Dynamics of Central Remyelination and Treatment Evolution in a Model of Multiple Sclerosis with Optic Coherence Tomography

The need for remyelinating drugs is essential for healing disabling diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to monitor remyelination in vivo, which is of utmost importance to perform effective clinical trials. Here, we show how optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to assess remyelination in vivo in MS patients. Our pioneer approach validates OCT as a technique to study remyelination of the optic nerve and reflects what is occurring in non-accessible central nervous system (CNS) structures, like the spinal cord. In this study we used the orally bioavailable small molecule VP3.15, confirming its therapeutical potential as a neuroprotective, anti-inflammatory, and probably remyelinating drug for MS. Altogether, our results confirm the usefulness of OCT to monitor the efficacy of remyelinating therapies in vivo and underscore the relevance of VP3.15 as a potential disease modifying drug for MS therapy.

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Dynamics of central remyelination and treatment evolution in a model of Multiple Sclerosis with Optic Coherence Tomography

10.1101/2020.10.22.350181 ◽

2020 ◽

Author(s):

Rocío Benítez-Fernández ◽

Carolina Melero-Jerez ◽

Carmen Gil ◽

Enrique de la Rosa ◽

Ana Martínez ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Clinical Trials ◽

Optical Coherence Tomography ◽

Invasive Technique ◽

Optic Coherence Tomography ◽

Non Invasive ◽

Disease Modifying ◽

Ms Therapy

AbstractThe need for remyelinating drugs is essential for healing important diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to follow remyelination in vivo, which is of utmost importance to perform good clinical trials. Here, we show how the optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to follow remyelination in vivo in MS patients. Our pioneer study validates the study of myelin/remyelination in the optic nerve using OCT and reflects what is occurring in non accessible CNS structures, like the spinal cord. For this study we used the oral bioavailable small molecule VP3.15, confirming its therapeutical potential as neuroprotective, antinflammatory and remyelinating drug for MS. Altogether, our present results confirm the usefulness of OCT to monitor the effectivity of remyelinating therapies in vivo and underscore the relevance of VP3.15 as potential disease modifying drug for MS therapy.

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Further studies on free-radical pathology in the major central nervous system disorders: effect of very high doses of methylprednisolone on the functional outcome, morphology, and chemistry of experimental spinal cord impact injury

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y82-210 ◽

1982 ◽

Vol 60 (11) ◽

pp. 1415-1424 ◽

Cited By ~ 150

Author(s):

H. B. Demopoulos ◽

E. S. Flamm ◽

M. L. Seligman ◽

D. D. Pietronigro ◽

J. Tomasula ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Free Radical ◽

Tissue Injury ◽

Functional Restoration ◽

Radical Reactions ◽

Free Radical Reactions ◽

Cord Injury

The hypothesis that pathologic free-radical reactions are initiated and catalyzed in the major central nervous system (CNS) disorders has been further supported by the current acute spinal cord injury work that has demonstrated the appearance of specific, cholesterol free-radical oxidation products. The significance of these products is suggested by the fact that: (i) they increase with time after injury; (ii) their production is curtailed with a steroidal antioxidant; (iii) high antioxidant doses of the steroidal antioxidant which curtail the development of free-radical product prevent tissue degeneration and permit functional restoration. The role of pathologic free-radical reactions is also inferred from the loss of ascorbic acid, a principal CNS antioxidant, and of extractable cholesterol. These losses are also prevented by the steroidal antioxidant. This model system is among others in the CNS which offer distinctive opportunities to study, in vivo, the onset and progression of membrane damaging free-radical reactions within well-defined parameters of time, extent of tissue injury, correlation with changes in membrane enzymes, and correlation with readily measurable in vivo functions.

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Neurotrophins affect the pattern of DRG neurite growth in a bioassay that presents a choice of CNS and PNS substrates

Development ◽

10.1242/dev.121.5.1301 ◽

1995 ◽

Vol 121 (5) ◽

pp. 1301-1309 ◽

Cited By ~ 1

Author(s):

R. Tuttle ◽

W.D. Matthew

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Sciatic Nerve ◽

Sympathetic Neurons ◽

Neurite Growth ◽

Drg Neurons ◽

Substrate Preferences

Neurons can be categorized in terms of where their axons project: within the central nervous system, within the peripheral nervous system, or through both central and peripheral environments. Examples of these categories are cerebellar neurons, sympathetic neurons, and dorsal root ganglion (DRG) neurons, respectively. When explants containing one type of neuron were placed between cryosections of neonatal or adult sciatic nerve and neonatal spinal cord, the neurites exhibited a strong preference for the substrates that they would normally encounter in vivo: cerebellar neurites generally extended only on spinal cord, sympathetic neurites on sciatic nerve, and DRG neurites on both. Neurite growth from DRG neurons has been shown to be stimulated by neurotrophins. To determine whether neurotrophins might also affect the substrate preferences of neurites, DRG were placed between cryosections of neonatal spinal cord and adult sciatic nerve and cultured for 36 to 48 hours in the presence of various neurotrophins. While DRG cultured in NGF-containing media exhibited neurite growth over both spinal cord and sciatic nerve substrates, in the absence of neurotrophins DRG neurites were found almost exclusively on the CNS cryosection. To determine whether these neurotrophin-dependent neurite patterns resulted from the selective survival of subpopulations of DRG neurons with distinct neurite growth characteristics, a type of rescue experiment was performed: DRG cultured in neurotrophin-free medium were fed with NGF-containing medium after 36 hours in vitro and neurite growth examined 24 hours later; most DRG exhibited extensive neurite growth on both peripheral and central nervous system substrates.(ABSTRACT TRUNCATED AT 250 WORDS)

