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BACKGROUND: Anti-IgLON5 disease is a rare neurological disorder associated with autoantibodies against the neuronal cell adhesion protein, IgLON5. Cellular investigations with human IgLON5 antibodies have suggested an antibody-mediated pathogenesis, but whether human IgLON5 autoantibodies can induce disease symptoms in mice is yet to be shown. Moreover, the effects of anti-IgLON5 autoantibodies on neurons and the precise molecular mechanisms in vivo remain controversial. METHODS: We investigated the effects of anti-IgLON5 antibodies in vivo and evaluated their long-term effects. We used two independent passive-transfer animal models and evaluated the effects of the antibodies on mouse behaviors at different time points from day 1 until day 30 after IgG infusion. A wide range of behaviors, including tests of locomotion, coordination, memory, anxiety, depression and social interactions were established. At termination, brain tissue was analyzed for human IgG, neuronal markers, glial markers, synaptic markers and RNA sequencing. RESULTS: These experiments showed that patient's anti-IgLON5 antibodies induced progressive and irreversible behavioral deficits in vivo. Notably, cognitive abnormality was supported by impaired average gamma power in the CA1 during novel object recognition testing. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies in the hippocampus of anti-IgLON5 IgG-injected mice, which persisted 30 days after the injection of patient's antibodies was stopped. Microglial and astrocyte density was increased in the hippocampus of anti-IgLON5 IgG-injected mice at Day 30. Whole-cell voltage clamp recordings proved that anti-IgLON5 antibodies affected synaptic homeostasis. Further western blot investigation of synaptic proteins revealed a reduction of presynaptic (synaptophysin) and post-synaptic (PSD95 and NMDAR1) expression in anti-IgLON5 IgG-injected mice. CONCLUSIONS: Overall, our findings indicated an irreversible effect of anti-IgLON5 antibodies and supported the pathogenicity of these antibodies in vivo.
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Moléculas de Adhesión Celular Neuronal , Enfermedades del Sistema Nervioso , Animales , Autoanticuerpos , Moléculas de Adhesión Celular Neuronal/metabolismo , Inmunoglobulina G/farmacología , Ratones , Enfermedades del Sistema Nervioso/patología , NeuronasRESUMEN
BACKGROUND: We conducted this study to describe detailed the clinical characteristics, ancillary test results and treatment response of a group of Chinese patients with anti-IgLON5 disease. METHODS: We recruited 13 patients with positive IgLON5 antibodies in serum and/or cerebrospinal fluid from nine tertiary referral centers. Patients were enrolled from February 2017 to July 2021. We retrospectively collected information on the presenting and main symptoms, treatment response and follow-up outcomes. RESULTS: The median age of onset for symptoms was 60 (range: 33-73) years and six of the 13 patients were females. The predominant clinical presentations included sleep disturbance (eight patients) and cognitive impairment (seven patients), followed by movement disorders (six patients). Parainfectious cause seemed plausible. Notably, we identified the first case of possible Epstein-Barr virus (EBV)-related anti-IgLON5 disease. Coexisting neural autoantibodies were identified in two patients. Furthermore, two patients had other autoimmune diseases. The IgG subclass was determined in four patients, including two with dominant IgG4 subtype and two with dominant IgG1 subtype. Additionally, 10 patients were treated with immunotherapy and four patients exhibited improvement. Overall, six of 10 patients for whom follow-up results were assessable had favorable clinical outcomes (modified Rankin Scale score ≤2). CONCLUSIONS: The clinical spectrum of anti-IgLON5 disease is variable. Our results highlight a boarder spectrum of anti-IgLON5 disease.
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Infecciones por Virus de Epstein-Barr , Enfermedad de Hashimoto , Adulto , Anciano , Autoanticuerpos , Moléculas de Adhesión Celular Neuronal , Femenino , Herpesvirus Humano 4 , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.
