RESUMEN

Perioperative neurocognitive disorders (PND) are intractable, indistinct, and considerably diminish the postoperative quality of life of patients. It has been proved that Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was involved in neurodegenerative diseases by regulating mitochondrial biogenesis. The underlying mechanisms of PGC-1α and Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in PND are not well understood. In this study, we constructed a model of laparotomy in aged mice, and then examined the cognition changes with novel object recognition tests and fear condition tests. The protein levels of PGC-1α and NLRP3 in the hippocampus were detect after surgery. Our results showed that NLRP3 and downstream PI3K/AKT pathway expressions were augmented in the hippocampus after surgery, whereas, the expressions of PGC-1α/estrogen-related receptor α (ERRα)/Unc-51-like autophagy activating kinase 1 (ULK1) pathway were diminished after surgery. In addition, we found that NLRP3 was mainly co-localized with neurons in the hippocampus, and synaptic-related proteins were reduced after surgery. At the same time, transmission electron microscopy (TEM) showed that mitochondria were impaired after surgery. Pharmacological treatment of MCC950, a selective NLRP3 inhibitor, effectively alleviated PND. Activation of PGC-1α with ZLN005 significantly ameliorated PND by enhancing the PGC-1α/ERRα/ULK1 signaling pathway, and further suppressing NLRP3 activation. As a result, we conclude that suppression of the PGC-1α/ERRα/ULK1 signaling pathway is the primary mechanism of PND which caused mitochondrial dysfunction, and activated NLRP3 inflammasome and downstream PI3K/AKT pathway, eventually improved cognitive dysfunction.

Asunto(s)

Homólogo de la Proteína 1 Relacionada con la Autofagia , Hipocampo , Inflamasomas , Ratones Endogámicos C57BL , Mitocondrias , Proteína con Dominio Pirina 3 de la Familia NLR , Trastornos Neurocognitivos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Receptores de Estrógenos , Transducción de Señal , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Inflamasomas/metabolismo , Ratones , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Hipocampo/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Mitocondrias/metabolismo , Masculino , Receptores de Estrógenos/metabolismo , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/etiología , Envejecimiento/metabolismo , Laparotomía/efectos adversos , Sulfonamidas/farmacología , Furanos , Indenos

RESUMEN

OBJECTIVE: Multiple factors contribute to the development of perioperative neurocognitive disorders (PND). This study was designed to investigate whether Histone Deacetylase 6 (HDAC6) was involved in the formation of postoperative cognitive dysfunction in elderly mice by regulating the degree of acetylation of heat shock protein (HSP90) and related protein functions and quantities. METHODS: C57BL/6 J male mice were randomly divided into six groups: control naive (group Control), anesthesia (group Anesthesia), splenectomy surgery (group Surgery), splenectomy surgery plus dissolvent (group Vehicles), splenectomy surgery plus the inhibitor ACY-1215 (group Ricolinostat), and splenectomy surgery plus the inhibitor RU-486(group Mifepristone). After the mice were trained for Morris Water Maze (MWM) test for five days, anesthesia and operational surgery were carried out the following day. Cognitive function was assessed on the 1st, 3rd and 7th days post-surgery. The hippocampi were harvested on days 1, 3, and 7 post-surgeries for Western blots and ELISA assays. RESULTS: Mice with the splenectomy surgery displayed the activation of the hypothalamic-pituitary-adrenal axis (HPA-axis), marked an increase in adrenocorticotropic hormone (ACTH), glucocorticoid, mineralocorticoid at the molecular level and impaired spatial memory in the MWM test. The hippocampus of surgical groups showed a decrease in acetylated HSP90, a rise in glucocorticoid receptor (GR)-HSP90 association, and an increase in GR phosphorylation and translocation. HDAC6 was increased after the surgical treated. Using two specific inhibitors, HDAC6 inhibitor Ricolinostat (ACY-1215) and GR inhibitor Mifepristone (RU-486), can partially mitigate the effects caused by surgical operation. CONCLUSIONS: Abdominal surgery may impair hippocampal spatial memory, possibly through the HDAC6-triggered increase in the function of HSP90, consequently strengthening the negative role of steroids in cognitive function. Targeting HDAC6- HSP90/GR signaling may provide a potential avenue for the treatment of the impairment of cognitive function after surgery.

