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The bumpy road of purinergic inhibitors to clinical application in immune-mediated diseases

Neural Regeneration Research 2024年第6期19卷 1206-1211页

作者： Matihias T.Wyss Christine Heuer Marina Herwerth Institute of pharmacology and Toxicology University of Zurich Neuroscience Center Zurich (ZNZ) University of Zurich and ETH Zurich 3. Neurology Department University Hospital of Zurich

Purinergic signaling plays important roles throughout the body in the regulation of organ functions during and following the disruption of homeostasis. This is also reflected by the widespread expression of two families of purinergic receptors(P1 and P2) with numerous subtypes. In the last few decades, there has been increasing evidence that purinergic signaling plays an important role in the regulation of immune functions. Mainly, signals mediated by P2 receptors have been shown to contribute to immune system-mediated pathologies. Thus, interference with P2 receptors may be a promising strategy for the modulation of immune responses. Although only a few clinical studies have been conducted in isolated entities with limited success, preclinical work suggests that the use of P2 receptor inhibitors may bear some promise in various autoimmune diseases. Despite the association of P2 receptors with several disorders from this field, the use of P2 receptor antagonists in clinical therapy is still very scarce. In this narrative review, we briefly review the involvement of the purinergic system in immunological responses and clinical studies on the effect of purinergic inhibition on autoimmune processes. We then open the aperture a bit and show some preclinical studies demonstrating a potential effect of purinergic blockade on autoimmune events. Using suramin, a non-specific purinergic inhibitor, as an example, we further show that off-target effects could be responsible for observed effects in immunological settings, which may have interesting implications. Overall, we believe that it is worthwhile to further investigate this hitherto underexplored area.

关键词： autoimmune diseases neurological disorders purinergic system P2 receptor inhibitors suramin

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Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

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Neural Regeneration Research 2024年第1期19卷 16-21页

作者： Marika Alborghetti Edoardo Bianchini Lanfranco De Carolis Silvia Galli Francesco E.Pontieri Domiziana Rinaldi neurology Unit NESMOS DepartmentFaculty of Medicine&PsychologySapienza-University of RomeSant’Andrea University HospitalRomeItaly Department of clinical and Behavioral neurology IRCCS-Fondazione Santa LuciaRomeItaly

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's *** drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the *** is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and *** studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic ***,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from *** to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now *** potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain *** purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

关键词： glial cell line-derived neurotrophic factor(GDNF) glutamate neurological disorders neuroprotection Parkinson's disease preclinical studies rasagiline safinamide selegiline type-B monoamine oxidase(MAO_(B))inhibitors

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Pathological and Physiological High-frequency Oscillations on Electroencephalography in Patients with Epilepsy

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Neuroscience Bulletin 2024年第5期40卷 609-620页

作者： Hongyi Ye Cong Chen Shennan A.Weiss Shuang Wang Department of neurology Epilepsy CenterSecond Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009China Department of neurology State University of New York DownstateBrooklynNY11203USA Department of Physiology and pharmacology State University of New York DownstateBrooklynNY11203USA Department of neurology New York City Health+Hospitals/Kings CountyBrooklynNY11203USA

High-frequency oscillations(HFOs)encompass ripples(80 Hz–200 Hz)and fast ripples(200 Hz–600 Hz),serving as a promising biomarker for localizing the epileptogenic zone in *** fast ripples are always pathological,while ripples may be physiological or *** physiological from pathological ripples is important not only for designating epileptogenic brain regions,but also for investigations that study ripples in the context of memory encoding,consolidation,and recall in patients with *** studies have sought to identify distinguishing features between pathological and physiological ripples over the past two *** and pathological ripples differ with respect to their spatial location,cellular mechanisms,morphology,and coupling with background electroencephalographic *** studies have demonstrated that differentiating between pathological and physiological ripples can improve surgical outcome *** this review,we summarize the characteristics,differences,and applications of pathological and physiological HFOs and discuss strategies for their clinical translation.

