel method for simultaneous extraction of arsenic and tungsten from TRW via alkaline pressure oxidative leaching was proposed. The results show that As in the TRW mainly exists in the form of As coprecipitated with Mn(Ⅱ) oxides and FeAsS. In addition, As coprecipitated with Mn(Ⅱ) oxides and W are encapsulated in Fe, Mn oxides. The structure of Fe, Mn oxides with dense surface can be destroyed and the chemically stable arsenopyrite can be efficiently oxidized by oxygen in alkaline solutions. The leaching efficiency of As and S reached 97% and 99% at 80 min, respectively, while that of W reached 82% at 10 min. The leaching rate of As and S is controlled by diffusion with the apparent activation energies of 16.67 kJ/mol and 15.66 kJ/mol, respectively. Compared with TRW, the leaching toxicity of As in the leach residue decreased from 10.2 mg/L to only 0.071 mg/L. The new process suggests new possibilities for removal and recovery of As and W from TRW that will contribute to circular economy and environmental protection.

Quercetin ameliorates memory impairment by inhibiting abnormal microglial activation in a mouse model of paradoxical sleep deprivation.

Paradoxical sleep deprivation (PSD) is prevalent in modern society, and impaired memory is one of its serious consequences. The pathogenic mechanism is still unclear, and the therapeutic strategies for PSD are limited. Here, we found that quercetin treatment ameliorated memory impairments caused by PSD in a dose-dependent manner in an animal model. Quercetin could restore the dynamic changes of the gamma band while the animals performed novel object recognition (NOR) tasks as determined by electroencephalogram analysis. Morphological analysis showed that quercetin, by targeting the hippocampal CA1 region, strikingly ameliorated the overactivation of microglia induced by PSD. Mechanistically, quercetin inhibited the toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa-b (NF-κB) cascade, which is critical for abnormal microglial activation following PSD stress. Our results provided experimental evidence for the therapeutic effects of quercetin on PSD-related memory impairments by suppressing TLR4/MyD88/NF-κB signaling that mediated abnormal microglia activation in the hippocampus.

ZFP804A mutant mice display sex-dependent schizophrenia-like behaviors.

Genome-wide association studies uncovered the association of ZNF804A (Zinc-finger protein 804A) with schizophrenia (SZ). In vitro data have indicated that ZNF804A might exert its biological roles by regulating spine and neurite morphogenesis. However, no in vivo data are available for the role of ZNF804A in psychiatric disorders in general, SZ in particular. We generated ZFP804A mutant mice, and they showed deficits in contextual fear and spatial memory. We also observed the sensorimotor gating impairment, as revealed by the prepulse inhibition test, but only in female ZFP804A mutant mice from the age of 6 months. Notably, the PPI difference between the female mutant and control mice was no longer existed with the administration of Clozapine or after the ovariectomy. Hippocampal long-term potentiation was normal in both genders of the mutant mice. Long-term depression was absent in male mutants, but facilitated in the female mutants. Protein levels of hippocampal serotonin-6 receptor and GABAB1 receptor were increased, while those of cortical dopamine 2 receptor were decreased in the female mutants with no obvious changes in the male mutants. Moreover, the spine density was reduced in the cerebral cortex and hippocampus of the mutant mice. Knockdown of ZFP804A impaired the neurite morphogenesis of cortical and hippocampal neurons, while its overexpression enhanced neurite morphogenesis only in the cortical neurons in vitro. Our data collectively support the idea that ZFP804A/ZNF804A plays important roles in the cognitive functions and sensorimotor gating, and its dysfunction may contribute to SZ, particularly in the female patients.

Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer's disease pathologies.

BDNF, an essential trophic factor implicated in synaptic plasticity and neuronal survival, is reduced in Alzheimer's disease (AD). BDNF deficiency's association with Tau pathology in AD is well documented. However, the molecular mechanisms accounting for these events remain incompletely understood. Here we show that BDNF deprivation triggers Tau proteolytic cleavage by activating δ-secretase [i.e., asparagine endopeptidase (AEP)], and the resultant Tau N368 fragment binds TrkB receptors and blocks its neurotrophic signals, inducing neuronal cell death. Knockout of BDNF or TrkB receptors provokes δ-secretase activation via reducing T322 phosphorylation by Akt and subsequent Tau N368 cleavage, inducing AD-like pathology and cognitive dysfunction, which can be restored by expression of uncleavable Tau N255A/N368A mutant. Blocking the Tau N368-TrkB complex using Tau repeat-domain 1 peptide reverses this pathology. Thus, our findings support that BDNF reduction mediates Tau pathology via activating δ-secretase in AD.