Asunto(s)

Proteínas HSP90 de Choque Térmico , Ratones Endogámicos C57BL , Receptores de Glucocorticoides , Transducción de Señal , Animales , Masculino , Ratones , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Histona Desacetilasa 6/antagonistas & inhibidores , Esplenectomía , Complicaciones Cognitivas Postoperatorias/metabolismo , Complicaciones Cognitivas Postoperatorias/etiología , Mifepristona/farmacología , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/etiología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Envejecimiento/metabolismo , Histona Desacetilasas/metabolismo , Pirimidinas/farmacología , Ácidos Hidroxámicos/farmacología

RESUMEN

An increasing number of people undergo anesthesia and surgery. Perioperative neurocognitive and depressive disorders are common central nervous system complications with similar pathogeneses. These conditions pose a deleterious threat to human health and a significant societal burden. In recent years, numerous studies have focused on the role of the gut microbiota and its metabolites in the central nervous system via the gut-brain axis. Its involvement in perioperative neurocognitive and depressive disorders has attracted considerable attention. This review aimed to elucidate the role of the gut microbiota and its metabolites in the pathogenesis of perioperative neurocognitive and depressive disorders, as well as the value of targeted interventions and treatments.

Asunto(s)

Eje Cerebro-Intestino , Trastorno Depresivo , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiología , Eje Cerebro-Intestino/fisiología , Trastorno Depresivo/metabolismo , Trastorno Depresivo/terapia , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/metabolismo , Animales , Encéfalo/metabolismo , Complicaciones Posoperatorias/microbiología

RESUMEN

Background: Perioperative neurocognitive disorders (PND) refer to neurocognitive abnormalities during perioperative period, which are a great challenge for elderly patients and associated with increased morbidity and mortality. Our studies showed that long non-coding RNAs (lncRNAs) regulate mitochondrial function and aging-related pathologies in the aged hippocampus after anesthesia, and lncRNAs are associated with multiple neurodegenerations. However, the regulatory role of lncRNAs in PND-related pathological processes remains unclear. Methods: A total of 18-month mice were assigned to control and surgery (PND) groups, mice in PND group received sevoflurane anesthesia and laparotomy. Cognitive function was assessed with fear conditioning test. Hippocampal RNAs were isolated for sequencing, lncRNA and microRNA libraries were constructed, mRNAs were identified, Gene Ontology (GO) analysis were performed, and lncRNA-microRNA-mRNA networks were established. qPCR was performed for gene expression verification. Results: A total of 312 differentially expressed (DE) lncRNAs, 340 DE-Transcripts of Uncertain Coding Potential (TUCPs), and 2,003 DEmRNAs were identified in the hippocampus between groups. The lncRNA-microRNA-mRNA competing endogenous RNA (ceRNA) network was constructed with 29 DElncRNAs, 90 microRNAs, 493 DEmRNAs, 148 lncRNA-microRNA interaction pairs, 794 microRNA-mRNA interaction pairs, and 110 lncRNA-mRNA co-expression pairs. 795 GO terms were obtained. Based on the frequencies of involved pathological processes, BP terms were divided into eight categories: neurological system alternation, neuronal development, metabolism alternation, immunity and neuroinflammation, apoptosis and autophagy, cellular communication, molecular modification, and behavior changes. LncRNA-microRNA-mRNA ceRNA networks in these pathological categories were constructed, and involved pathways and targeted genes were revealed. The top relevant lncRNAs in these ceRNA networks included RP23-65G6.4, RP24-396L14.1, RP23-251I16.2, XLOC_113622, RP24-496E14.1, etc., and the top relevant mRNAs in these ceRNA networks included Dlg4 (synaptic function), Avp (lipophagy), Islr2 (synaptic function), Hcrt (regulation of awake behavior), Tnc (neurotransmitter uptake). Conclusion: In summary, we have constructed the lncRNA-associated ceRNA network during PND development in mice, explored the role of lncRNAs in multiple pathological processes in the mouse hippocampus, and provided insights into the potential mechanisms and therapeutic gene targets for PND.