关键词： Ripples Epilepsy Memory Sleep Surgical outcome

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Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia

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Neural Regeneration Research 2025年第3期20卷 873-886页

作者： Ying Wang Xiang Zhang Henrik Biverstål Nicolas GBazan Shuai Tan Nailin Li Makiko Ohshima Marianne Schultzberg Xiaofei Li Department of Neurobiology Care Sciences&SocietyDivision of NeurogeriatricsKarolinska InstitutetStockholmSweden Department of neurology Neuroscience CenterThe First Hospital of Jilin UniversityChangchunJilin ProvinceChina Department of Physiology and pharmacology Karolinska InstitutetStockholmSweden Department of Biosciences and Nutrition Karolinska InstitutetHuddingeSweden Neuroscience Center of Excellence Louisiana State UniversityNew OrleansLAUSA Department of Medicine SolnaClinical Pharmacology GroupKarolinska University HospitalStockholmSweden

Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

关键词： Alzheimer's disease amyloid-β maresin microglia monocyte neuroinflammation resolution RNA-sequencing specialized pro-resolving lipid mediator

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Alzheimer's disease and low-dose radiation therapy:A new hope

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Radiation Medicine and Protection 2024年第1期5卷 1-6页

作者： Neal E.Dunlap Robert P.Friedland Lu Cai Department of Radiation Oncology University of Louisville School of MedicineLouisvilleKY40202USA Department of neurology The University of Louisville School of MedicineLouisvilleKY40202USA Pediatric Research Institute Departments of PediatricsPharmacology and ToxicologyUniversity of Louisville School of MedicineLouisvilleKY40202USA

The concept of low-dose radiation(LDR)-induced hormetic responses was initially observed approximately 70 years ago and systematically reviewed along with the discovery of LDR-induced adaptive responses in a cytogenetic in vitro study in *** the end of the 1990s,discussions regarding the potential applications of LDRinduced hormesis and adaptive responses for preventing or treating chronic diseases,such as Alzheimer’s disease(AD)had taken *** 2016,reports on radiotherapy for the subjects with AD and for genetic AD model mice were ***,several preclinical studies with animal models of AD and clinical studies in AD subjects were conducted.A significant milestone was achieved with the online availability of a new Systematic Review based on qualified publications from these preclinical and clinical *** mini-review provides a concise historical introduction to LDR-induced hormesis and adaptive responses with discussion of AD radiotherapy with either LDR or relatively high dose *** of this Systematic Review cover promising outcomes,challenges,and new questions,followed by discussion of potential mechanisms.

关键词： Alzheimer’s disease Low-dose radiation Radiation adaptive response Radiation hormesis

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Activation of glutamatergic neurons in the somatosensory cortex promotes remyelination in ischemic vascular dementia

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Fundamental Research 2024年第1期4卷 188-198页

作者： Yi-Ting Zhou Da-Dao An Yi-Xin Xu Ying Zhou Qing-Qing Li Hai-Bin Dai Xiang-Nan Zhang Yi Wang Min Lou Zhong Chen Wei-Wei Hu Department of pharmacology and Department of Pharmacy of the Second Affiliated Hospital NHC and CAMS Key Laboratory of Medical NeurobiologySchool of Basic Medical SciencesCollege of Pharmaceutical SciencesZhejiang University School of MedicineHangzhou 310058China Department of Pharmacy Sir Run Run Shaw HospitalHangzhou 310012China Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou 310053China Department of neurology the Second Affiliated Hospital of Zhejiang UniversitySchool of MedicineHangzhou 310003China

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia,however no effective treatments are ***,based on magnetic resonance imaging studies of patients with white matter damage,we found that this damage is associated with disorganized cortical *** a mouse model,optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell(OPC)proliferation,remyelination in the corpus callosum,and recovery of cognitive ability after cerebral *** therapeutic effect of such stimulation was restricted to the upper layers of the cortex,but also spanned a wide time window after ***,enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic ***,skin stroking,an easier method to translate into clinical practice,activated the somatosensory cortex,thereby promoting OPC proliferation,remyelination and cognitive recovery following cerebral *** summary,we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral *** should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