Leonurine Reduces Oxidative Stress and Provides Neuroprotection against Ischemic Injury via Modulating Oxidative and NO/NOS Pathway.

Leonurine (Leo) has been found to have neuroprotective effects against cerebral ischemic injury. However, the exact molecular mechanism underlying its neuroprotective ability remains unclear. The aim of the present study was to investigate whether Leo could provide protection through the nitric oxide (NO)/nitric oxide synthase (NOS) pathway. We firstly explored the effects of NO/NOS signaling on oxidative stress and apoptosis in in vivo and in vitro models of cerebral ischemia. Further, we evaluated the protective effects of Leo against oxygen and glucose deprivation (OGD)-induced oxidative stress and apoptosis in PC12 cells. We found that the rats showed anxiety-like behavior, and the morphology and number of neurons were changed in a model of photochemically induced cerebral ischemia. Both in vivo and in vitro results show that the activity of superoxide dismutase (SOD) and glutathione (GSH) contents were decreased after ischemia, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels were increased, indicating that cerebral ischemia induced oxidative stress and neuronal damage. Moreover, the contents of NO, total NOS, constitutive NOS (cNOS) and inducible NOS (iNOS) were increased after ischemia in rat and PC12 cells. Treatment with L-nitroarginine methyl ester (L-NAME), a nonselective NOS inhibitor, could reverse the change in NO/NOS expression and abolish these detrimental effects of ischemia. Leo treatment decreased ROS and MDA levels and increased the activity of SOD and GSH contents in PC12 cells exposed to OGD. Furthermore, Leo reduced NO/NOS production and cell apoptosis, decreased Bax expression and increased Bcl-2 levels in OGD-treated PC12 cells. All the data suggest that Leo protected against oxidative stress and neuronal apoptosis in cerebral ischemia by inhibiting the NO/NOS system. Our findings indicate that Leo could be a potential agent for the intervention of ischemic stroke and highlighted the NO/NOS-mediated oxidative stress signaling.

New Insights into TETs in Psychiatric Disorders.

Psychiatric disorders are complex and heterogeneous disorders arising from the interaction of multiple factors based on neurobiology, genetics, culture, and life experience. Increasing evidence indicates that sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Over the past decade, the critical, non-redundant roles of the ten-eleven translocation (TET) family of dioxygenase enzymes have been identified in the brain during developmental and postnatal stages. Specifically, TET-mediated active demethylation, involving the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and subsequent oxidative derivatives, is dynamically regulated in response to environmental stimuli such as neuronal activity, learning and memory processes, and stressor exposure. Here, we review the progress of studies designed to provide a better understanding of how profiles of TET proteins and 5hmC are powerful mechanisms by which to explain neuronal plasticity and long-term behaviors, and impact transcriptional programs operative in the brain that contribute to psychiatric disorders.

An auto real-time jump tagging system for exploring stereotyped jumping behavior in mice.

The jump is one of the common stereotyped behavior in rodents which can be found in certain types of disease models, such as addiction. It can be easily identified by the human eye. However, it is difficult to be tagged in real-time by manual operation, which limits the detailed exploration of its neural mechanisms with the new techniques, such as fiber photometry recording. Here we introduced an auto real-time jump tagging system (Art-JT system) to record the jump based on online monitoring the pressure changes of the floor in which the mouse is free exploring. Meanwhile, the Art-JT system can send the digital signal of the jump timing to the external device for tagging the events in the fiber photometry system. We tested it with the mice induced by Naloxone precipitated withdrawal jumping and found that it could accurately record the jump events and provide several detailed parameters of the jump. We also confirmed that the jump was correlated with the medial prefrontal cortex and primary motor cortex neuronal activities by combining the Art-JT system, GCaMP6 mice, and fiber photometry system. Our results suggested that the Art-JT system may be a powerful tool for recording and analyzing jumps efficiently and helping us to understand stereotyped behavior.

