Endogenous 24S-hydroxycholesterol modulates NMDAR-mediated function in hippocampal slices

N-methyl-d-aspartate receptors (NMDARs), a major subtype of glutamate receptors mediating excitatory transmission throughout the central nervous system (CNS), play critical roles in governing brain function and cognition. Because NMDAR dysfunction contributes to the etiology of neurological and psychiatric disorders including stroke and schizophrenia, NMDAR modulators are potential drug candidates. Our group recently demonstrated that the major brain cholesterol metabolite, 24 S-hydroxycholesterol (24S-HC), positively modulates NMDARs when exogenously administered. Here, we studied whether endogenous 24S-HC regulates NMDAR activity in hippocampal slices. In CYP46A1−/−(knockout; KO) slices where endogenous 24S-HC is greatly reduced, NMDAR tone, measured as NMDAR-to-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) excitatory postsynaptic current (EPSC) ratio, was reduced. This difference translated into more NMDAR-driven spiking in wild-type (WT) slices compared with KO slices. Application of SGE-301, a 24S-HC analog, had comparable potentiating effects on NMDAR EPSCs in both WT and KO slices, suggesting that endogenous 24S-HC does not saturate its NMDAR modulatory site in ex vivo slices. KO slices did not differ from WT slices in either spontaneous neurotransmission or in neuronal intrinsic excitability, and exhibited LTP indistinguishable from WT slices. However, KO slices exhibited higher resistance to persistent NMDAR-dependent depression of synaptic transmission induced by oxygen-glucose deprivation (OGD), an effect restored by SGE-301. Together, our results suggest that loss of positive NMDAR tone does not elicit compensatory changes in excitability or transmission, but it protects transmission against NMDAR-mediated dysfunction. We expect that manipulating this endogenous NMDAR modulator may offer new treatment strategies for neuropsychiatric dysfunction.

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Awake functional MRI detects neural circuit dysfunction in a mouse model of autism

Science Advances ◽

10.1126/sciadv.aav4520 ◽

2020 ◽

Vol 6 (6) ◽

pp. eaav4520 ◽

Cited By ~ 8

Author(s):

Tomokazu Tsurugizawa ◽

Kota Tamada ◽

Nobukazu Ono ◽

Sachise Karakawa ◽

Yuko Kodama ◽

...

Keyword(s):

Functional Mri ◽

Brain Function ◽

Copy Number ◽

Diffusion Mri ◽

Neural Circuit ◽

Ex Vivo ◽

Disease Model ◽

Wild Type ◽

Number Variation ◽

Translational Approach

MRI has potential as a translational approach from rodents to humans. However, given that mouse functional MRI (fMRI) uses anesthetics for suppression of motion, it has been difficult to directly compare the result of fMRI in “unconsciousness” disease model mice with that in “consciousness” patients. We develop awake fMRI to investigate brain function in 15q dup mice, a copy number variation model of autism. Compared to wild-type mice, we find that 15q dup is associated with whole-brain functional hypoconnectivity and diminished fMRI responses to odors of stranger mice. Ex vivo diffusion MRI reveals widespread anomalies in white matter ultrastructure in 15q dup mice, suggesting a putative anatomical substrate for these functional hypoconnectivity. We show that d-cycloserine (DCS) treatment partially normalizes these anormalies in the frontal cortex of 15q dup mice and rescues some social behaviors. Our results demonstrate the utility of awake rodent fMRI and provide a rationale for further investigation of DCS therapy.

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The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

Clinical Science ◽

10.1042/cs20140683 ◽

2015 ◽

Vol 128 (12) ◽

pp. 839-861 ◽

Cited By ~ 131

Author(s):

Dionne E.M. Maessen ◽

Coen D.A. Stehouwer ◽

Casper G. Schalkwijk

Keyword(s):

Advanced Glycation Endproducts ◽

Treatment Strategies ◽

Glyoxalase System ◽

Dicarbonyl Compound ◽

Glycation Endproducts ◽

Age Related ◽

Key Enzyme ◽

The Central Nervous System ◽

New Treatment

The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.