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Movimientos Oculares/fisiología , Vías Nerviosas/fisiología , Receptores Muscarínicos/genética , Sueño/fisiología , Área Tegmental Ventral/fisiología , Animales , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacología , Dopamina/metabolismo , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/fisiología , Núcleo Dorsal del Rafe/anatomía & histología , Núcleo Dorsal del Rafe/efectos de los fármacos , Núcleo Dorsal del Rafe/fisiología , Electrodos Implantados , Electroencefalografía , Genes Reporteros , Ácido Iboténico/toxicidad , Locus Coeruleus/anatomía & histología , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiología , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Mesencéfalo/anatomía & histología , Mesencéfalo/efectos de los fármacos , Mesencéfalo/fisiología , Vías Nerviosas/anatomía & histología , Vías Nerviosas/efectos de los fármacos , Optogenética , Porción Compacta de la Sustancia Negra/anatomía & histología , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Porción Compacta de la Sustancia Negra/fisiología , Ratas , Ratas Sprague-Dawley , Receptores Muscarínicos/metabolismo , Privación de Sueño/fisiopatología , Técnicas Estereotáxicas , Área Tegmental Ventral/anatomía & histología , Área Tegmental Ventral/efectos de los fármacos , Vigilia/fisiología , Ácido gamma-Aminobutírico/metabolismo , Proteína Fluorescente RojaRESUMEN
Adenosine (AD) is a nucleic acid component that is critical for energy metabolism in the body. AD modulates numerous neural functions in the central nervous system, including the sleep-wake cycle. Previous studies have indicated that the A1 receptor (A1R) or A2A receptor (A2AR) may mediate the effects of AD on the sleep-wake cycle. The hypothalamic ventrolateral preoptic area (VLPO) initiates and maintains normal sleep. Histological studies have shown A1R are widely expressed in brain tissue, whereas A2AR expression is limited in the brain and undetectable in the VLPO. We hypothesize therefore, that AD modulates the sleep-wake cycle through A1R in the VLPO. In the present study, bilateral microinjection of AD or an AD transporter inhibitor (s-(4-nitrobenzyl)-6-thioinosine) into the VLPO of rats decreased non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. An A1R agonist (N6-cyclohexyladenosine) produced similar effects in the VLPO. Microinjection of an A1R antagonist (8-cyclopentyl-1,3-dimethylxanthine) into the VLPO enhanced NREM sleep and diminished AD-induced wakefulness. These data indicate that AD enhances wakefulness in the VLPO via A1R in rats.
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Adenosina/administración & dosificación , Área Preóptica/metabolismo , Receptor de Adenosina A1/fisiología , Vigilia/efectos de los fármacos , Adenosina/farmacología , Animales , Masculino , Microinyecciones , Ratas , Ratas Sprague-DawleyRESUMEN
The management of autoimmune encephalitis (AE) with immunotherapy is non-standardized, especially in refractory AE. Ofatumumab (OFA), an anti-CD20 antibody, has not been reported in the treatment of AE. This study presented three AE cases that received the OFA treatment. OFA was administered subcutaneously at a dose of 20 mg two or three times within three weeks. There were some mild adverse effects, including low-grade fever and dizziness. They had favorable responses (reduced antibody titer and clinical symptom improvement). Their symptoms were stable and even improved during a three-month follow-up. Thus, OFA injection is demonstrated to be safe and effective in treating AE. This is the first report about OFA treatment in AE, depicting its potential as a therapeutic option.
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Anticuerpos Monoclonales , Enfermedades Autoinmunes del Sistema Nervioso , Humanos , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20 , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , RituximabRESUMEN
Anti-IgLON5 disease is a recently defined autoimmune disorder of the nervous system associated with autoantibodies against IgLON5. Given its broad clinical spectrum and extremely complex pathogenesis, as well as difficulties in its early diagnosis and treatment, anti-IgLON5 disease has become the subject of considerable research attention in the field of neuroimmunology. Anti-IgLON5 disease has characteristics of both autoimmunity and neurodegeneration due to the unique activity of the anti-IgLON5 antibody. Neuropathologic examination revealed the presence of a tauopathy preferentially affecting the hypothalamus and brainstem tegmentum, potentially broadening our understanding of tauopathies. In contrast to that seen with other autoimmune encephalitis-related antibodies, basic studies have demonstrated that IgLON5 antibody-induced neuronal damage and degeneration are irreversible, indicative of a potential link between autoimmunity and neurodegeneration in anti-IgLON5 disease. Herein, we comprehensively review and discuss basic and clinical studies relating to anti-IgLON5 disease to better understand this complicated disorder.
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Paraneoplastic amyotrophic lateral sclerosis (ALS) is a rare and special type of ALS. The pathogenesis, clinical presentation, treatment and prognosis remain poorly understood. We herein presented three cases of paraneoplastic ALS. In case 1, we first reported an ALS patient with the positive serum antibodies against both Sry-like high mobility group box 1 (SOX1) and glutamic acid decarboxylase 65 (GAD65). However, immunotherapy did not improve his neurological symptoms. We also reported two ALS patients with renal clear cell carcinoma and chronic myelogenous leukemia. No positive paraneoplastic antibodies were detected in either the serum or the cerebrospinal fluid of the two patients, and their clinical symptoms progressed slowly after tumor treatment. The three cases enriched the existing case pool of this rare disorder. In addition, we have comprehensively reviewed the literature of paraneoplastic ALS. The clinical features, treatment effect and prognosis were summarized to broaden our understanding of paraneoplastic ALS.