LF-rTMS ameliorates social dysfunction of FMR1-/- mice via modulating Akt/GSK-3ß signaling.

Autism spectrum disorders (ASD) are a group of neurological disorders which affect approximately 1% of children around the world. Social dysfunction is one of the two core syndromes of ASD, and still lacks effective treatment. Transcranial magnetic stimulation (TMS) is a noninvasive and safe procedure that uses magnetic fields to modulate neural activity. Whether it were effective in modulating social function remains unclear. By using 3-chamber test, ultrasonic vocalization recording and Western-blotting, we demonstrated that FMR1 (fragile X mental retardation protein) mutant mice, a model of ASD, exhibited obvious defects in social preference and ultrasonic communication. In addition, we detected increase of p-Akt (S473) and p-GSK-3ß (S9), and decrease of p-PSD-95 (T19) in the anterior cingulate cortex (ACC) of FMR1-/- mice. Treating FMR1-/- mice with 1 Hz repetitive TMS (rTMS) exerted a long lasting effect in improving both the ultrasonic communication and social preference, as well as restoring the levels of Akt/GSK-3ß activity and spine density in the FMR1-/-ACC. Our data, for the first time, demonstrated a beneficial effect of low frequency rTMS (LF-rTMS) on the social function of FMR1-/- mice and an involvement of Akt/GSK-3ß signaling in this process, indicating LF-rTMS as a potential therapeutic strategy for ASD patients.

Chronic intermittent hypoxia alters the dendritic mitochondrial structure and activity in the pre-Bötzinger complex of rats.

Mitochondrial bioenergetics is dynamically coupled with neuronal activities, which are altered by hypoxia-induced respiratory neuroplasticity. Here we report structural features of postsynaptic mitochondria in the pre-Bötzinger complex (pre-BötC) of rats treated with chronic intermittent hypoxia (CIH) simulating a severe condition of obstructive sleep apnea. The subcellular changes in dendritic mitochondria and histochemistry of cytochrome c oxidase (CO) activity were examined in pre-BötC neurons localized by immunoreactivity of neurokinin 1 receptors. Assays of mitochondrial electron transport chain (ETC) complex I, IV, V activities, and membrane potential were performed in the ventrolateral medulla containing the pre-BötC region. We found significant decreases in the mean length and area of dendritic mitochondria in the pre-BötC of CIH rats, when compared to the normoxic control and hypoxic group with daily acute intermittent hypoxia (dAIH) that evokes robust synaptic plasticity. Notably, these morphological alterations were mainly observed in the mitochondria in close proximity to the synapses. In addition, the proportion of mitochondria presented with enlarged compartments and filamentous cytoskeletal elements in the CIH group was less than the control and dAIH groups. Intriguingly, these distinct characteristics of structural adaptability were observed in the mitochondria within spatially restricted dendritic spines. Furthermore, the proportion of moderately to darkly CO-reactive mitochondria was reduced in the CIH group, indicating reduced mitochondrial activity. Consistently, mitochondrial ETC enzyme activities and membrane potential were lowered in the CIH group. These findings suggest that hypoxia-induced respiratory plasticity was characterized by spatially confined mitochondrial alterations within postsynaptic spines in the pre-BötC neurons. In contrast to the robust plasticity evoked by dAIH preconditioning, a severe CIH challenge may weaken the local mitochondrial bioenergetics that the fuel postsynaptic activities of the respiratory motor drive.

TRPC1/4/5 channels contribute to morphine-induced analgesic tolerance and hyperalgesia by enhancing spinal synaptic potentiation and structural plasticity.

