Regulation of neuroinflammatory properties of glial cells by T cell effector molecules

Multiple sclerosis （MS） is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system （CNS）. The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.

The lymphatic system:a therapeutic target for central nervous system disorders

The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology.They emerge as major pathways for fluid exchange.The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity.The lymphatic system,through its role in the clearance of neurotoxic proteins,autoimmune cell infiltration,and the transmission of pro-inflammatory signals,participates in the pathogenesis of a variety of neurological disorders,including neurodegenerative and neuroinflammatory diseases and traumatic injury.Vascular endothelial growth factor C is the master regulator of lymphangiogenesis,a process that is critical for the maintenance of central nervous system homeostasis.In this review,we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.

Mechanisms of neuroplasticity and brain degeneration: strategies for protection during the aging process

Aging is a dynamic and progressive process that begins at conception and continues until death.This process leads to a decrease in homeostasis and morphological,biochemical and psychological changes,increasing the individual’s vulnerability to various diseases.The growth in the number of aging populations has increased the prevalence of chronic degenerative diseases,impairment of the central nervous system and dementias,such as Alzheimer’s disease,whose main risk factor is age,leading to an increase of the number of individuals who need daily support for life activities.Some theories about aging suggest it is caused by an increase of cellular senescence and reactive oxygen species,which leads to inflammation,oxidation,cell membrane damage and consequently neuronal death.Also,mitochondrial mutations,which are generated throughout the aging process,can lead to changes in energy production,deficiencies in electron transport and apoptosis induction that can result in decreased function.Additionally,increasing cellular senescence and the release of proinflammatory cytokines can cause irreversible damage to neuronal cells.Recent reports point to the importance of changing lifestyle by increasing physical exercise,improving nutrition and environmental enrichment to activate neuroprotective defense mechanisms.Therefore,this review aims to address the latest information about the different mechanisms related to neuroplasticity and neuronal death and to provide strategies that can improve neuroprotection and decrease the neurodegeneration caused by aging and environmental stressors.

Neural progenitor cells but not astrocytes respond distally to thoracic spinal cord injury in rat models

Traumatic spinal cord injury （SCI） is a detrimental condition that causes loss of sensory and motor function in an individual. Many complex secondary injury cascades occur after SCI and they offer great potential for therapeutic targeting. In this study, we investigated the response of endogenous neural progenitor cells, astrocytes, and microglia to a localized thoracic SCI throughout the neuroaxis. Twenty-five adult female Sprague-Dawley rats underwent mild-contusion thoracic SCI （n = 9）, sham surgery （n = 8）, or no surgery （n = 8）. Spinal cord and brain tissues were fixed and cut at six regions of the neuroaxis. Immunohistochem- istry showed increased reactivity of neural progenitor cell marker nestin in the central canal at all levels of the spinal cord. Increased reactivity of astrocyte-specific marker glial fibrillary acidic protein was found only at the lesion epicenter. The number of activated microglia was significantly increased at the lesion site, and activated microglia extended to the lumbar enlargement. Phagocytic microglia and macrophages were significantly increased only at the lesion site. There were no changes in nestin, glial fibrillary acidic protein, microglia and macrophage response in the third ventricle of rats subjected to mild-contusion thoracic SCI compared to the sham surgery or no surgery. These findings indicate that neural progenitor cells, astrocytes and microglia respond differently to a localized SCI, presumably due to differences in inflammatory signaling. These different cellular responses may have implications in the way that neural progenitor cells can be manipulated for neuroregeneration after SCI. This needs to be further investigated.