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Ginseng is an important medicinal plant benefiting human health for thousands of years. Root disease is the main cause of ginseng yield loss. It is difficult to detect ginseng root disease by manual observation on the changes of leaves, as it takes a long time until symptoms appear on leaves after the infection on roots. In order to detect root diseases at early stages and limit their further spread, an efficient and non-destructive testing (NDT) method is urgently needed. Hyperspectral remote sensing technology was performed in this study to discern whether ginseng roots were diseased. Hyperspectral reflectance of leaves at 325-1,075 nm were collected from the ginsengs with no symptoms on leaves at visual. These spectra were divided into healthy and diseased groups according to the symptoms on roots after harvest. The hyperspectral data were used to construct machine learning classification models including random forest, extreme random tree (ET), adaptive boosting and gradient boosting decision tree respectively to identify diseased ginsengs, while calculating the vegetation indices and analyzing the region of specific spectral bands. The precision rates of the ET model preprocessed by savitzky golay method for the identification of healthy and diseased ginsengs reached 99% and 98%, respectively. Combined with the preliminary analysis of band importance, vegetation indices and physiological characteristics, 690-726 nm was screened out as a specific band for early detection of ginseng root diseases. Therefore, underground root diseases can be effectively detected at an early stage by leaf hyperspectral reflectance. The NDT method for early detection of ginsengs root diseases is proposed in this study. The method is helpful in the prevention and control of root diseases of ginsengs to prevent the reduction of ginseng yield.
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Ischemic stroke (IS) poses a heavy burden on the healthcare system, and revascularization is the most effective treatment. However, ischemia/reperfusion (I/R) injury, one main cause of revascularization complications, significantly hinders IS recovery. Unfortunately, none of the neuroprotectants tested to date has been successfully translated clinically for post-revascularization I/R injury therapy. In multiple pathophysiological processes, apoptosis antagonizing transcription factor (AATF) serves as a cell protector, but its role in neuronal I/R injury is unknown. Therefore, we firstly demonstrated the expression profiles of AATF in a distal middle cerebral artery occlusion/reperfusion (dMCAO/R) model and found that AATF expression was increased in cortical neuron after dMCAO/R. Over-expressing AATF reduced infarct volume, alleviated neuronal death, and promoted neurological functions. Next, we used an oxygen-glucose deprivation/reoxygenation (OGD/R) model to investigate the mechanism of AATF. Results indicated that AATF alleviated OGD/R-induced large-scale DNA fragmentation, which suggested that the protective effect of AATF may be attributed to parthanatos inhibition. After that, we examined the regulatory mechanism of AATF. We found that AATF did not affect poly (ADP-ribose) accumulation and apoptosis-inducing factor (AIF) nucleus translocation. AATF competitively interacted with nuclear AIF, which inhibited AIF from binding DNA. At last, we verified the effect and mechanism of AATF in dMCAO/R model. The present study, for the first time, demonstrates the expression, function, and mechanism of AATF in the context of neuronal I/R injury via dMCAO/R and OGD/R model, which provides new evidence in this area and may facilitate exploring new therapeutic targets.
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Factor Inductor de la Apoptosis , Factores de Transcripción , Factor Inductor de la Apoptosis/genética , NeuronasRESUMEN
Glial fibrillary acidic protein astrocytopathy (GFAP-A) is a rare autoimmune disease of the central nervous system that was newly reported in 2016. Previous studies have speculated that the pathological mechanism and clinical outcome of GFAP-A lie in the demyelination of the central nervous system, but due to the limitations of MR, this conclusion has not been further confirmed from the perspective of neuroimaging. A non-invasive, quantitative measurement of demyelination would be clinically valuable, given its critical role in mediating GFAP-A. Here, we report a case in which we use 18F-florbetapir positron emission tomography-magnetic resonance imaging (PET/MRI) to evaluate myelin recovery with follow-up in the patient with GFAP-A. Our patient displayed a decreased uptake of PET tracer 18F-florbetapir in the brain lesions and lower distribution volume ratio in the damaged white matter lesions compared to the normal-appearing white matter, indicating significant intracranial demyelination. After treatment, the 18F-florbetapir PET/MRI examination showed a significant increase in the uptake of 18F-florbetapir in the brain lesions, along with a reduced Expanded Disability Status Scale score. Although only a small number of patients have been validated, this case first reported 18F-florbetapir PET/MRI could quantitatively and non-invasively assess the myelin recovery in GFAP-A patients, which may lead to improvements in the early diagnosis and long-term prognosis.
