Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Schampel, Andrea; Volovitch, Oleg; Koeniger, Tobias; Scholz, Claus‐Jürgen; Jörg, Stefanie; Linker, Ralf A.; Wischmeyer, Erhard; Wunsch, Marie; Hell, Johannes; Ergün, Süleyman; Küerten, Stefanie

doi:10.1073/pnas.1620052114

Cited by 53 publications

(66 citation statements)

References 52 publications

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“…However, the role of melatonin in long‐range peripheral nerve defect was not discussed before. Appropriate microenvironment is important to correct remyelination and axonal regrowth that can be disturbed by excessive reactive oxygen species, ischemic and inflammatory processes . In this study, we fabricated a 3D melatonin/polycaprolactone nerve guide conduit using multilayer molding method and investigated its effects on Schwann cell proliferation and neural expression in vitro.…”

Section: Introductionmentioning

confidence: 99%

3D melatonin nerve scaffold reduces oxidative stress and inflammation and increases autophagy in peripheral nerve regeneration

Qian

Han

Zhao

et al. 2018

Journal of Pineal Research

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Peripheral nerve defect is a common and severe kind of injury in traumatic accidents. Melatonin can improve peripheral nerve recovery by inhibiting oxidative stress and inflammation after traumatic insults. In addition, it triggers autophagy pathways to increase regenerated nerve proliferation and to reduce apoptosis. In this study, we fabricated a melatonin-controlled-release scaffold to cure long-range nerve defects for the first time. 3D manufacture of melatonin/polycaprolactone nerve guide conduit increased Schwann cell proliferation and neural expression in vitro and promoted functional, electrophysiological and morphological nerve regeneration in vivo. Melatonin nerve guide conduit ameliorated immune milieu by reducing oxidative stress, inflammation and mitochondrial dysfunction. In addition, it activated autophagy to restore ideal microenvironment, to provide energy for nerves and to reduce nerve cell apoptosis, thus facilitating nerve debris clearance and neural proliferation. This innovative scaffold will have huge significance in the nerve engineering.

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Section: Introductionmentioning

confidence: 99%

3D melatonin nerve scaffold reduces oxidative stress and inflammation and increases autophagy in peripheral nerve regeneration

Qian

Han

Zhao

et al. 2018

Journal of Pineal Research

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“…NG2 + cell density was similarly reduced in the corpus callosum of P60 + 10 CaV1.2-deleted mice, when compared to control mice ( Figure S4e-g), confirming that CaV1.2 deletion resulted in OPC loss rather than the loss of PDGFRα expression by OPCs. As this reduction in OPC density was not recapitulated by the partial pharmacological blockade of CaV1.2, achieved by giving daily injections of nimodipine (as per Schampel et al (2017)) for up to seven consecutive days ( Figure S5), it is likely that OPC density can only be compromised by the complete and sustained loss of CaV1.2 signaling, as was achieved by our gene deletion approach.…”

Section: Cav12 Is Essential For the Survival Of Opcs In The Adult mentioning

confidence: 91%

“…j) Quantification of PDGFRα + OPCs density (per mm 2 ; x‐y plane with fixed z‐depth of 30 μm) in the corpus callosum of mice that received vehicle or nimodipine for 4 or 7 days. Schampel et al () reported that nimodipine delivery resulted in the apoptotic loss of microglia from the spinal cord of mice with experimental autoimmune encephalomyelitis, but not from healthy mice. We confirm that nimodipine does not alter microglial number in the spinal cord or brain of healthy mice.…”

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confidence: 99%

The voltage‐gated calcium channel CaV1.2 promotes adult oligodendrocyte progenitor cell survival in the mouse corpus callosum but not motor cortex