Asunto(s)

Redes Reguladoras de Genes , Hipocampo , MicroARNs , ARN Largo no Codificante , ARN Mensajero , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Ratones , MicroARNs/genética , MicroARNs/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Trastornos Neurocognitivos/genética , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/patología , Masculino , Periodo Perioperatorio , Sevoflurano , Ratones Endogámicos C57BL , ARN Endógeno Competitivo

RESUMEN

The M4 muscarinic acetylcholine receptor (mAChR) is a biological target for neurocognitive disorders. Compound 1 is an ago-PAM for the M4 mAChR. Herein, we report the design, synthesis, and evaluation of novel putative M4 mAChR PAMs based on 1. These analogs were screened and then fully characterized in two functional assays (GoB protein activation and CAMYEL activation) to quantify their allosteric and ago-PAM properties against ACh. A selection of 7 M4 PAMs were assessed for their ability to modulate ACh-mediated ß-arrestin recruitment and revealed 4 distinct clusters of M4 PAM activity: (1) analogs similar to 1 (24d), (2) analogs demonstrating only allosteric agonism (23d), (3) analogs with increased allosteric properties in CAMYEL activation (23b/23f and 24a/24b), and (4) analogs with a biased modulatory effect toward ß-arrestin recruitment (23i). These novel M4 chemical tools disclose discrete molecular determinants, allowing further interrogation of the therapeutic roles of cAMP and ß-arrestin pathways in neurocognitive disorders.

Asunto(s)

Piridinas , Receptor Muscarínico M4 , Regulación Alostérica/efectos de los fármacos , Humanos , Animales , Piridinas/farmacología , Piridinas/síntesis química , Piridinas/química , Receptor Muscarínico M4/agonistas , Receptor Muscarínico M4/metabolismo , Cricetulus , Trastornos Neurocognitivos/tratamiento farmacológico , Trastornos Neurocognitivos/metabolismo , Células CHO , Relación Estructura-Actividad , Descubrimiento de Drogas , beta-Arrestinas/metabolismo , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Pirazoles/uso terapéutico

RESUMEN

Gut microbiota and metabolites are considered key factors in the pathogenesis of perioperative neurocognitive disorders (PND), and the brain-gut axis may be a promising target for PND treatment. Electroacupuncture has been shown to improve a wide range of neurological disorders and to restore function to the gastrointestinal tract. Thus, we hypothesized whether electroacupuncture could remodel gut microbiota and neuroinflammation induced by anesthesia/surgery. First, we observed electroacupuncture at acupoints GV20, LI4 and PC6 significantly improved memory in behavioral tests. Next, we found electroacupuncture decreased the levels of inflammatory factors (NSE, S-100ß, IL-6, etc.) in the hippocampus, indicating that nerve inflammation was blocked by electroacupuncture. Furthermore, via 16S rRNA sequence analysis and LC-MS analysis, the gut microbiota and its metabolites were appropriately restored after electroacupuncture treatment. Additionally, we further confirmed the restorative effect of electroacupuncture on PND by fecal transplantation. In conclusion, the role of electroacupuncture in improving cognitive function and protecting neurons may be related to the modulation of gut microbiota and their metabolite dysregulation, thereby inhibiting neuroinflammation in PND mice.

Asunto(s)

Electroacupuntura , Microbioma Gastrointestinal , Hipocampo , Animales , Electroacupuntura/métodos , Microbioma Gastrointestinal/fisiología , Masculino , Ratones , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Eje Cerebro-Intestino/fisiología , Trasplante de Microbiota Fecal , Modelos Animales de Enfermedad , Trastornos Neurocognitivos/terapia , Trastornos Neurocognitivos/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Memoria , Cognición

RESUMEN

BACKGROUND: Perioperative neurocognitive disorders (PND) is a neurological complication in the perioperative period, which may lead to severe poor prognosis. Dexmedetomidine (Dex) is a commonly used sedative in the perioperative period. However, the effect of intraoperative anesthetic Dex on PND remains complicated and confusing. METHODS: PND model was established using aged male mice, treated with Dex, and subjected to behavioral tests. The effect of Dex on pyroptosis was assessed by western blot, enzyme-linked immunosorbent assay and immunofluorescence. In addition, the miRNA expression profile of PND mice was identified by small RNA sequencing and performed PCR to detect miRNAs. Finally, the effect of miRNA on mice neuron pyroptosis was verified in vitro. RESULTS: We found postoperative cognitive was declined in PND mice compared with control group, while preoperative injection of Dex improved short-term working memory and anxious exploration behavior, alleviated the cognitive impairment. Intriguingly, Dex ameliorated hippocampal inflammation and neuron pyroptosis in PND mice as evidenced by the reduced GSDMD, NLRP3, IL-1ß and IL-18. The miRNA expression profile of PND mice hippocampus was disordered, including 5 miRNAs up-regulated and 17 miRNAs down-regulated, compared to the sham group. Dysregulated miRNAs were mainly enriched in biological functions related to neuronal development and signaling pathways related to pyroptosis. MiR-184-3p was the key miRNA, overexpression of miR-184-3p blocked the inhibitory effect of Dex on neuron pyroptosis, which was manifested as increased expression of GSDMD and NLRP3, increased inflammatory factors IL-1ß and IL-18. CONCLUSIONS: This study revealed that miR-184-3p may mediate NLRP3 to prevent the alleviating effect of Dex on PND, which provides a new potential way to improve the therapeutic intervention of PND.