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Defensive behavior, a group of responses that evolved due to threatening stimuli, is crucial for animal survival in the natural environment. For defensive measures to be timely and successful, a high arousal state and immediate sleep-to-wakefulness transition are required. Recently, the glutamatergic basal forebrain (BF) has been implicated in sleep-wake regulation; however, the associated physiological functions and underlying neural circuits remain unknown. Here, using in vivo fiber photometry, we found that BF glutamatergic neuron is activated by various threatening stimuli, including predator odor, looming threat, sound, and tail suspension. Optogenetic activation of BF glutamatergic neurons induced a series of context-dependent defensive behaviors in mice, including escape, fleeing, avoidance, and hiding. Similar to the effects of activated BF glutamatergic cell body, photoactivation of BF glutamatergic terminals in the ventral tegmental area (VTA) strongly drove defensive behaviors in mice. Using synchronous electroencephalogram (EEG)/electromyogram (EMG) recording, we showed that photoactivation of the glutamatergic BF-VTA pathway produced an immediate transition from sleep to wakefulness and significantly increased wakefulness. Collectively, our results clearly demonstrated that the glutamatergic BF is a key neural substrate involved in wakefulness and defensive behaviors, and encodes these behaviors through glutamatergic BF-VTA pathway. Overexcitation of the glutamatergic BF-VTA pathway may be implicated in clinical psychiatric diseases characterized by exaggerated defensive responses, such as autism spectrum disorders.
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Prosencéfalo Basal , Vigilia , Animales , Prosencéfalo Basal/fisiología , Electroencefalografía/métodos , Mesencéfalo , Ratones , Sueño/fisiología , Vigilia/fisiologíaRESUMEN
Autoimmune neurologic diseases are a new category of immune-mediated disease demonstrating a widely varied spectrum of clinical manifestations. Recently, sleep disturbances in patients with autoimmune neurologic diseases have been reported to have an immense negative impact on the quality of life. Excessive daytime sleep, rapid eye movement sleep behavior disorder (RBD), and narcolepsy are the most frequent sleep disorders associated with autoimmune neurologic diseases. Sleep disturbances might be the initial symptoms of disease or persist throughout the course of the disease. In this review, we have discussed sleep disturbances in different autoimmune neurologic diseases and their potential pathophysiological mechanisms.
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The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells (OPCs) to differentiate, since OPCs and oligodendrocyte-lineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid (SA) is mainly derived from star anise, and is reported to have anti-influenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis (EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination. Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated mTOR. Taken together, our results demonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.
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Diferenciación Celular/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Remielinización/efectos de los fármacos , Ácido Shikímico/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Enfermedades Desmielinizantes/prevención & control , Encefalitis/prevención & control , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Ratones Endogámicos C57BL , Proteína Básica de Mielina/metabolismo , Células Precursoras de Oligodendrocitos/metabolismo , Ratas , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Glutamate is the major excitatory neurotransmitter in the brain and plays an essential role in regulating wakefulness. Histaminergic neurons, which are exclusively localized in the tuberomammillary nucleus (TMN) of the hypothalamus, have a pivotal role in the regulation of sleep-wake patterns by sending widespread projections into many brain areas implicated in sleep-wake control. The role of glutamate in histaminergic neurons within the TMN and the resulting sleep-wake profile remains unknown. We found that glutamate, NMDA, AMPA or dihydrokainate, a glutamate-uptake inhibitor, dose-dependently increased wakefulness when microinjected into the rat TMN. Glutamate, NMDA, and AMPA also increased the firing rate of action potentials in TMN histaminergic neurons. The arousal-promoting effect of glutamate was inhibited by NMDA and histamine H1 receptor antagonists. Furthermore, MK-801, an NMDA receptor antagonist, inhibited the firing rate of histaminergic neurons and increased non-rapid eye movement sleep after microinjection into rat TMN. Taken together, these findings demonstrated that glutamate activated histaminergic neurons in the TMN and increased wakefulness in rats, possibly via the action of NMDA and histamine H1 receptors.
