The protein kinase C modulator bryostatin-1 therapeutically targets microglia to attenuate neuroinflammation and promote remyelination.

In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance among demyelination, neurodegeneration, and myelin repair. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the lack of therapies aimed at promoting remyelination and slowing disease progression for individuals with MS.

Meningeal Dissemination and Drop Metastasis From Glioma Presenting With Non-Epileptic Myoclonus and Minipolymyoclonus.

We describe the case of a 36-year-old woman with a past medical history of low grade right frontal lobe glioma and focal epilepsy presenting with subacute, progressive, multifocal myoclonus and neck and back pain. Unlike her typical seizures, the myoclonus exhibited a distinct semiology, involving both positive and negative muscle jerks affecting multiple limb muscles while sparing the face. In addition, neurological examination revealed low-amplitude, arrhythmic movements of the hands and fingers, resembling minipolymyoclonus.

Restoring the Multiple Sclerosis Associated Imbalance of Gut Indole Metabolites Promotes Remyelination and Suppresses Neuroinflammation.

In multiple sclerosis (MS) the circulating metabolome is dysregulated, with indole lactate (ILA) being one of the most significantly reduced metabolites. We demonstrate that oral supplementation of ILA impacts key MS disease processes in two preclinical models. ILA reduces neuroinflammation by dampening immune cell activation as well as infiltration; and promotes remyelination and oligodendrocyte differentiation through the aryl hydrocarbon receptor (AhR).

Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism.

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state.

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis.

Protein kinase C (PKC) plays a key role in modulating the activities of the innate immune cells of the central nervous system (CNS). A delicate balance between pro-inflammatory and regenerative activities by microglia and CNS-associated macrophages is necessary for the proper functioning of the CNS. Thus, a maladaptive activation of these CNS innate immune cells results in neurodegeneration and demyelination associated with various neurologic disorders, such as multiple sclerosis (MS) and Alzheimer's disease.

Multiple Sclerosis and Other Acquired Demyelinating Diseases of the Central Nervous System.

Acquired demyelinating diseases of the central nervous system (CNS) comprise inflammatory conditions, including multiple sclerosis (MS) and related diseases, as well as noninflammatory conditions caused by toxic, metabolic, infectious, traumatic, and neurodegenerative insults. Here, we review the spectrum of diseases producing acquired CNS demyelination before focusing on the prototypical example of MS, exploring the pathologic mechanisms leading to myelin injury in relapsing and progressive MS and summarizing the mechanisms and modulators of remyelination. We highlight the complex interplay between the immune system, oligodendrocytes and oligodendrocyte progenitor cells (OPCs), and other CNS glia cells such as microglia and astrocytes in the pathogenesis and clinical course of MS.

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis.

Protein kinase C (PKC) plays a key role in modulating the activities of the innate immune cells of the central nervous system (CNS). A delicate balance between pro-inflammatory and regenerative activities by microglia and CNS-associated macrophages is necessary for the proper functioning of the CNS. Thus, a maladaptive activation of these CNS innate immune cells results in neurodegeneration and demyelination associated with various neurologic disorders, such as multiple sclerosis (MS) and Alzheimer's disease.

The role of multiple sclerosis subtype in microvascular decompression outcomes for patients with trigeminal neuralgia.

Objectives: While patients with concomitant trigeminal neuralgia (TN) and multiple sclerosis (MS) are understood to experience a more intractable pain phenotype, whether TN pain outcomes differ by the presenting MS subtype is not well characterized. This study's objective is to compare post-operative pain and numbness outcomes following microvascular decompression (MVD) in TN patients with either relapsing-remitting MS (RRMS) or progressive MS.

Methods: We retrospectively reviewed all TN patients who underwent MVDs at our institution from 2007 to 2020.

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination.

In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS.

Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS). Although classically considered a demyelinating disease, neuroaxonal injury occurs in both the acute and chronic phases and represents a pathologic substrate of disability not targeted by current therapies. Nitric oxide (NO) generated by CNS macrophages and microglia contributes to neuroaxonal injury in all phases of MS, but candidate therapies that prevent NO-mediated injury have not been identified.

Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis.

Background: Intermittent fasting or calorie restriction (CR) diets provide anti-inflammatory and neuroprotective advantages in models of multiple sclerosis (MS); data in humans are sparse.

Methods: We conducted a randomised-controlled feeding study of different CR diets in 36 people with MS over 8 weeks. Participants were randomised to 1 of 3 diets: 1) a control diet, in which the participant received 100% of his or her calorie needs 7 days per week, 2) a daily CR diet, in which the participant received 78% of his or her calorie needs 7 days per week, or 3) an intermittent CR diet, in which the participant received 100% of his or her calorie needs on 5 days per week and 25% of his or her calorie needs 2 days per week (i.

Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.

Inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in various cellular functions including neuroprotection. Absence of IP6K2 causes impairment of oxidative phosphorylation regulated by creatine kinase-B. In the present study, we show that IP6K2 is involved in attenuation of PINK1-mediated mitochondrial autophagy (mitophagy) in the brain.

DICAM, a molecular passport for T17 cell entry into the brain.

DICAM, a trafficking molecule preferentially expressed by T17 cells, may be a therapeutic target for treating neuroinflammation (Charabati ).

Targeting PKC in microglia to promote remyelination and repair in the CNS.

Microglia and CNS-infiltrating macrophages play significant roles in the pathogenesis of neuroinflammatory and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Prolonged and dysregulated inflammatory responses by these innate immune cells can have deleterious effects on the surrounding CNS microenvironment, which can worsen neurodegeneration and demyelination. However, although chronic activation of pro-inflammatory microglia is maladaptive, other functional microglial subtypes play beneficial roles during CNS repair and regeneration.

Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism.

The circulating metabolome provides unique insights into multiple sclerosis (MS) pathophysiology, but existing studies are relatively small or characterized limited metabolites. We test for differences in the metabolome between people with MS (PwMS; n = 637 samples) and healthy controls (HC; n = 317 samples) and assess the association between metabolomic profiles and disability in PwMS. We then assess whether metabolic differences correlate with changes in cellular gene expression using publicly available scRNA-seq data and whether identified metabolites affect human immune cell function.

D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain.

d-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, the d-stereoisomer of the amino acid with the fastest spontaneous racemization ratein vitro in vitro, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and a stereospecific luciferase assay, we identify endogenous d-cysteine in the mammalian brain.

Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration.

COVID-19 and Vaccination in the Setting of Neurologic Disease: An Emerging Issue in Neurology.

The COVID-19 pandemic caused by the SARS-CoV-2 virus has left many unanswered questions for patients with neurological disorders and the providers caring for them. Elderly and immunocompromised patients are at increased risk for severe symptoms due to COVID-19, and the virus may increase symptoms of underlying neurological illness, particularly for those with significant bulbar and respiratory weakness or other neurologic disability. Emerging SARS-CoV-2 vaccines offer substantial protection from symptomatic infection, but both patients and providers may have concerns regarding theoretical risks of vaccination, including vaccine safety and efficacy in the context of immunotherapy and the potential for precipitating or exacerbating neurological symptoms.

Inositol hexakisphosphate kinase-2 determines cellular energy dynamics by regulating creatine kinase-B.

Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. IP6Ks convert IP6 to pyrophosphates such as diphosphoinositol pentakisphosphate (IP7) and bis-diphosphoinositol tetrakisphosphate (IP8). IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions.

Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation.

Neuroinflammation characterizes multiple neurologic diseases, including primary inflammatory conditions such as multiple sclerosis and classical neurodegenerative diseases. Aberrant activation of the innate immune system contributes to disease progression, but drugs modulating innate immunity, particularly within the central nervous system (CNS), are lacking. The CNS-penetrant natural product bryostatin-1 attenuates neuroinflammation by targeting innate myeloid cells.

The Role of Metabolic Enzymes in the Regulation of Inflammation.

Immune cells undergo dramatic metabolic reprogramming in response to external stimuli. These metabolic pathways, long considered as simple housekeeping functions, are increasingly understood to critically regulate the immune response, determining the activation, differentiation, and downstream effector functions of both lymphoid and myeloid cells. Within the complex metabolic networks associated with immune activation, several enzymes play key roles in regulating inflammation and represent potential therapeutic targets in human disease.

The immunologic Warburg effect: Evidence and therapeutic opportunities in autoimmunity.

Pro-inflammatory signals induce metabolic reprogramming in innate and adaptive immune cells of both myeloid and lymphoid lineage, characterized by a shift to aerobic glycolysis akin to the Warburg effect first described in cancer. Blocking the switch to aerobic glycolysis impairs the survival, differentiation, and effector functions of pro-inflammatory cell types while favoring anti-inflammatory and regulatory phenotypes. Glycolytic reprogramming may therefore represent a selective vulnerability of inflammatory immune cells, providing an opportunity to modulate immune responses in autoimmune disease without broad toxicity in other tissues of the body.

DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism.

Racial/ethnic disparities have a significant impact on bladder cancer outcomes with African American patients demonstrating inferior survival over European-American patients. We hypothesized that epigenetic difference in methylation of tumor DNA is an underlying cause of this survival health disparity. We analyzed bladder tumors from African American and European-American patients using reduced representation bisulfite sequencing (RRBS) to annotate differentially methylated DNA regions.

Dimethyl fumarate treatment induces lipid metabolism alterations that are linked to immunological changes.

Objective: Identify metabolic changes produced by dimethyl fumarate (DMF) treatment and link them to immunological effects.

Methods: We enrolled 18 MS patients and obtained blood prior to DMF and 6 months postinitiation. We also enrolled 18 healthy controls for comparison.