Asunto(s)

Dexmedetomidina , Hipocampo , MicroARNs , Proteína con Dominio Pirina 3 de la Familia NLR , Trastornos Neurocognitivos , Piroptosis , Animales , MicroARNs/metabolismo , MicroARNs/genética , Dexmedetomidina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Masculino , Ratones , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/tratamiento farmacológico , Piroptosis/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Complicaciones Cognitivas Postoperatorias/metabolismo , Modelos Animales de Enfermedad , Periodo Perioperatorio

RESUMEN

OBJECTIVE: Perioperative neurocognitive disorders (PND) are a group of prevalent neurological complications that often occur in elderly individuals following major or emergency surgical procedures. The etiologies are not fully understood. This study endeavored to investigate novel targets and prediction methods for the occurrence of PND. METHODS: A total of 229 elderly patients diagnosed with prostatic hyperplasia who underwent transurethral resection of the prostate (TURP) combined with spinal cord and epidural analgesia were included in this study. The patients were divided into two groups, the PND group and non-PND group, based on the Z-score method. According to the principle of maintaining consistency between preoperative and intraoperative conditions, three patients from each group were randomly chosen for serum sample collection. isobaric tags for relative and absolute quantification (iTRAQ) proteomics technology was employed to analyze and identify the proteins that exhibited differential expression in the serum samples from the two groups. Bioinformatics analysis was performed on the proteins that exhibited differential expression. RESULTS: Among the 1101 serum proteins analyzed in the PND and non-PND groups, eight differentially expressed proteins were identified in PND patients. Of these, six proteins showed up-regulation, while two proteins showed down-regulation. Further bioinformatics analysis of the proteins that exhibited differential expression revealed their predominant involvement in cellular biological processes, cellular component formation, as well as endocytosis and phagocytosis Additionally, these proteins were found to possess the RING domain of E3 ubiquitin ligase. CONCLUSION: The iTRAQ proteomics technique was employed to analyze the variation in protein expression in serum samples from patients with PND and those without PND. This study successfully identified eight proteins that exhibited differential expression levels between the two groups. Bioinformatics analysis indicates that proteins exhibiting differential expression are primarily implicated in the biological processes associated with microtubules. Investigating the microtubule formation process as it relates to neuroplasticity and synaptic formation may offer valuable insights for enhancing our comprehension and potential prevention of PND. CLINICAL TRIAL REGISTRATION: Registered (ChiCTR2000028836). Date (20190306).

Asunto(s)

Resección Transuretral de la Próstata , Humanos , Masculino , Anciano , Resección Transuretral de la Próstata/efectos adversos , Proteómica , Hiperplasia Prostática/cirugía , Hiperplasia Prostática/sangre , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/sangre , Trastornos Neurocognitivos/metabolismo , Complicaciones Cognitivas Postoperatorias/etiología , Complicaciones Cognitivas Postoperatorias/sangre , Periodo Perioperatorio , Anciano de 80 o más Años , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/análisis , Biología Computacional

RESUMEN

BACKGROUND & OBJECTIVES: Currently, there is a significant focus on the decrease of soluble receptor of advanced glycation end products (sRAGE) in neurocognitive and neuropsychiatric disorders. sRAGE plays a decoy role against the inflammatory response of advanced glycation end products (AGE), which has led to increased interest in its role in these disorders. This meta-analysis aimed to investigate the significant differences in sRAGE levels between neurocognitive and neuropsychiatric disorders compared to control groups. METHOD: A systematic review was conducted using the PUBMED, Scopus and Embase databases up to October 2023. Two reviewers assessed agreement for selecting papers based on titles and abstracts, with kappa used to measure agreement and finally publications were scanned according to controlled studies. Effect sizes were calculated as weighted mean differences (WMD) and pooled using a random effects model. Heterogeneity was assessed using I2, followed by subgroup analysis and meta-regression tests. Quality assessment was performed using the Newcastle-Ottawa Quality Assessment Scale. RESULTS: In total, 16 studies were included in the present meta-analysis. Subjects with neurocognitive (n = 1444) and neuropsychiatric (n = 444) disorders had lower sRAGE levels in case-control (WMD: -0.21, 95% CI: -0.33, -0.10; p <.001) and cross-sectional (WMD: -0.29, 95% CI = -0.44, -0.13, p <.001) studies with high heterogeneity and no publication bias. In subgroup analysis, subjects with cognitive impairment (WMD: -0.87, 95% CI: -1.61, -0.13, p =.000), and age >50 years (WMD: -0.39, 95% CI: -0.74, -0.05, p =.000), had lower sRAGE levels in case-control studies. Also, dementia patients (WMD: -0.41, 95% CI: -0.72, -0.10, p =.014) with age >50 years (WMD: -0.33, 95% CI: -0.54, -0.13, p = 0.000) and in Asian countries (WMD: -0.28, 95% CI: -0.42, -0.13, p =.141) had lower sRAGE levels in cross-sectional studies. CONCLUSION: This meta-analysis revealed a significant reduction in sRAGE in neurocognitive and neuropsychiatric disorders particularly in Asians and moderate age.

