Small compounds mimicking the adhesion molecule L1 improve recovery in a zebrafish demyelination model

Abstract

Demyelination leads to a loss of neurons, which results in, among other consequences, a severe reduction in locomotor function, and underlies several diseases in humans including multiple sclerosis and polyneuropathies. Considerable clinical progress has been made in counteracting demyelination. However, there remains a need for novel methods that reduce demyelination while concomitantly achieving remyelination, thus complementing the currently available tools to ameliorate demyelinating diseases. In this study, we used an established zebrafish demyelination model to test selected compounds, following a screening in cell culture experiments and in a mouse model of spinal cord injury that was aimed at identifying beneficial functions of the neural cell adhesion molecule L1. In comparison to mammalian nervous system disease models, the zebrafish allows testing of potentially promotive compounds more easily than what is possible in mammals. We found that our selected compounds tacrine and duloxetine significantly improved remyelination in the peripheral and central nervous system of transgenic zebrafish following pharmacologically induced demyelination. Given that both molecules are known to positively affect functions other than those related to L1 and in other disease contexts, we propose that their combined beneficial function raises hope for the use of these compounds in clinical settings.

Antagonistic L1 Adhesion Molecule Mimetic Compounds Inhibit Glioblastoma Cell Migration In Vitro

“…Indeed, when applied in spinal cord injury models as a recombinant glycoprotein or when overexpressed by adeno-associated virus in stem cell-derived neural Biomolecules 2022, 12, 439 2 of 16 aggregates, Schwann cells and radial glial cells, L1 accelerated remyelination and improved axonal regrowth/sprouting/sparing proximal, distal and across the lesion site [9][10][11][12]. In addition, L1 ameliorated the severe consequences of injury in experimental models of neurodegenerative diseases in vitro and in vivo [13][14][15][16][17]. Since the viral delivery of L1, application of recombinant L1, and injection of stem cells overexpressing L1 are expected to meet difficulties in translation to therapy, libraries of small organic molecules were screened for compounds that structurally and functionally mimic L1, and several molecules were found to act as L1 agonistic mimetics [18].…”

Single Nucleotide Polymorphism in Cell Adhesion Molecule L1 Affects Learning and Memory in a Mouse Model of Traumatic Brain Injury

“…L1 cell adhesion molecule (L1CAM, hereafter abbreviated L1) has been shown to reduce the severe consequences of neurological diseases, such as multiple sclerosis [1], Parkinson's [2], and Alzheimer's [3] disease, in mouse and zebrafish models. The study of these models has led to the view that the disease-adverse phenotypes could be reduced by treatment with neural stem cells overexpressing L1, administration of recombinant extracellular domain of L1, function triggering L1 antibodies, and L1-derived peptide interacting with itself, i.e., homophilically with L1 [4].…”

Hydroalcoholic extract of Centella asiatica ameliorate on 3-nitropropionic acid induced Huntington's like symptoms in adult zebrafish

“…In this context, zebrafish is an outstanding model system to perform number of neurodegenerative disorders (HD, AD, PD, PD, and MS), due to several advantages over the other experimental animals which includes, easy to genetic manipulation, low cost, fast development and large progeny (16,17).The physiology of zebrafish is similar to human being (more than 75%). Evidenced suggested that zebrafish as an excellent animal model for the study of several brain disorders such as Alzheimer's disease (AD) (18,19), Parkinson's disease (20), stress (21), epilepsy (22,23), dementia (24), cognition (25,26), Multiple sclerosis (MS) (27), Amyotropic lateral sclerosis (ALS) (28,29), and TBI (30).…”