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Multiple Sclerosis

Neuropathic Pain ◽

10.1093/med/9780190298357.003.0024 ◽

2018 ◽

pp. 209-216

Author(s):

Samuel W. Samuel ◽

Jianguo Cheng

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Neuropathic Pain ◽

Demyelinating Disease ◽

Spontaneous Pain ◽

Disease Course ◽

The Central Nervous System ◽

Disease Modifying ◽

Multiple Treatments ◽

Surgical Treatments

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS). The diagnosis is based on evidence of at lease two different lesions in the CNS, at least two different episodes in the disease course, and chronic inflammation of the CNS as determined by analysis of the cerebrospinal fluid. Central neuropathic pain is the most common form of pain in patients with MS, with an estimated prevalence of about 50%. Along with the classical neuropathic pain features, such as spontaneous pain (dysesthesia and burning) and evoked pain (allodynia and hyperalgesia), patients with MS may also suffer from intermittent neuropathic pain, such as trigeminal neuralgia, Lhermitte sign, and glossopharyngeal neuralgia. In addition to disease-modifying therapies of MS, multiple treatments are available to manage neuropathic pain secondary to MS, including medical, interventional, and surgical treatments with varying levels of evidence.

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Individual neuronal subtypes control initial myelin sheath growth and stabilization

Neural Development ◽

10.1186/s13064-020-00149-3 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Heather N. Nelson ◽

Anthony J. Treichel ◽

Erin N. Eggum ◽

Madeline R. Martell ◽

Amanda J. Kaiser ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Myelin Sheath ◽

Time Lapse ◽

Marked Individual ◽

Larval Zebrafish ◽

Sheath Formation ◽

Time Lapse Imaging

Abstract Background In the developing central nervous system, pre-myelinating oligodendrocytes sample candidate nerve axons by extending and retracting process extensions. Some contacts stabilize, leading to the initiation of axon wrapping, nascent myelin sheath formation, concentric wrapping and sheath elongation, and sheath stabilization or pruning by oligodendrocytes. Although axonal signals influence the overall process of myelination, the precise oligodendrocyte behaviors that require signaling from axons are not completely understood. In this study, we investigated whether oligodendrocyte behaviors during the early events of myelination are mediated by an oligodendrocyte-intrinsic myelination program or are over-ridden by axonal factors. Methods To address this, we utilized in vivo time-lapse imaging in embryonic and larval zebrafish spinal cord during the initial hours and days of axon wrapping and myelination. Transgenic reporter lines marked individual axon subtypes or oligodendrocyte membranes. Results In the larval zebrafish spinal cord, individual axon subtypes supported distinct nascent sheath growth rates and stabilization frequencies. Oligodendrocytes ensheathed individual axon subtypes at different rates during a two-day period after initial axon wrapping. When descending reticulospinal axons were ablated, local spinal axons supported a constant ensheathment rate despite the increased ratio of oligodendrocytes to target axons. Conclusion We conclude that properties of individual axon subtypes instruct oligodendrocyte behaviors during initial stages of myelination by differentially controlling nascent sheath growth and stabilization.

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Optical coherence tomography imaging of oral mucosa bullous diseases: a preliminary study

Dentomaxillofacial Radiology ◽

10.1259/dmfr.20190071 ◽

2020 ◽

Vol 49 (2) ◽

pp. 20190071

Author(s):

Dario Di Stasio ◽

Dorina Lauritano ◽

Francesca Loffredo ◽

Enrica Gentile ◽

Fedora Della Vella ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Oral Mucosa ◽

Statistical Power ◽

Pemphigus Vulgaris ◽

Invasive Technique ◽

Optical Coherence ◽

Non Invasive ◽

Bullous Diseases ◽

Subepithelial Layer

Objectives: Optical coherence tomography (OCT) is a non-invasive technique based on optical imaging with a micrometre resolution. The purpose of this study is to investigate the potential role of OCT in evaluating oral mucosa bullous diseases. Methods: two patients with bullous pemphigoid (BP) and one patient with pemphigus vulgaris (PV) were examined and images of their oral lesions were performed using OCT. Results: In OCT images, the BP blister has a clearly different morphology from the PV one compared to the blistering level. Conclusion: This exploratory study suggests that the OCT is able to distinguish epithelial and subepithelial layer in vivo images of healthy oral mucosa from those with bullous diseases, assisting the clinicians in differential diagnosis.The presented data are in accordance with the scientific literature, although a wider pool of cases is needed to increase statistical power. Histological examination and immunofluorescence methods remain the gold standard for the diagnosis of oral bullous diseases. In this context, the OCT can provide the clinician with a valuable aid both as an additional diagnostic tool and in the follow up of the disease.