Asunto(s)

Biomarcadores , Trastornos Mentales , Trastornos Neurocognitivos , Receptor para Productos Finales de Glicación Avanzada , Humanos , Biomarcadores/sangre , Biomarcadores/metabolismo , Estudios de Casos y Controles , Disfunción Cognitiva/metabolismo , Productos Finales de Glicación Avanzada , Trastornos Mentales/sangre , Trastornos Mentales/diagnóstico , Trastornos Mentales/metabolismo , Trastornos Neurocognitivos/sangre , Trastornos Neurocognitivos/diagnóstico , Trastornos Neurocognitivos/metabolismo , Receptor para Productos Finales de Glicación Avanzada/sangre , Receptor para Productos Finales de Glicación Avanzada/metabolismo

RESUMEN

Human immunodeficiency virus type-1 (HIV-1) is responsible for significant mortality and morbidity worldwide. Despite complete control of viral replication with antiretrovirals, cells with integrated HIV-1 provirus can produce viral transcripts. In a cross-sectional study of 84 HIV+ individuals of whom 43 were followed longitudinally, we found that HIV-1 RNAs are present in extracellular vesicles (EVs) derived from cerebrospinal fluid and serum of all individuals. We used seven digital droplet polymerase chain reaction assays to evaluate the transcriptional status of the latent reservoir. EV-associated viral RNA was more abundant in the CSF and correlated with neurocognitive dysfunction in both, the cross-sectional and longitudinal studies. Sequencing studies suggested compartmentalization of defective viral transcripts in the serum and CSF. These findings suggest previous studies have underestimated the viral burden and there is a significant relationship between latent viral transcription and CNS complications of long-term disease despite the adequate use of antiretrovirals.

Asunto(s)

Vesículas Extracelulares , Infecciones por VIH , VIH-1 , ARN Viral , Humanos , Vesículas Extracelulares/metabolismo , VIH-1/genética , VIH-1/fisiología , ARN Viral/genética , Masculino , Estudios Transversales , Infecciones por VIH/virología , Infecciones por VIH/sangre , Femenino , Adulto , Persona de Mediana Edad , Estudios Longitudinales , Carga Viral , Latencia del Virus/genética , Trastornos Neurocognitivos/virología , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/etiología

RESUMEN

Perioperative neurocognitive disorders (PND) are cognitive dysfunctions that usually occur in elderly patients after anesthesia and surgery. Microglial overactivation is a key underlying mechanism. Interleukin-33 (IL-33) is a member of the IL-1 family that orchestrates microglial function. In the present study, we explored how IL-33, which regulates microglia, contributes to cognitive improvement in a male mouse model of PND. An exploratory laparotomy was performed to establish a PND model. The expression levels of IL-33 and its receptor ST2 were evaluated using Western blot. IL-33/ST2 secretion, microglial density, morphology, phagocytosis of synapse, and proliferation, and dystrophic microglia were assessed using immunofluorescence. Synaptic plasticity was measured using Golgi staining and long-term potentiation. The Morris water maze and open field test were used to evaluate cognitive function and anxiety. Hippocampal expression of IL-33 and ST2 were elevated on postoperative day 3. We confirmed that IL-33 was secreted by astrocytes and neurons, whereas ST2 mainly colocalized with microglia. IL-33 treatment induced microgliosis after anesthesia and surgery. These microglia had larger soma sizes and shorter and fragmented branches. Compared to the Surgery group, IL-33 treatment reduced the synaptic phagocytosis of microglia and increased microglial proliferation and dystrophic microglia. IL-33 treatment also reversed the impaired synaptic plasticity and cognitive function caused by anesthesia and surgery. In conclusion, these results indicate that IL-33 plays a key role in regulating microglial state and synaptic phagocytosis in a PND mouse model. IL-33 treatment has a therapeutic potential for improving cognitive dysfunction in PND.

