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Pediatric Research Jun 2024Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the...
BACKGROUND
Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day.
METHODS
Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment.
RESULTS
Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed C 44.0 ng/mL, t 4.6 h, and AUC 280.1 ng*hr/mL.
CONCLUSIONS
Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI.
IMPACT
Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates. Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment. The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials. We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.
PubMed: 38942888
DOI: 10.1038/s41390-024-03326-w -
FEBS Open Bio Jun 2024Peripheral nerve injuries result in significant loss of motor and sensory function, and the slow rate of nerve regeneration can prolong recovery time. Thus, approaches...
Peripheral nerve injuries result in significant loss of motor and sensory function, and the slow rate of nerve regeneration can prolong recovery time. Thus, approaches that promote axonal regeneration are critical to improve the outcomes for patients with peripheral nerve injuries. In this study, we investigated the effects of Ficus carica L. (fig) and Vaccinium macrocarpon Ait. (cranberry), which are rich in phytochemicals with demonstrable and diverse medicinal properties, on nerve regeneration in a mouse model of sciatic nerve crush. Our investigation revealed that fig extract, but not cranberry extract, prevented the decline in muscle weight and nerve conduction velocity induced by nerve crush. The fig extract also mitigated motor function impairment, myelin thinning, and axon diameter reduction, indicating its potential to promote nerve regeneration. Furthermore, the fig extract enhanced macrophage infiltration into the nerve tissue, suggesting that it could ameliorate nerve injury by promoting tissue repair via increased macrophage infiltration. The study provides valuable insights into the potential of the fig extract as a novel agent promoting nerve regeneration. Further investigation into the mechanisms underlying the action of fig extracts is needed to translate these findings into clinical applications for patients with peripheral nerve injuries.
PubMed: 38942739
DOI: 10.1002/2211-5463.13859 -
Neuroimaging Clinics of North America Aug 2024Optic neuritis is a common feature in multiple sclerosis and in 2 other autoimmune demyelinating disorders such as aquaporin-4 IgG antibody-associated neuromyelitis... (Review)
Review
Optic neuritis is a common feature in multiple sclerosis and in 2 other autoimmune demyelinating disorders such as aquaporin-4 IgG antibody-associated neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease. Although serologic testing is critical for differentiating these different autoimmune-mediated disorders, MR imaging, which is the preferred imaging modality for assessing the optic nerve, can provide valuable information, suggesting a specific diagnosis and guiding the appropriate serologic testing.
Topics: Humans; Multiple Sclerosis; Optic Nerve; Magnetic Resonance Imaging; Optic Neuritis; Neuromyelitis Optica; Neuroimaging
PubMed: 38942524
DOI: 10.1016/j.nic.2024.03.005 -
Neuroimaging Clinics of North America Aug 2024Spinal cord MRI plays an important role in the diagnosis and prognosis of multiple sclerosis (MS) and related disorders. The ANATOMICAL, pathologic, imaging and... (Review)
Review
Spinal cord MRI plays an important role in the diagnosis and prognosis of multiple sclerosis (MS) and related disorders. The ANATOMICAL, pathologic, imaging and prognostic consideriations for the spinal cord for MS and the most important other demyelinating disorders, neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-associated disease, are reviewed. Finally, differential diagnostic considerations of spinal cord MRI in MS and related disorders are discussed.
Topics: Humans; Multiple Sclerosis; Magnetic Resonance Imaging; Spinal Cord; Neuromyelitis Optica; Diagnosis, Differential
PubMed: 38942523
DOI: 10.1016/j.nic.2024.03.011 -
Neuroimaging Clinics of North America Aug 2024In recent decades, advances in neuroimaging have profoundly transformed our comprehension of central nervous system demyelinating diseases. Remarkable technological... (Review)
Review
In recent decades, advances in neuroimaging have profoundly transformed our comprehension of central nervous system demyelinating diseases. Remarkable technological progress has enabled the integration of cutting-edge acquisition and postprocessing techniques, proving instrumental in characterizing subtle focal changes, diffuse microstructural alterations, and macroscopic pathologic processes. This review delves into state-of-the-art modalities applied to multiple sclerosis, neuromyelitis optica spectrum disorders, and myelin oligodendrocyte glycoprotein antibody-associated disease. Furthermore, it explores how this dynamic landscape holds significant promise for the development of effective and personalized clinical management strategies, encompassing support for differential diagnosis, prognosis, monitoring treatment response, and patient stratification.
Topics: Humans; Neuroimaging; Brain; Demyelinating Diseases; Neuromyelitis Optica; Magnetic Resonance Imaging; Multiple Sclerosis
PubMed: 38942520
DOI: 10.1016/j.nic.2024.03.003 -
Neuroimaging Clinics of North America Aug 2024The diagnostic workup of multiple sclerosis (MS) has evolved considerably. The 2017 revision of the McDonald criteria shows high sensitivity and accuracy in predicting... (Review)
Review
The diagnostic workup of multiple sclerosis (MS) has evolved considerably. The 2017 revision of the McDonald criteria shows high sensitivity and accuracy in predicting clinically definite MS in patients with a typical clinically isolated syndrome and allows an earlier MS diagnosis. Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disease (MOGAD) are recognized as separate conditions from MS, with specific diagnostic criteria. New MR imaging markers may improve diagnostic specificity for these conditions, thus reducing the risk of misdiagnosis. This study summarizes the most recent updates regarding the application of MR imaging for the diagnosis of MS, NMOSD, and MOGAD.
Topics: Humans; Neuromyelitis Optica; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Magnetic Resonance Imaging; Immunoglobulin G; Diagnosis, Differential
PubMed: 38942518
DOI: 10.1016/j.nic.2024.03.001 -
Neurology(R) Neuroimmunology &... Sep 2024To systematically describe the clinical picture of double-antibody seronegative neuromyelitis optica spectrum disorders (DN-NMOSD) with specific emphasis on retinal...