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Ácido Glutámico/farmacología , Área Hipotalámica Lateral/efectos de los fármacos , Receptores Histamínicos/metabolismo , Promotores de la Vigilia/farmacología , Vigilia/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Antagonistas de los Receptores Histamínicos H1/farmacología , Área Hipotalámica Lateral/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Sueño/efectos de los fármacos , Sueño/fisiología , Técnicas de Cultivo de Tejidos , Vigilia/fisiologíaRESUMEN
Spinal cord injury (SCI) is a devastating type of central nervous system (CNS) trauma with limited therapeutic treatments. The polarization of microglia into the M1 or M2 state has been documented to play important roles in the pathogenesis of SCI, although the complete repertoire of underlying factors has not been identified. Interestingly, the time point at which hematomyelia (intramedullary spinal cord hemorrhage) is alleviated coincides with a decrease in the number of M2 microglia. Here the function of Hemopexin (Hpx), a hematogenous glycoprotein, was examined in the crush model of SCI. Hpx levels were elevated at the lesion site during hematomyelia and were synchronously correlated with the level of the M2 marker Arginase-1 (Arg-1). Ablation of Hpx in vivo affected the polarization state of lipopolysaccharide (LPS)-stimulated microglia, as mirrored by a lower percentage of M2 microglia and a higher percentage of M1 microglia in the lesion site, which delayed the recovery and exacerbated the behavioral dysfunction after SCI. However, Hpx induced a rapid switch from the M1 to M2 phenotype in LPS-stimulated primary cultured microglia in a heme scavenging-independent manner. The supernant of Hpx-treated microglia ameliorated neuronal degeneration, alleviated demyelination, and promoted oligodendrocyte precursor cell (OPC) maturation. This modulatory effect of Hpx on microglia polarization was at least partially mediated by the LRP-1 receptor. Based on these results, Hpx is considered a novel modulator of the polarization of microglia during the pathogenesis of SCI and may play a crucial role in the recovery from SCI.
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Arginasa/metabolismo , Hemopexina/metabolismo , Microglía/metabolismo , Traumatismos de la Médula Espinal/sangre , Animales , Polaridad Celular/efectos de los fármacos , Polaridad Celular/fisiología , Células Cultivadas , Hemopexina/farmacología , Lipopolisacáridos/farmacología , Ratones , Microglía/efectos de los fármacos , Microglía/patología , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Células Precursoras de Oligodendrocitos/patología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patologíaRESUMEN
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system. Currently, there is no drug available to cure this kind of disease. Diosgenin is a plant-derived steroid saponin. A previous study in our lab revealed that diosgenin can promote oligodendrocyte progenitor cell differentiation and accelerate remyelination. In the present study, we found that diosgenin dose-dependently alleviated the progression of experimental autoimmune encephalomyelitis with reduced central nervous system inflammation and demyelination. We also found that diosgenin treatment can significantly inhibit the activation of microglia and macrophages, suppress CD4+ T cell proliferation and hinder Th1/Th17 cell differentiation. Therefore, we suggested that diosgenin may be a potential therapeutic drug for inflammatory demyelinating diseases, such as MS.
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Antiinflamatorios/uso terapéutico , Diosgenina/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Animales , Antígenos CD/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Encefalitis/tratamiento farmacológico , Encefalitis/etiología , Encefalomielitis Autoinmune Experimental/complicaciones , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/patología , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
RATIONAL: Neuropathic pain is frequently comorbid with sleep disturbances. Paeoniflorin, a main active compound of total glucosides of paeony, has been well documented to exhibit neuroprotective bioactivity. OBJECTIVE: The present study evaluated effects of paeoniflorin on neuropathic pain and associated insomnia and the mechanisms involved. METHODS: The analgesic and hypnotic effects of paeoniflorin were measured by mechanical threshold and thermal latency, electroencephalogram (EEG) and electromyogram, and c-Fos expression in a neuropathic pain insomnia model. RESULTS: The data revealed that paeoniflorin (50 or 100 mg/kg, i.p.) significantly increased the mechanical threshold and prolonged the thermal latency in partial sciatic nerve ligation (PSNL) mice. Meanwhile, paeoniflorin increased non-rapid eye movement (NREM) sleep amount and concomitantly decreased wakefulness time. However, pretreatment with l,3-dimethy-8-cyclopenthylxanthine, an adenosine A1 receptor (R, A1R) antagonist, abolished the analgesic and hypnotic effects of paeoniflorin. Moreover, paeoniflorin at 100 mg/kg failed to change mechanical threshold and thermal latency and NREM sleep in A1R knockout PSNL mice. Immunohistochemical study showed that paeoniflorin inhibited c-Fos overexpression induced by PSNL in the anterior cingulate cortex and ventrolateral periaqueductal gray. CONCLUSIONS: The present findings indicated that paeoniflorin exerted analgesic and hypnotic effects via adenosine A1Rs and might be of potential use in the treatment of neuropathic pain and associated insomnia.