Asunto(s)

Interleucina-33 , Ratones Endogámicos C57BL , Microglía , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Interleucina-33/metabolismo , Masculino , Ratones , Plasticidad Neuronal/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Complicaciones Cognitivas Postoperatorias/metabolismo , Fagocitosis/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/tratamiento farmacológico , Modelos Animales de Enfermedad , Neuronas/efectos de los fármacos , Neuronas/metabolismo

RESUMEN

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood-brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND.

Asunto(s)

Barrera Hematoencefálica , Humanos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Infecciones por VIH/patología , Infecciones por VIH/metabolismo , Complejo SIDA Demencia/metabolismo , Complejo SIDA Demencia/patología , VIH-1 , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/patología , Animales

RESUMEN

Our previous findings demonstrated that astrocytic HIF-1α plays a major role in HIV-1 Tat-mediated amyloidosis which can lead to Alzheimer's-like pathology-a comorbidity of HIV-Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV-1 Tat stimulated astrocyte-derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF-1α could likely mitigate HIV-1 Tat-ADEV-mediated neuronal injury. Rat hippocampal neurons when exposed to HIV-1 Tat-ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF-1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV-1 Tat-ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV-1 Tat-ADEVs, exhibited behavioural changes, and Alzheimer's 's-like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF-1α silenced ADEVs. This is the first report demonstrating the role of amyloid-carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF-1α.

Asunto(s)

Astrocitos , Vesículas Extracelulares , VIH-1 , Hipocampo , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neuronas , Vesículas Extracelulares/metabolismo , Animales , Astrocitos/metabolismo , Ratones , Ratas , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , VIH-1/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Humanos , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/etiología , Infecciones por VIH/metabolismo , Infecciones por VIH/complicaciones , Masculino , Complejo SIDA Demencia/metabolismo

RESUMEN

Perioperative neurocognitive disorders (PND) are a cognitive impairment that occurs after anesthesia, especially in elderly patients and significantly affects their quality of life. The hippocampus, as a critical region for cognitive function and an important location in PND research, has recently attracted increasing attention. However, in the hippocampus the impact of anesthesia and its underlying mechanisms remain unclear. This review focuses on investigation of the effects of anesthesia on the hippocampal dopamine (DA) system and explores its potential association with PND. Through comprehensive review of existing studies, it was found that anesthesia affects the hippocampus through various pathways involved in metabolism, synaptic plasticity and oxygenation. Anesthesia may also influence the DA neurotransmitter system in the brain which plays a role in emotions, rewards, learning and memory functions. Specifically, anesthesia may participate in the pathogenesis of PND by affecting the DA system within the hippocampus. Future studies should explore the molecular mechanisms of these effects through techniques such as neuroimaging to study real-time effects to improve animal models to better simulate clinical observations. For clinical application, it is recommended that physicians exercise caution when selecting and managing anesthetic drugs by adopting comprehensive cognitive assessment methods to reduce post-anesthesia cognitive risk. Overall, this review provides a better understanding of the relationship between the hippocampal DA system and perioperative neurocognitive function and provides valuable guidance for prevention and treatment strategies for PND.

Asunto(s)

Disfunción Cognitiva , Dopamina , Animales , Humanos , Anciano , Dopamina/metabolismo , Dopamina/farmacología , Calidad de Vida , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/patología , Hipocampo/metabolismo

RESUMEN

HIV-associated neurocognitive disorder (HAND) has become a chronic neurodegenerative disease affecting the quality of life in people living with HIV (PLWH). Despite an established association between HAND and neuroinflammation induced by HIV proteins (gp120, Tat, Rev., Nef, and Vpr), the pathogenesis of HAND remains to be fully elucidated. Accumulating evidence demonstrated that the gut microbiome is emerging as a critical regulator of various neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease), suggesting that the crosstalk between the gut microbiome and neuroinflammation may contribute to the development of these diseases, for example, gut dysbiosis and microbiota-derived metabolites can trigger inflammation in the brain. However, the potential role of the gut microbiome in the pathogenesis of HAND remains largely unexplored. In this review, we aim to discuss and elucidate the HAND pathogenesis correlated with gut microbiome and neuroinflammation, and intend to explore the probable intervention strategies for HAND.