The mechanism behind activation of the Nod-like receptor family protein 3 inflammasome in Parkinson's disease

Previous studies have shown that the ATP-P2 X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3(NLRP3)inflammasome.The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy.As inflammation also plays an important role in the pathogenesis of Parkinson's disease,we hypothesized that the ATP-P2 X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson's disease.A male rat model of Parkinson's disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra.The P2 X4 receptor and the NLRP3 inflammasome(interleukin-1βand interleukin-18)were activated.Intracerebroventricular injection of the selective P2 X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2 H-benzofuro[3,2-e]-1,4-diazepin-2-one(5-BDBD)or knockdown of P2 X4 receptor expression by si RNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation.Our results suggest that the ATP-P2 X4 receptor signaling pathway mediates NLRP3 inflammasome activation,dopaminergic neurodegeneration,and dopamine levels.These findings reveal a novel role of the ATP-P2 X4 axis in the molecular mechanisms underlying Parkinson's disease,thus providing a new target for treatment.This study was approved by the Animal Ethics Committee of Qingdao University,China,on March 5,2015(approval No.QYFYWZLL 26119).

Inhibition of glycolysis mitigate microglial-activation mediated neuroinflammation in vitro and in vivo

OBJECTIVE Microglial activation-mediated neuroinflammation plays an important pathological basis in the progression of many neurodegenerative diseases.Activated microglia cells show a metabolic shift from oxidative phos⁃phorylation to aerobic glycolysis.However,the molecular mechanism underlying the role of glycolysis in microglial activation and progres⁃sion of neuroinflammatory diseases have not yet been fully understood.METHODS The anti-inflammatory effects and its underlying mecha⁃nisms of glycolytic inhibition in vitro were exam⁃ined in lipopolysaccharide(LPS)activated BV-2 microglial cells or primary microglial cells by enzyme-linked immunosorbent assay(ELISA),quantitative reverse transcriptase polymerase chain reaction(RT-PCR),Western blotting,immunoprecipitation,Flow cytometry and nuclear factor kappa B(NF-κB)luciferase reporter assays.In vivo,the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-or LPS-induced Par⁃kinson disease(PD)models were constructed to explored the anti-inflammatory and neuropro⁃tective effects of glycolytic inhibitor.RESULTS Inhibition of glycolysis by specific inhibitors[2-DG and 3-bromopyruvic acid(3-BPA)],knockdown of glucose transporter type 1(Glut-1)or hexoki⁃nase(HK)Ⅱabolished LPS-induced expres⁃sion of proinflammatory genes in microglia cells.Mechanistic studies demonstrated that glyco⁃lytic inhibitors significantly inhibited LPS-induced mTOR phosphorylation,IKKβphosphorylation,IκB phosphorylation,IκB degradation,nuclear translocation of P65 and NF-κB luciferase activity.Furthermore,LPS-induced P65 acetyla⁃tion on lysine 310,which is mediated by NAD-dependent protein deacetylase sirtuin-1 and is critical for NF-kB activation,were inhibited by glycolytic inhibitors.A coculture study revealed that 2-DG reduced the cytotoxicity of activated microglia toward MES23.5 dopaminergic neuron cells with no direct protective effect.In vivo,2-DG significantly ameliorated MPTP or LPS induced DA neuron loss and glial cell activation.CONCLUSION Glycolysis is actively involved in microglial activation.Inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.

Neurobiological mechanisms underlying delayed expression of posttraumatic stress disorder:A scoping review

BACKGROUND The capacity of posttraumatic stress disorder(PTSD)to occur with delayed onset has been documented in several systematic reviews and meta-analyses.Neurobiological models of PTSD may provide insight into the mechanisms underlying the progressive increase in PTSD symptoms over time as well as into occasional occurrences of long-delayed PTSD with few prodromal symptoms.AIM To obtain an overview of key concepts explaining and types of evidence supporting neurobiological underpinnings of delayed PTSD.METHODS A scoping review of studies reporting neurobiological findings relevant to delayed PTSD was performed,which included 38 studies in the qualitative synthesis.RESULTS Neurobiological mechanisms underlying PTSD symptoms,onset,and course involve several interconnected systems.Neural mechanisms involve the neurocircuitry of fear,comprising several structures,such as the hippocampus,amygdala,and prefrontal cortex,that are amenable to time-dependent increases in activity through sensitization and kindling.Neural network models explain generalization of the fear response.Neuroendocrine mechanisms consist of autonomic nervous system and hypothalamic-pituitary-adrenocortical axis responses,both of which may be involved in sensitization to stress.Neuroinflammatory mechanisms are characterized by immune activation,which is sometimes due to the effects of traumatic brain injury.Finally,neurobehavioral/contextual mechanisms involve the effects of intervening stressors and mental and physical disorder comorbidities,and these may be particularly relevant in cases of long-delayed PTSD.CONCLUSION Thus,delayed PTSD may result from multiple underlying neurobiological mechanisms that may influence the likelihood of developing prodromal symptoms preceding the onset of full-blown PTSD.