关键词： Chronic cerebral hypoperfusion Optogenetic stimulation Oligodendrocyte progenitor cellIschemic vascular dementia Glutamatergic neuron Remyelination

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Mechanisms of glutamate metabolic function and dysfunction in vasculardementia

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Neuroprotection 2024年第1期2卷 33-48页

作者： Jiawen Wang Yingmei Zhang Ning Tian Dongshan Ya Jiaxin Yang Yanlin Jiang Xiaoxia Li Xiaohui Lin Bin Yang Qinghua Li Rujia Liao Laboratory of Neuroscience Afliated Hospital of Guilin Medical UniversityGuilin Medical UniversityGuilinGuangxiChina Department of neurology Affliated Hospital of Guilin Medical UniversityGuilin Medical UniversityGuilinGuangxiChina Department of pharmacology Affliated Hospital of Guilin Medical UniversityGuilin Medical UniversityGuilinGuangxiChina Department of Geriatrics Affliated Hospital of Guilin Medical UniversityGuilin Medical UniversityGuilinGuangxiChina Guangxi clinical Research Center for NeurologicalDiseases Afiliated Hospitalof Guilin Medical UniversityGuilin Medical UniversityGuilinGuangxiChina

As the global population ages,research on the pathogenesis and treatment options for older patients with dementia has become increasingly *** dementia(VaD),the second most frequent type of dementia,is characterized by vascular impairment caused by inadequate blood supply to the *** is a complex neurological disorder involving multiple cells and signaling pathways,and its prevention and treatment pose clinical challenges with significant behavioral ***,the most abundant amino acid in the brain,plays a critical role as an excitatory neurotransmitter,impacting cognitive function,learning,and *** glutamate metabolism has been closely linked to dementia,and reduced blood flow to the brain can lead to excessive glutamate accumulation,resulting in neuronal *** article highlights the connection between VaD and glutamate metabolism,aiming to identify better methods for preventing and treating VaD via regulating glutamate metabolism.

关键词： glutamate ionotropic glutamate receptors metabolism metabotropic glutamate receptors vasculardementia

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Electroacupuncture Alleviates HIF1-α-mediated Early Mitophagy in Spinal Cord Injury

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clinical Complementary Medicine and pharmacology 2024年第1期4卷 26-35页

作者： Rong Hu Xingying Wu Kelin He Mengting Shi Haipeng Xu Yi Chen Bowen Chen Lei Wu Ruijie Ma Kang Liang Key Laboratory of Acupuncture and neurology of Zhejiang Province The Third School of Clinical Medicine(School of Rehabilitation Medicine)Zhejiang Chinese Medical UniversityHangzhou 310053ZhejiangChina Department of Acupuncture and Moxibustion The Third Affiliated Hospital of Zhejiang Chinese Medical University(Zhongshan Hospital of Zhejiang Province)Zhejiang Chinese Medical UniversityHangzhou 310053ZhejiangChina

Background:The inhibitory microenvironment around spinal cord injury(SCI)severely restricted functional repair after *** was one of the important measures to maintain cellular homeostasis and ensure the harmonious nerve cell ***-inducible factor1α(HIF1-α)can mediate mitochondrial autophagy in neurodegenerative diseases,but the mechanisms are complex and diverse,which need to be further *** plays a significant role in improving the neural microenvironment after spinal cord injury,promote long-term neurological function recovery in SCI patients,but whether electroacupuncture can participate in HIF1-α mediated mitophagy remains ***:Investigated the effects of HIF1-α on mitochondrial autophagy in rats with spinal cord contusion and the potential mechanism of ***:Following the successful construction of an SCI model of Sprague-Dawley rat utilizing a modified Allen method,electroacupuncture intervention was performed at T9 and T11 Jiaji acupoint(EX-B2),with further molecular biology and morphology examined by *** observe the effect of HIF1-α on local damage repair,the stereotypic injection of Hif1a knockdown virus was performed,and the changes of mitophagy in damaged local area was detected employing Western blotting,real-time fluorescence quantitative PCR,immunofluorescence,transmission electron microscopy and Nissl ***:HIF1-α as well as its mitophagy receptor BNIP3 and NIX are upregulated after spinal cord ***-troacupuncture treatment or local inhibition of HIF1-α expression can reverse the early autophagy state after spinal cord injury,reduce cell apoptosis and injury area,promote neuronal ***:Electroacupuncture may serve as a promising strategy for spinal cord injury treatment,by alleviating HIF1-α mediated early mitochondrial autophagy.