Asunto(s)

Microbioma Gastrointestinal , Infecciones por VIH , Enfermedades Neurodegenerativas , Humanos , Enfermedades Neurodegenerativas/patología , Enfermedades Neuroinflamatorias , VIH , Calidad de Vida , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/patología , Encéfalo/patología , Infecciones por VIH/complicaciones

RESUMEN

This study investigates the potential of ellagic acid (EA), a phytochemical with antioxidant and anti-inflammatory properties, in managing perioperative neurocognitive disorders (PND). PND, which represents a spectrum of cognitive impairments often faced by elderly patients, is principally linked to surgical and anesthesia procedures, and heavily impacted by oxidative stress in the hippocampus and microglia-induced neuroinflammation. Employing an aged mice model subjected to abdominal surgery, we delve into EA's ability to counteract postoperative oxidative stress and cerebral inflammation by engaging the Insulin-like growth factor-1 (IGF-1) pathway. Our findings revealed that administering EA orally notably alleviated post-surgical cognitive decline in older mice, a fact that was manifested in improved performance during maze tests. This enhancement in the behavioral performance of the EA-treated mice corresponded with the rejuvenation of IGF-1 signaling, a decrease in oxidative stress markers in the hippocampus (like MDA and carbonylated protein), and an increase in the activity of antioxidant enzymes such as SOD and CAT. Alongside these, we observed a decrease in microglia-driven neuroinflammation in the hippocampus, thus underscoring the antioxidant and anti-inflammatory roles of EA. Interestingly, when EA was given in conjunction with an IGF1R inhibitor, these benefits were annulled, accentuating the pivotal role that the IGF-1 pathway plays in the neuroprotective potential of EA. Hence, EA could serve as a potent candidate for safeguarding against PND in older patients by curbing oxidative stress and neuroinflammation through the activation of the IGF-1 pathway.

Asunto(s)

Antioxidantes , Ácido Elágico , Humanos , Ratones , Animales , Anciano , Antioxidantes/farmacología , Antioxidantes/metabolismo , Ácido Elágico/farmacología , Enfermedades Neuroinflamatorias , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estrés Oxidativo , Trastornos Neurocognitivos/metabolismo , Hipocampo/metabolismo , Antiinflamatorios/farmacología , Administración Oral

RESUMEN

Accumulating evidence indicates that microglia-mediated neuroinflammation in the hippocampus contributes to the development of perioperative neurocognitive disorder (PND). P38MAPK, a point of convergence for different signaling processes involved in inflammation, can be activated by various stresses. This study aims to investigate the role of the P38MAPK/ATF2 signaling pathway in the development of PND in mice. Aged C57BL/6 mice were subjected to tibial fracture surgery under isoflurane anesthesia to establish a PND animal model. The open field test was used to evaluate the locomotor activity of the mice. Neurocognitive function was assessed with the Morris water maze (MWM) and fear conditioning test (FCT) on postoperative days 1, 3 and 7. The mice exhibited cognitive impairment accompanied by increased expression of proinflammatory factors (IL-1ß, TNF-α), proapoptotic molecules (caspase-3, bax) and microglial activation in the hippocampus 1, 3 and 7 days after surgery. Treatment with SB239063 (a P38MAPK inhibitor) decreased the expression of proinflammatory factors, proapoptotic molecules and Iba-1 in the CA1 region of the hippocampus. The number of surviving neurons was significantly increased. Inhibition of the P38MAPK/ATF2 signaling pathway attenuates hippocampal neuroinflammation and neuronal apoptosis in aged mice with PND, thus improving the perioperative cognitive function of the mice.

Asunto(s)

Disfunción Cognitiva , Enfermedades Neuroinflamatorias , Animales , Ratones , Disfunción Cognitiva/metabolismo , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Trastornos Neurocognitivos/metabolismo , Transducción de Señal/fisiología , Proteína Quinasa 14 Activada por Mitógenos