Opioid analgesics remain the mainstay for managing intractable chronic pain, but their use is limited by detrimental side effects such as analgesic tolerance and hyperalgesia. Calcium-dependent synaptic plasticity is a key determinant in opiates tolerance and hyperalgesia. However, the exact substrates for this calcium-dependent synaptic plasticity in mediating these maladaptive processes are largely unknown. Canonical transient receptor potential 1, 4, and 5 (TRPC1, 4, 5) proteins assemble into heteromultimeric nonselective cation channels with high Ca2+ permeability and influence various neuronal functions. However, whether and how TRPC1/4/5 channels contribute to the development of opiates tolerance and hyperalgesia remains elusive. Here, we show that TRPC1/4/5 channels contribute to the generation of morphine tolerance and hyperalgesia. Chronic morphine exposure leads to upregulation of TRPC1/4/5 channels in the spinal cord. Spinally expressed TRPC1, TPRC4, and TRPC5 are required for chronic morphine-induced synaptic long-term potentiation (LTP) as well as remodeling of synaptic spines in the dorsal horn, thereby orchestrating functional and structural plasticity during the course of morphine-induced hyperalgesia and tolerance. These effects are attributed to TRPC1/4/5-mediated Ca2+ elevation in the spinal dorsal horn induced by chronic morphine treatment. This study identifies TRPC1/4/5 channels as a promising novel target to prevent the unwanted morphine tolerance and hyperalgesia.

Melatonin pretreatment alleviates the long-term synaptic toxicity and dysmyelination induced by neonatal Sevoflurane exposure via MT1 receptor-mediated Wnt signaling modulation.

Sevoflurane (Sev) is one of the most widely used pediatric anesthetics. The major concern of neonatal repeated application of Sev is its potential long-term impairment of cognition and learning/memory, for which there still lacks effective treatment. At the cellular level, Sev exerts toxic effects in multiple aspects, making it difficult for effective interference. Melatonin is a pineal hormone regulated by and feedbacks to biological rhythm at physiological condition. Recent studies have revealed significant neuroprotective effects of exogenous melatonin or its agonists under various pathological conditions. Whether melatonin could prevent the long-term toxicity of Sev remains elusive. Here, we report that neonatal repeated Sev exposure up-regulated MT1 receptor in hippocampal neurons and oligodendrocytes. Pretreatment with melatonin significantly alleviated Sev-induced synaptic deficiency, dysmyelination, and long-term learning impairment. Both MT1-shRNA and MT1 knockout effectively blocked the protective effects of melatonin on synaptic development, myelination, and behavior performance. Interestingly, long-lasting suppression of Wnt signaling, instead of cAMP/PKA signaling, was observed in hippocampal neurons and oligodendrocytes after neonatal Sev exposure. Pharmacologically activating Wnt signaling rescued both the long-term synaptic deficits and dysmyelination induced by Sev. Further analysis showed that MT1 receptor co-expressed well with ß-catenin and Axin2 and bound to ß-catenin by its C-terminal. Melatonin pretreatment effectively rescued Sev-induced Wnt suppression. Wnt signaling inhibitor XAV939 significantly compromised the protective effects of melatonin. Taken together, our data demonstrated a beneficial effect of melatonin pretreatment on the long-term synaptic impairment and dysmyelination induced by neonatal Sev exposure, and a novel MT1 receptor-mediated interaction between melatonin and canonical Wnt signaling, indicating that melatonin may be clinically applied for improving the safety of pediatric Sev anesthesia.

Olig2 regulates terminal differentiation and maturation of peripheral olfactory sensory neurons.

The bHLH transcription factor Olig2 is required for sequential cell fate determination of both motor neurons and oligodendrocytes and for progenitor proliferation in the central nervous system. However, the role of Olig2 in peripheral sensory neurogenesis remains unknown. We report that Olig2 is transiently expressed in the newly differentiated olfactory sensory neurons (OSNs) and is down-regulated in the mature OSNs in mice from early gestation to adulthood. Genetic fate mapping demonstrates that Olig2-expressing cells solely give rise to OSNs in the peripheral olfactory system. Olig2 depletion does not affect the proliferation of peripheral olfactory progenitors and the fate determination of OSNs, sustentacular cells, and the olfactory ensheathing cells. However, the terminal differentiation and maturation of OSNs are compromised in either Olig2 single or Olig1/Olig2 double knockout mice, associated with significantly diminished expression of multiple OSN maturation and odorant signaling genes, including Omp, Gnal, Adcy3, and Olfr15. We further demonstrate that Olig2 binds to the E-box in the Omp promoter region to regulate its expression. Taken together, our results reveal a distinctly novel function of Olig2 in the periphery nervous system to regulate the terminal differentiation and maturation of olfactory sensory neurons.

Involvement of homodomain interacting protein kinase 2-c-Jun N-terminal kinase/c-Jun cascade in the long-term synaptic toxicity and cognition impairment induced by neonatal Sevoflurane exposure.