BACKGROUND AND OBJECTIVES
To systematically describe the clinical picture of double-antibody seronegative neuromyelitis optica spectrum disorders (DN-NMOSD) with specific emphasis on retinal involvement.
METHODS
Cross-sectional data of 25 people with DN-NMOSD (48 eyes) with and without a history of optic neuritis (ON) were included in this study along with data from 25 people with aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD, 46 eyes) and from 25 healthy controls (HCs, 49 eyes) for comparison. All groups were matched for age and sex and included from the collaborative retrospective study of retinal optical coherence tomography (OCT) in neuromyelitis optica (CROCTINO). Participants underwent OCT with central postprocessing and local neurologic examination and antibody testing. Retinal neurodegeneration was quantified as peripapillary retinal nerve fiber layer thickness (pRNFL) and combined ganglion cell and inner plexiform layer thickness (GCIPL).
RESULTS
This DN-NMOSD cohort had a history of [median (inter-quartile range)] 6 (5; 9) attacks within their 5 ± 4 years since onset. Myelitis and ON were the most common attack types. In DN-NMOSD eyes after ON, pRNFL ( < 0.001) and GCIPL ( = 0.023) were thinner compared with eyes of HCs. Even after only one ON episode, DN-NMOSD eyes already had considerable neuroaxonal loss compared with HCs. In DN-NMOSD eyes without a history of ON, pRNFL ( = 0.027) and GCIPL ( = 0.022) were also reduced compared with eyes of HCs. However, there was no difference in pRNFL and GCIPL between DN-NMOSD and AQP4-NMOSD for the whole group and for subsets with a history of ON and without a history of ON-as well as between variances of retinal layer thicknesses.
DISCUSSION
DN-NMOSD is characterized by severe retinal damage after ON and attack-independent retinal neurodegeneration. Most of the damage occurs during the first ON episode, which highlights the need for better diagnostic markers in DN-NMOSD to facilitate an earlier diagnosis as well as for effective and early treatments. In this study, people with DN-NMOSD presented with homogeneous clinical and imaging findings potentially suggesting a common retinal pathology in these patients.
Topics: Humans; Neuromyelitis Optica; Female; Male; Adult; Cross-Sectional Studies; Middle Aged; Tomography, Optical Coherence; Aquaporin 4; Retrospective Studies; Autoantibodies; Retina
PubMed: 38941573
DOI: 10.1212/NXI.0000000000200273 -
Molecular Therapy : the Journal of the... Jun 2024Galactosyl-ceramidase (GALC) is a ubiquitous lysosomal enzyme crucial for the correct myelination of the mammalian nervous system during early postnatal development....
Deficiency of galactosylceramidase in adult oligodendrocytes worsens the neurological deficits and shortens the survival during chronic experimental allergic encephalomyelitis.
Galactosyl-ceramidase (GALC) is a ubiquitous lysosomal enzyme crucial for the correct myelination of the mammalian nervous system during early postnatal development. However, the physiological consequence of GALC deficiency in the adult brain remains unknown. In this study, we found that mice with conditional ablation of GALC activity in post-myelinating oligodendrocytes were lethally sensitized when challenged with chronic experimental allergic encephalomyelitis (EAE), in contrast to the non-lethal dysmyelination observed in GALC-ablated mice without the EAE challenge. Mechanistically, we found a strong inflammatory demyelination without remyelination and an impaired fusion of lysosomes and autophagosomes with accumulation of myelin debris following a TFEB-dependent increase in the lysosomal autophagosome flux. These results indicate that the physiological impact of GALC deficiency is highly influenced by the cell context (oligodendroglial vs global expression), the presence of inflammation, and the developmental time when it happens (pre-myelination vs post-myelination). We conclude that GALC expression in adult oligodendrocytes is crucial for the maintenance of adult central myelin and to reduce vulnerability to additional demyelinating insults.
PubMed: 38937968
DOI: 10.1016/j.ymthe.2024.06.035 -
Nature Neuroscience Jun 2024Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer's disease remains uncertain, despite age being a major risk factor. Using a...
Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer's disease remains uncertain, despite age being a major risk factor. Using a mouse model of Alzheimer's disease, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8 T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, our data suggest that immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis.
PubMed: 38937583
DOI: 10.1038/s41593-024-01682-8 -
Cell Reports Jun 2024Oligodendrocyte death is common in aging and neurodegenerative disease. In these conditions, dying oligodendrocytes must be efficiently removed to allow remyelination...
Oligodendrocyte death is common in aging and neurodegenerative disease. In these conditions, dying oligodendrocytes must be efficiently removed to allow remyelination and to prevent a feedforward degenerative cascade. Removal of this cellular debris is thought to primarily be carried out by resident microglia. To investigate the cellular dynamics underlying how microglia do this, we use a single-cell cortical demyelination model combined with longitudinal intravital imaging of dual-labeled transgenic mice. Following phagocytosis, single microglia clear the targeted oligodendrocyte and its myelin sheaths in one day via a precise, rapid, and stereotyped sequence. Deletion of the fractalkine receptor, CX3CR1, delays the microglial phagocytosis of the cell soma but has no effect on clearance of myelin sheaths. Unexpectedly, deletion of the phosphatidylserine receptor, MERTK, has no effect on oligodendrocyte or myelin sheath clearance. Thus, separate molecular signals are used to detect, engage, and clear distinct sub-compartments of dying oligodendrocytes to maintain tissue homeostasis.
PubMed: 38935500
DOI: 10.1016/j.celrep.2024.114385