Pitman

Ricci

Gasperini

et al. 2019

Glia

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Throughout life, oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes. OPCs express cell surface receptors and channels that allow them to detect and respond to neuronal activity, including voltage‐gated calcium channel (VGCC)s. The major L‐type VGCC expressed by developmental OPCs, CaV1.2, regulates their differentiation. However, it is unclear whether CaV1.2 similarly influences OPC behavior in the healthy adult central nervous system (CNS). To examine the role of CaV1.2 in adulthood, we conditionally deleted this channel from OPCs by administering tamoxifen to P60 Cacna1c fl/fl (control) and Pdgfrα‐CreER:: Cacna1c fl/fl (CaV1.2‐deleted) mice. Whole cell patch clamp analysis revealed that CaV1.2 deletion reduced L‐type voltage‐gated calcium entry into adult OPCs by ~60%, confirming that it remains the major L‐type VGCC expressed by OPCs in adulthood. The conditional deletion of CaV1.2 from adult OPCs significantly increased their proliferation but did not affect the number of new oligodendrocytes produced or influence the length or number of internodes they elaborated. Unexpectedly, CaV1.2 deletion resulted in the dramatic loss of OPCs from the corpus callosum, such that 7 days after tamoxifen administration CaV1.2‐deleted mice had an OPC density ~42% that of control mice. OPC density recovered within 2 weeks of CaV1.2 deletion, as the lost OPCs were replaced by surviving CaV1.2‐deleted OPCs. As OPC density was not affected in the motor cortex or spinal cord, we conclude that calcium entry through CaV1.2 is a critical survival signal for a subpopulation of callosal OPCs but not for all OPCs in the mature CNS.

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“…; Schampel et al . ). For reasons that are not well understood, remyelination is incomplete in most of MS patients (Patrikios et al .…”

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confidence: 97%

“…On the cellular levels, steps involved in remyelination include the activation and proliferation of oligodendrocyte progenitor cells (OPCs), the migration of these OPCs toward the demyelinated axon, and the interaction of OPCs with the axon, which culminates in OPC differentiation and finally remyelination. The beneficial effects of remyelination are well known and include the restoration of axonal conduction properties that are lost following demyelination (Honmou et al 1996) as well as axonal protection (Funfschilling et al 2012;Moore et al 2013;Schampel et al 2017). For reasons that are not well understood, remyelination is incomplete in most of MS patients (Patrikios et al 2006), and remyelination efficacy decreases with age (Sim et al 2002).…”

mentioning

confidence: 99%

Chemical hypoxia‐induced integrated stress response activation in oligodendrocytes is mediated by the transcription factor nuclear factor (erythroid‐derived 2)‐like 2 (NRF2)

Teske

Liessem

Fischbach

et al. 2018

Journal of Neurochemistry

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The extent of remyelination in multiple sclerosis lesions is often incomplete. Injury to oligodendrocyte progenitor cells can be a contributing factor for such incomplete remyelination. The precise mechanisms underlying insufficient repair remain to be defined, but oxidative stress appears to be involved. Here, we used immortalized oligodendrocyte cell lines as model systems to investigate a causal relation of oxidative stress and endoplasmic reticulum stress signaling cascades. OLN93 and OliNeu cells were subjected to chemical hypoxia by blocking the respiratory chain at various levels. Mitochondrial membrane potential and oxidative stress levels were quantified by flow cytometry. Endoplasmic reticulum stress was monitored by the expression induction of activating transcription factor 3 and 4 (Atf3, Atf4), DNA damage-inducible transcript 3 protein (Ddit3), and glucose-regulated protein 94. Lentiviral silencing of nuclear factor (erythroid-derived 2)-like 2 or kelch-like ECH-associated protein 1 was applied to study the relevance of NRF2 for endoplasmic reticulum stress responses. We demonstrate that inhibition of the respiratory chain induces oxidative stress in cultured oligodendrocytes which is paralleled by the expression induction of distinct mediators of the endoplasmic reticulum stress response, namely Atf3, Atf4, and Ddit3. Atf3 and Ddit3 expression induction is potentiated in kelch-like ECH-associated protein 1-deficient cells and absent in cells lacking the oxidative stress-related transcription factor NRF2. This study provides strong evidence that oxidative stress in oligodendrocytes activates endoplasmic reticulum stress response in a NRF2-dependent manner and, in consequence, might regulate oligodendrocyte degeneration in multiple sclerosis and other neurological disorders.

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Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Cited by 53 publications

References 52 publications

3D melatonin nerve scaffold reduces oxidative stress and inflammation and increases autophagy in peripheral nerve regeneration

3D melatonin nerve scaffold reduces oxidative stress and inflammation and increases autophagy in peripheral nerve regeneration

The voltage‐gated calcium channel CaV1.2 promotes adult oligodendrocyte progenitor cell survival in the mouse corpus callosum but not motor cortex

Chemical hypoxia‐induced integrated stress response activation in oligodendrocytes is mediated by the transcription factor nuclear factor (erythroid‐derived 2)‐like 2 (NRF2)

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