Sevoflurane is one of the most widely used anesthetics with recent concerns rising about its pediatric application. The synaptic toxicity and mechanisms underlying its long-term cognition impairment remain unclear. In this study, we investigated the expression and roles of homeodomain interacting protein kinase 2 (HIPK2), a stress activating kinase involved in neuronal survival and synaptic plasticity, and its downstream c-Jun N-terminal kinase (JNK)/c-Jun signaling in the long-term toxicity of neonatal Sevoflurane exposure. Our data showed that neonatal Sevoflurane exposure results in impairment of memory, enhancement of anxiety, less number of excitatory synapses and lower levels of synaptic proteins in the hippocampus of adult rats without significant changes of hippocampal neuron numbers. Up-regulation of HIPK2 and JNK/c-Jun was observed in hippocampal granular neurons shortly after Sevoflurane exposure and persisted to adult. 5-((6-Oxo-5-(6-(piperazin-1-yl)pyridin-3-yl)-1,6-dihydropyridin-3-yl)methylene)thiazolidine-2,4-dione trifluoroacetate, antagonist of HIPK2, could significantly rescue the cognition impairment, decrease in long-term potentiation, reduction in spine density and activation of JNK/c-Jun induced by Sevoflurane. JNK antagonist SP600125 partially restored synapse development and cognitive function without affecting the expression of HIPK2. These data, in together, revealed a novel role of HIPK2-JNK/c-Jun signaling in the long-term synaptic toxicity and cognition impairment of neonatal Sevoflurane exposure, indicating HIPK2-JNK/c-Jun cascade as a potential target for reducing the synaptic toxicity of Sevoflurane. Cover Image for this issue: doi: 10.1111/jnc.14757.

Inhibiting HMGB1-RAGE axis prevents pro-inflammatory macrophages/microglia polarization and affords neuroprotection after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) favors a persistent pro-inflammatory macrophages/microglia-mediated response with only a transient appearance of anti-inflammatory phenotype of immune cells. However, the mechanisms controlling this special sterile inflammation after SCI are still not fully elucidated. It is known that damage-associated molecular patterns (DAMPs) released from necrotic cells after injury can trigger severe inflammation. High mobility group box 1(HMGB1), a ubiquitously expressed DNA binding protein, is an identified DAMP, and our previous study demonstrated that reactive astrocytes could undergo necroptosis and release HMGB1 after SCI in mice. The present study aimed to explore the effects and the possible mechanism of HMGB1on macrophages/microglia polarization, as well as the neuroprotective effects by HMGB1 inhibition after SCI. METHODS: In this study, the expression and the concentration of HMGB1 was determined by qRT-PCR, ELISA, and immunohistochemistry. Glycyrrhizin was applied to inhibit HMGB1, while FPS-ZM1 to suppress receptor for advanced glycation end products (RAGE). The polarization of macrophages/microglia in vitro and in vivo was detected by qRT-PCR, immunostaining, and western blot. The lesion area was detected by GFAP staining, while neuronal survival was examined by Nissl staining. Luxol fast blue (LFB) staining, DAB staining, and western blot were adopted to evaluate the myelin loss. Basso-Beattie-Bresnahan (BBB) scoring and rump-height Index (RHI) assay was applied to evaluate locomotor functional recovery. RESULTS: Our data showed that HMGB1 can be elevated and released from necroptotic astrocytes and HMGB1 could induce pro-inflammatory microglia through the RAGE-nuclear factor-kappa B (NF-κB) pathway. We further demonstrated that inhibiting HMGB1 or RAGE effectively decreased the numbers of detrimental pro-inflammatory macrophages/microglia while increased anti-inflammatory cells after SCI. Furthermore, our data showed that inhibiting HMGB1 or RAGE significantly decreased neuronal loss and demyelination, and improved functional recovery after SCI. CONCLUSIONS: The data implicated that HMGB1-RAGE axis contributed to the dominant pro-inflammatory macrophages/microglia-mediated pro-inflammatory response, and inhibiting this pathway afforded neuroprotection for SCI. Thus, therapies designed to modulate immune microenvironment based on this cascade might be a prospective treatment for SCI.