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Analgésicos/farmacología , Glucósidos/farmacología , Hipnóticos y Sedantes/farmacología , Monoterpenos/farmacología , Neuralgia/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Receptor de Adenosina A1/efectos de los fármacos , Antagonistas del Receptor de Adenosina A1/farmacología , Animales , Electroencefalografía/efectos de los fármacos , Electromiografía/efectos de los fármacos , Glucósidos/antagonistas & inhibidores , Ratones , Ratones Noqueados , Monoterpenos/antagonistas & inhibidores , Umbral del Dolor/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Desempeño Psicomotor/efectos de los fármacos , Receptor de Adenosina A1/genética , Nervio Ciático/patología , Sueño/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológicoRESUMEN
The basal forebrain (BF) cholinergic neurons have long been thought to be involved in behavioral wakefulness and cortical activation. However, owing to the heterogeneity of BF neurons and poor selectivity of traditional methods, the precise role of BF cholinergic neurons in regulating the sleep-wake cycle remains unclear. We investigated the effects of cell-selective manipulation of BF cholinergic neurons on the sleep-wake behavior and electroencephalogram (EEG) power spectrum using the pharmacogenetic technique, the 'designer receptors exclusively activated by designer drugs (DREADD)' approach, and ChAT-IRES-Cre mice. Our results showed that activation of BF cholinergic neurons expressing hM3Dq receptors significantly and lastingly decreased the EEG delta power spectrum, produced low-delta non-rapid eye movement sleep, and slightly increased wakefulness in both light and dark phases, whereas inhibition of BF cholinergic neurons expressing hM4Di receptors significantly increased EEG delta power spectrum and slightly decreased wakefulness. Next, the projections of BF cholinergic neurons were traced by humanized Renilla green fluorescent protein (hrGFP). Abundant and highly dense hrGFP-positive fibers were observed in the secondary motor cortex and cingulate cortex, and sparse hrGFP-positive fibers were observed in the ventrolateral preoptic nucleus, a known sleep-related structure. Finally, we found that activation of BF cholinergic neurons significantly increased c-Fos expression in the secondary motor cortex and cingulate cortex, but decreased c-Fos expression in the ventrolateral preoptic nucleus. Taken together, these findings reveal that the primary function of BF cholinergic neurons is to inhibit EEG delta activity through the activation of cerebral cortex, rather than to induce behavioral wakefulness.
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Prosencéfalo Basal/fisiología , Neuronas Colinérgicas/fisiología , Ritmo Delta , Sueño , Vigilia , Animales , Prosencéfalo Basal/citología , Corteza Cerebral/citología , Neuronas Colinérgicas/citología , Electroencefalografía , Masculino , Ratones , Ratones Transgénicos , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Fases del SueñoRESUMEN
To evaluate the antinociceptive and hypnotic effects of pregabalin, we established a neuropathic pain-like model in mice using partial sciatic nerve ligation (PSNL), and examined thermal hyperalgesia, mechanical allodynia, electroencephalogram, rota-rod testing, and c-Fos expression in the anterior cingulate cortex. Gabapentin was used as a reference drug in the study. Pregabalin administered i.g. at 12.5 and 25mg/kg prolonged the duration of thermal latencies by 1.4- and 1.6-fold and increased the mechanical threshold by 2.2- and 3.1-fold 3h after administration, respectively, but did not affect motor coordination in PSNL mice, compared with vehicle control. Pregabalin (12.5 and 25mg/kg) given at 6:30 increased the amount of non-rapid eye movement sleep in a 4-h period by 1.3- and 1.4-fold, respectively, in PSNL mice. However, pregabalin (25mg/kg) given at 20:30 did not alter the sleep pattern in normal mice. Immunohistochemical study showed that PSNL increased c-Fos expression in the neurons of anterior cingulate cortex by 2.1-fold, which could be reversed by pregabalin. These results indicate that pregabalin is an effective treatment for both neuropathic pain and sleep disturbance in PSNL mice.