RESUMEN

During the antiretroviral era, individuals living with HIV continue to experience milder forms of HIV-associated neurocognitive disorder (HAND). Viral proteins, including Tat, play a pivotal role in the observed alterations within the central nervous system (CNS), with mitochondrial dysfunction emerging as a prominent hallmark. As a result, our objective was to examine the expression of genes associated with mitophagy and mitochondrial biogenesis in the brain exposed to the HIV-1 Tat protein. We achieved this by performing bilateral stereotaxic injections of 100 ng of HIV-1 Tat into the hippocampus of Sprague-Dawley rats, followed by immunoneuromagnetic cell isolation. Subsequently, we assessed the gene expression of Ppargc1a, Pink1, and Sirt1-3 in neurons using RT-qPCR. Additionally, to understand the role of Tert in telomeric dysfunction, we quantified the activity and expression of Tert. Our results revealed that only Ppargc1a, Pink1, and mitochondrial Sirt3 were downregulated in response to the presence of HIV-1 Tat in hippocampal neurons. Interestingly, we observed a reduction in the activity of Tert in the experimental group, while mRNA levels remained relatively stable. These findings support the compelling evidence of dysregulation in both mitophagy and mitochondrial biogenesis in neurons exposed to HIV-1 Tat, which in turn induces telomeric dysfunction.

Asunto(s)

Infecciones por VIH , VIH-1 , Trastornos Neurocognitivos , Sirtuina 3 , Productos del Gen tat del Virus de la Inmunodeficiencia Humana , Animales , Ratas , Productos del Gen tat/metabolismo , Infecciones por VIH/metabolismo , VIH-1/metabolismo , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/virología , Neuronas/metabolismo , Biogénesis de Organelos , Proteínas Quinasas/metabolismo , Ratas Sprague-Dawley , Sirtuina 3/genética , Sirtuina 3/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma

RESUMEN

Perioperative neurocognitive disorder (PND) is a common complication of surgery and anesthesia, especially among older patients. Microglial activation plays a crucial role in the occurrence and development of PND and transforming growth factor beta 1 (TGF-ß1) can regulate microglial homeostasis. In the present study, abdominal surgery was performed on 12-14 months-old C57BL/6 mice to establish a PND model. The expression of TGF-ß1, TGF-ß receptor 1, TGF-ß receptor 2, and phosphor-smad2/smad3 (psmad2/smad3) was assessed after anesthesia and surgery. Additionally, we examined changes in microglial activation, morphology, and polarization, as well as neuroinflammation and dendritic spine density in the hippocampus. Behavioral tests, including the Morris water maze and open field tests, were used to examine cognitive function, exploratory locomotion, and emotions. We observed decreased TGF-ß1 expression after surgery and anesthesia. Intranasally administered exogenous TGF-ß1 increased psmad2/smad3 colocalization with microglia positive for ionized calcium-binding adaptor molecule 1. TGF-ß1 treatment attenuated microglial activation, reduced microglial phagocytosis, and reduced surgery- and anesthesia-induced changes in microglial morphology. Compared with the surgery group, TGF-ß1 treatment decreased M1 microglial polarization and increased M2 microglial polarization. Additionally, surgery- and anesthesia-induced increase in interleukin 1 beta and tumor necrosis factor-alpha levels was ameliorated by TGF-ß1 treatment at postoperative day 3. TGF-ß1 also ameliorated cognitive function after surgery and anesthesia as well as rescue dendritic spine loss. In conclusion, surgery and anesthesia induced decrease in TGF-ß1 levels in older mice, which may contribute to PND development; however, TGF-ß1 ameliorated microglial activation and cognitive dysfunction in PND mice.

Asunto(s)

Microglía , Factor de Crecimiento Transformador beta1 , Humanos , Ratones , Animales , Lactante , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Microglía/metabolismo , Ratones Endogámicos C57BL , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Trastornos Neurocognitivos/metabolismo , Factor de Crecimiento Transformador beta

RESUMEN

Perioperative neurocognitive disorders (PND) increases postoperative dementia and mortality in patients and has no effective treatment. Although the detailed pathogenesis of PND is still elusive, a large amount of evidence suggests that damaged mitochondria may play an important role in the pathogenesis of PND. A healthy mitochondrial pool not only provides energy for neuronal metabolism but also maintains neuronal activity through other mitochondrial functions. Therefore, exploring the abnormal mitochondrial function in PND is beneficial for finding promising therapeutic targets for this disease. This article summarizes the research advances of mitochondrial energy metabolism disorder, inflammatory response and oxidative stress, mitochondrial quality control, mitochondria-associated endoplasmic reticulum membranes, and cell death in the pathogenesis of PND, and briefly describes the application of mitochondria-targeted therapies in PND.

Asunto(s)

Enfermedades Mitocondriales , Trastornos Neurocognitivos , Humanos , Trastornos Neurocognitivos/metabolismo , Mitocondrias/metabolismo , Enfermedades Mitocondriales/patología , Estrés Oxidativo , Neuronas/metabolismo