关键词： Spinal cord injury Electroacupuncture Hypoxia-inducible factor1α Mitophagy

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Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1412-1427页

作者： Jianpei Xu Yinzhe Sun Yang You Yuwen Zhang Dan Huang Songlei Zhou Yipu Liu Shiqiang Tong Fenfen Ma Qingxiang Song Chengxiang Dai Suke Li Jigang Lei Zhihua Wang Xiaoling Gao Jun Chen Shanghai Pudong Hospital&Department of Pharmaceutics School of PharmacyFudan UniversityShanghai 201203China Key Laboratory of Smart Drug Delivery Ministry of EducationSchool of PharmacyFudan UniversityShanghai 201203China Department of pharmacology and Chemical Biology State Key Laboratory of Oncogenes and Related GenesShanghai Universities Collaborative Innovation Center for Translational MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Emergency Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghai 201399China Institute of Science and Technology for Brain-Inspired Intelligence&Department of neurology Fudan UniversityShanghai 201203China Department of Rehabilitation Medicine Huashan HospitalFudan UniversityShanghai 201203China Daxing Research Institute University of Science and Technology BeijingBiomedical Industry BaseZhongguancun Science and Technology ParkBeijing 102600China Cellular Biomedicine Group Inc. Shanghai 201210China

Mesenchymal stem cells(MSCs)experience substantial viability issues in the stroke infarct region,limiting their therapeutic efficacy and clinical *** levels of deadly reactive oxygen radicals(ROS)and proinflammatory cytokines(PC)in the infarct milieu kill transplanted MSCs,whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs’*** on the intrinsic hormesis effects in cellular biology,we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC *** system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective *** this system,extracellular ROSscavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a microlivable niche at the level of a single MSC for ***,the infarct’s inanimate milieu is transformed at the tissue level into a new living niche to facilitate *** engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 *** vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.

关键词： Ischemic stroke Mesenchymal stem cell Cell engineering Hormesis effect Bioorthogonal chemistry Microglia Reactive oxygen spices Proinflammatory cytokines

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CDP-choline to promote remyelination in multiple sclerosis:the need for a clinical trial

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Neural Regeneration Research 2023年第12期18卷 2599-2605页

作者： Viktoria Gudi PawełGrieb Ralf ALinker Thomas Skripuletz Department of neurology Hannover Medical SchoolHannoverGermany Department of Experimental pharmacology Mossakowski Medical Research InstitutePolish Academy of SciencesWarsawPoland Department of neurology University Hospital RegensburgRegensburgGermany

Multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death,resulting in functional *** is the natural repair process of demyelination,but it is often incomplete or fails in multiple *** therapies reduce the inflammatory state and prevent clinical ***,therapeutic approaches to increase myelin repair in humans are not yet *** substance cytidine-5′-diphosphocholine,CDP-choline,is ubiquitously present in eukaryotic cells and plays a crucial role in the synthesis of cellular *** properties have been shown in various animal models of diseases of the central nervous *** have already shown that the compound CDPcholine improves myelin regeneration in two animal models of multiple ***,the results from the animal models have not yet been studied in patients with multiple *** this review,we summarise the beneficial effects of CDP-choline on biolipid metabolism and turnover with regard to inflammatory and regenerative *** also explain changes in phospholipid and sphingolipid homeostasis in multiple sclerosis and suggest a possible therapeutic link to CDP-choline.

关键词： astrocytes CDP-choline cuprizone microglia multiple sclerosis oligodendrocytes

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