Bioinspired metal-organic framework nanozyme reinforced with thermosensitive hydrogel for regulating inflammatory responses in Parkinson’s disease

Parkinson’s disease(PD)is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory injury.Anti-inflammatory intervention to regulate oxidative stress in the brain is beneficial for managing PD.However,traditional natural antioxidants have failed to meet the clinical treatment demands due to insufficient activity and sustainability.Herein,Cu-doping zeolite imidazolate framework-8(ZIF-8)nanozyme is designed to simulate Cu/Zn superoxide dismutase(SOD)by biomimetic mineralization.The nanozyme composite is then integrated into thermosensitive hydrogel(poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid)(PLGA-PEG-PLGA))to form an effective antioxidant system(Cu-ZIF@Hydrogel).The thermosensitive hydrogel incorporating nanozymes demonstrate distinct viscoelastic properties aimed at enhancing local nanozyme adhesion,prolonging nanozyme retention time,and modulating antioxidant activity,thus significantly improving the bioavailability of nanozymes.At the cellular and animal levels of PD,we find that Cu-ZIF@Hydrogel bypass the blood-brain barrier and efficiently accumulate in the nerve cells.Moreover,the Cu-ZIF@Hydrogel significantly alleviate the PD’s behavioral and pathological symptoms by reducing the neuroinflammatory levels in the lesion site.Therefore,the hydrogel-incorporating nanozyme system holds great potential as a simple and reliable avenue for managing PD.

Complementary and alternative medicine on cognitive defects and neuroinflammation after sepsis

Sepsis-associated encephalopathy(SAE)is a common manifestation of sepsis,ranging from mild confusion and delirium to severe cognitive impairment and deep coma.SAE is associated with higher mortality and long-term outcomes,particularly substantial declines in cognitive function.The mechanisms of SAE probably include neuroinflammation that is mediated by systemic inflammation and ischemic lesions in the brain,a disrupted blood–brain barrier,oxidative stress,neurotransmitter dysfunction,and severe microglial activation.Increasing evidence suggests that complementary and alternative medicine,especially Traditional Chinese Medicine(TCM),is favorable in alleviating cognitive decline after sepsis.Here,we summarized the studies of traditional herbal remedies,TCM formulas and acupuncture therapy in animal models of neurological dysfunctions after sepsis in recent decades and reviewed their potential mechanisms.

Bilirubin and inflammation in neurodegenerative and other neurological diseases

Inflammation links neurodegenerative,neuropsychiatric and other neurological diseases(NDs)with acute brain events.It is responsible for the alteration of neurotransmission and circuity,brain architecture,and cell fate,affecting mood and personality(anxiety,depression and schizophrenia)and behavior(decline in cognitive,motor and speech abilities,altered sleep,fatigue,pain sensitivity and dementia).Inflammation is also a key component in systemic chronic diseases(cardiovascular disease,cancer,diabetes,and metabolic syndrome),in which bilirubin has been demonstrated to improve the diseases by acting as a multi-target antiinflammatory molecule,and where the evaluation of pharmacological modulation of the pigment level as a therapeutic approach has already started.While altered serum bilirubin levels have been reported in ND patients,the potential activity of bilirubin in the brain is vague.This review summarizes the available fragmentary information on the interplay of bilirubin with neuroinflammation,aiming to elucidate the pigment's role in the central nervous system environment.