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Progress in the Application of Drugs for the Treatment of Multiple Sclerosis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.724718 ◽

2021 ◽

Vol 12 ◽

Author(s):

Weipeng Wei ◽

Denglei Ma ◽

Lin Li ◽

Lan Zhang

Keyword(s):

Multiple Sclerosis ◽

Demyelinating Disease ◽

Treatment Strategies ◽

New Drugs ◽

Focal Lesion ◽

Disease Modifying Drugs ◽

Physical Disorders ◽

The Central Nervous System ◽

Control Disease ◽

New Treatment

Multiple sclerosis (MS) is an autoimmune and chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesion in CNS and cause physical disorders. Although environmental factors and susceptibility genes are reported to play a role in the pathogenesis of MS, its etiology still remains unclear. At present, there is no complete cure, but there are drugs that decelerate the progression of MS. Traditional therapies are disease-modifying drugs that control disease severity. MS drugs that are currently marketed mainly aim at the immune system; however, increasing attention is being paid to the development of new treatment strategies targeting the CNS. Further, the number of neuroprotective drugs is presently undergoing clinical trials and may prove useful for the improvement of neuronal function and survival. In this review, we have summarized the recent application of drugs used in MS treatment, mainly introducing new drugs with immunomodulatory, neuroprotective, or regenerative properties and their possible treatment strategies for MS. Additionally, we have presented Food and Drug Administration-approved MS treatment drugs and their administration methods, mechanisms of action, safety, and effectiveness, thereby evaluating their treatment efficacy.

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An Overview of Peptide-Based Molecules as Potential Drug Candidates for Multiple Sclerosis

Molecules ◽

10.3390/molecules26175227 ◽

2021 ◽

Vol 26 (17) ◽

pp. 5227

Author(s):

Annarita Del Gatto ◽

Michele Saviano ◽

Laura Zaccaro

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Treatment Strategies ◽

Autoimmune Encephalitis ◽

Demyelinating Diseases ◽

Experimental Autoimmune Encephalitis ◽

Drug Candidates ◽

Life Threatening ◽

New Treatment ◽

Experimental Autoimmune

Multiple sclerosis (MS) belongs to demyelinating diseases, which are progressive and highly debilitating pathologies that imply a high burden both on individual patients and on society. Currently, several treatment strategies differ in the route of administration, adverse events, and possible risks. Side effects associated with multiple sclerosis medications range from mild symptoms, such as flu-like or irritation at the injection site, to serious ones, such as progressive multifocal leukoencephalopathy and other life-threatening events. Moreover, the agents so far available have proved incapable of fully preventing disease progression, mostly during the phases that consist of continuous, accumulating disability. Thus, new treatment strategies, able to halt or even reverse disease progression and specific for targeting solely the pathways that contribute to the disease pathogenesis, are highly desirable. Here, we provide an overview of the recent literature about peptide-based systems tested on experimental autoimmune encephalitis (EAE) models. Since peptides are considered a unique therapeutic niche and important elements in the pharmaceutical landscape, they could open up new therapeutic opportunities for the treatment of MS.

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Endocannabinoid System Unlocks the Puzzle of Autism Treatment via Microglia

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.734837 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tangfeng Su ◽

Yu Yan ◽

Qiang Li ◽

Jiacai Ye ◽

Lei Pei

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurodevelopmental Disorder ◽

Treatment Strategies ◽

Endocannabinoid System ◽

Autism Spectrum ◽

Autism Treatment ◽

Patterns Of Behavior ◽

The Central Nervous System ◽

New Treatment

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder and characterized by early childhood-onset impairments in social interaction and communication, restricted and repetitive patterns of behavior or interests. So far there is no effective treatment for ASD, and the pathogenesis of ASD remains unclear. Genetic and epigenetic factors have been considered to be the main cause of ASD. It is known that endocannabinoid and its receptors are widely distributed in the central nervous system, and provide a positive and irreversible change toward a more physiological neurodevelopment. Recently, the endocannabinoid system (ECS) has been found to participate in the regulation of social reward behavior, which has attracted considerable attention from neuroscientists and neurologists. Both animal models and clinical studies have shown that the ECS is a potential target for the treatment of autism, but the mechanism is still unknown. In the brain, microglia express a complete ECS signaling system. Studies also have shown that modulating ECS signaling can regulate the functions of microglia. By comprehensively reviewing previous studies and combining with our recent work, this review addresses the effects of targeting ECS on microglia, and how this can contribute to maintain the positivity of the central nervous system, and thus improve the symptoms of autism. This will provide insights for revealing the mechanism and developing new treatment strategies for autism.

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A human ex vivo coculture model to investigate peritoneal metastasis and innovative treatment options

Pleura and Peritoneum ◽

10.1515/pp-2021-0128 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Dina Mönch ◽

Jana Koch ◽

Annika Maaß ◽

Nicole Janssen ◽

Thomas Mürdter ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Peritoneal Metastasis ◽