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Confocal Raman spectroscopy: Evaluation of a non-invasive technique for the detection of topically applied ketorolac tromethamine in vitro and in vivo

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2019.118641 ◽

2019 ◽

Vol 570 ◽

pp. 118641 ◽

Cited By ~ 3

Author(s):

Christian J.F. Bertens ◽

Shuo Zhang ◽

Roel J. Erckens ◽

Frank J.H.M. van den Biggelaar ◽

Tos T.J.M. Berendschot ◽

...

Keyword(s):

Raman Spectroscopy ◽

Invasive Technique ◽

Ketorolac Tromethamine ◽

Confocal Raman Spectroscopy ◽

Non Invasive ◽

Confocal Raman

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Neuromyelitis Optica

10.1093/med/9780199937837.003.0088 ◽

2017 ◽

Cited By ~ 1

Author(s):

Teri L. Schreiner ◽

Jeffrey L. Bennett

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Optic Neuritis ◽

Neuromyelitis Optica ◽

Water Channel ◽

Transverse Myelitis ◽

Inflammatory Disorder ◽

The Central Nervous System

Neuromyelitis optica (NMO), or Devic’s disease is an inflammatory disorder of the central nervous system that preferentially affects the optic nerves and spinal cord. Initially considered a variant of multiple sclerosis (MS), NMO is now clearly recognized to have distinct clinical, radiographic, and pathologic characteristics. Historically, the diagnosis of NMO required bilateral optic neuritis and transverse myelitis; however, the identification of a specific biomarker, NMO-IgG, an autoantibody against the aquaporin-4 (AQP4) water channel, has broadened NMO spectrum disease to include patients with diverse clinical and radiographic presentations. This chapter addresses the diagnosis, pathophysiology, and management of the disease.

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Cerebrospinal fluid biomarkers of β-amyloid metabolism in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458512460603 ◽

2012 ◽

Vol 19 (5) ◽

pp. 543-552 ◽

Cited By ~ 32

Author(s):

Kristin Augutis ◽

Markus Axelsson ◽

Erik Portelius ◽

Gunnar Brinkmalm ◽

Ulf Andreasson ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Inflammatory Diseases ◽

Amyloid Β ◽

Csf Biomarkers ◽

Aβ Peptide ◽

Aβ Peptides ◽

App Metabolism ◽

Disease Modifying

Background: Amyloid precursor protein (APP) and amyloid β (Aβ) peptides are intensely studied in neuroscience and their cerebrospinal fluid (CSF) measurements may be used to track the metabolic pathways of APP in vivo. Reduced CSF levels of Aβ and soluble APP (sAPP) fragments are reported in inflammatory diseases, including multiple sclerosis (MS); but in MS, the precise pathway of APP metabolism and whether it can be affected by disease-modifying treatments remains unclear. Objective: To characterize the CSF biomarkers of APP degradation in MS, including the effects of disease-modifying therapy. Methods: CSF samples from 87 MS patients (54 relapsing–remitting (RR) MS; 33 secondary progressive (SP) MS and 28 controls were analyzed for sAPP and Aβ peptides by immunoassays, plus a subset of samples was analyzed by immunoprecipitation and mass spectrometry (IP-MS). Patients treated with natalizumab or mitoxantrone were examined at baseline, and after 1–2 years of treatment. Results: CSF sAPP and Aβ peptide levels were reduced in MS patients; but they increased again towards normal, after natalizumab treatment. A multivariate model of IP-MS-measured Aβ species separated the SPMS patients from controls, with RRMS patients having intermediate levels. Conclusions: We confirmed and extended our previous observations of altered CSF sAPP and Aβ peptide levels in MS patients. We found that natalizumab therapy may be able to counteract the altered APP metabolism in MS. The CSF Aβ isoform distribution was found to be distinct in SPMS patients, as compared to the controls.

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Natalizumab (Tysabri) in multiple sclerosis patients

Farmeconomia Health economics and therapeutic pathways ◽

10.7175/fe.v9i2.222 ◽

2008 ◽

Vol 9 (2) ◽

pp. 109-114

Author(s):

Viola Sacchi

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Symptom Relief ◽

Interferon Β ◽

Disease Modifying Therapies ◽

Mental Symptoms ◽

The Central Nervous System ◽

Disease Modifying ◽

Multiple Sclerosis Patients ◽

Immunomodulating Drugs

Multiple sclerosis (MS) is an autoimmune disease where dysregulated immune system elements (i.e. leucocytes) react against different components of the central nervous system (CNS), in particular myelin structures, causing several physical and mental symptoms,often progressing to total disability. While some treatments for MS provide only symptom relief, the most commonly drugs administered for altering the course of the disease are DMTs (disease-modifying therapies); nevertheless for more than ten years the only DMTs available were interferon β, glatiramer acetate (two immunomodulating drugs) and mitoxantrone (an immunosuppressant).

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