Ex Vivo ◽

Treatment Options ◽

Treatment Strategies ◽

Average Survival ◽

Extracellular Matrix Components ◽

Coculture Model ◽

New Treatment

Abstract Objectives Peritoneal metastasis (PM) is commonly observed in patients with colorectal cancer (CRC). The outcome of these patients is poor, with an average survival of only six months without therapy, which requires a better understanding of PM biology and new treatment strategies. Methods We established and characterized a human ex vivo peritoneal model to investigate the mechanisms of peritoneal seeding and possible treatment options. For this, CRC cell lines and patient-derived tumor organoids were cultured together with human peritoneum to investigate the invasion of malignant cells and the effects of local chemotherapy. Results Fresh human peritoneum was cultured for up to three weeks in a stainless steel ring system, allowing for survival of all peritoneal structures. Peritoneal cell survival was documented by light microscopy and immunohistochemical staining. Further, immunohistological characterization of the tissue revealed CD3-positive T-lymphocytes and vimentin-positive fibroblasts within the peritoneum. In addition, extracellular matrix components (collagens, matrix metalloproteinases) were localized within the tissue. Coculture with CRC cell lines and patient-derived CRC organoids revealed that cancer cells grew on the peritoneum and migrated into the tissue. Coculture with CRC cells confirmed that hyperthermal treatment at 41 °C for 90 min significantly enhanced the intracellular entry of doxorubicin. Moreover, treatment with mitomycin C under hyperthermic conditions significantly reduced the amount of cancer cells within the peritoneum. Conclusions This human ex vivo peritoneal model provides a stringent and clinically relevant platform for the investigation of PM and for further elucidation of possible treatment options.

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Phantom Restless Legs Syndrome

European Neurology ◽

10.1159/000503103 ◽

2019 ◽

Vol 81 (5-6) ◽

pp. 302-308

Author(s):

Alberto Raggi ◽

Raffaele Ferri

Keyword(s):

Restless Legs Syndrome ◽

Marked Reduction ◽

Treatment Strategies ◽

Phantom Limb ◽

Limb Amputation ◽

Phantom Pain ◽

Restless Legs ◽

The Central Nervous System ◽

New Treatment ◽

Internal Body

Background: Amputees often experience a phantom limb consisting in the vivid impression that the limb is not only still present, but in many cases, painful. These patients may also become restless legs syndrome (RLS) sufferers; conversely, a preexisting RLS may persist after limb amputation. Summary: In this brief essay, papers on phantom RLS (pRLS) are reviewed in order to provide clinical elements for the diagnosis and treatment of this peculiar condition. It is relevant that dopamine receptor agonists yielded a marked reduction of the RLS symptoms in all cases reported. Key Messages: pRLS indirectly confirms the innate capacity of the central nervous system to retain a primordial internal body image responsible of phantom sensations. Moreover, it has been hypothesized that pRLS may provide clues for a better comprehension of some mechanisms underlying phantom pain and for the development of new treatment strategies.

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Brain–body communication in stroke

Neuroforum ◽

10.1515/nf-2021-0030 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Katarzyna Winek ◽

Daniel Cuervo Zanatta ◽

Marietta Zille

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Stroke Risk ◽

Treatment Strategies ◽

The Body ◽

Cns Injury ◽

Stroke Risk Factors ◽

The Central Nervous System ◽

New Treatment ◽

The Brain

Abstract Stroke is a leading cause of death and disability worldwide with limited therapeutic options available for selected groups of patients. The susceptibility to stroke depends also on systemic parameters, and some stroke risk factors are modifiable, such as atrial fibrillation (AF) or hypertension. When considering new treatment strategies, it is important to remember that the consequences of stroke are not limited to the central nervous system (CNS) injury, but reach beyond the boundaries of the brain. We provide here a brief overview of the mechanisms of how the brain communicates with the body, focusing on the heart, immune system, and gut microbiota (GM).

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Formyl peptide receptor agonist Ac2-26 alleviates neuroinflammation in a mouse model of pneumococcal meningitis

10.21203/rs.3.rs-28938/v1 ◽

2020 ◽

Author(s):

Marvin Rüger ◽

Eugenia Kipp ◽

Nadine Schubert ◽

Nicole Schröder ◽

Thomas Pufe ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Mouse Model ◽

Treatment Strategies ◽

Neutrophil Infiltration ◽

Brain Regions ◽

Formyl Peptide Receptor ◽

Formyl Peptide ◽

The Central Nervous System ◽

New Treatment ◽

Deficient Mice

Abstract BackgroundBacterial meningitis is, despite progress in research and the development of new treatment strategies, still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands including pro- and anti-inflammatory ones. Here, we investigated the effects of the AnnexinA1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis.MethodsWildtype (WT), Fpr1 and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8 and 24 hour after the infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time RT-PCR 30 h after infection.ResultsAc2-26 treated mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glia cell responses. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice.ConclusionsEven with appropriate antimicrobial therapy, mortality during bacterial meningitis is high and so attention has recently focused on adjunctive therapies. Our results suggest that Ac2-26 might be a novel adjunctive therapy for Streptococcus pneumoniae-induced meningitis.* The two last authors contributed equally to this study.

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