Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

Mi, Guiyun; Gao, Yunyun; Liu, Shuai; Ye, Enmao; Li, Yanyan; Jin, Xiaoyue; Yang, Hongju; Yang, Zheng

doi:10.1080/15384101.2016.1220458

Cited by 11 publications

(4 citation statements)

References 67 publications

(74 reference statements)

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“…Thus, abnormal re‐initiation of cell cycle activity and expression of cell cycle markers such as Ki‐67 or proliferating cell nuclear antigen (PCNA) in mature neurons (Yang et al , ) might lead to cell apoptosis through p14 ARF ‐, p53‐, Bax‐, and Apaf‐1‐mediated caspase‐9 and caspase‐3 activities or cell death by B‐myb, C‐myb, and BIM activities induced by E2F1 upregulation (Ranganathan & Bowser, ). In contrast, inhibitors of cyclin‐dependent kinases or other cell cycle components can exert neuroprotective effects ameliorating this deregulation (Sanphui et al , ; Mi et al , ).…”

Section: Introductionmentioning

confidence: 99%

HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies

Jin

Wang

et al. 2020

EMBO Mol Med

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TAR DNA-binding protein 43 (TDP-43) has been implicated in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis. Histone deacetylase 1 (HDAC1) is involved in DNA repair and neuroprotection in numerous neurodegenerative diseases. However, the pathological mechanisms of FTLD-TDP underlying TDP-43 proteinopathies are unclear, and the role of HDAC1 is also poorly understood. Here, we found that aberrant cell cycle activity and DNA damage are important pathogenic factors in FTLD-TDP transgenic (Tg) mice, and we further identified these pathological features in the frontal cortices of patients with FTLD-TDP. TDP-43 proteinopathies contributed to pathogenesis by inducing cytosolic mislocalization of HDAC1 and reducing its activity. Pharmacological recovery of HDAC1 activity in FTLD-TDP Tg mice ameliorated their cognitive and motor impairments, normalized their aberrant cell cycle activity, and attenuated their DNA damage and neuronal loss. Thus, HDAC1 deregulation is involved in the pathogenesis of TDP-43 proteinopathies, and HDAC1 is a potential target for therapeutic interventions in FTLD-TDP.

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Section: Introductionmentioning

confidence: 99%

HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies

Jin

Wang

et al. 2020

EMBO Mol Med

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“…To identify proliferating glial cells during demyelination, BrdU (100μg, Sigma) was administered intraperitoneally for six consecutive days at five weeks of cuprizone treatment 48 . At the end of the demyelination period (2 hrs post-last BrdU injection), animals were euthanized and brain samples were collected for IHC analysis 49 .…”

Section: Brdu Incorporation Assaymentioning

confidence: 99%

Dicer deficiency in microglia leads to accelerated demyelination and failed remyelination

Tripathi,

Rai,

Perles

et al. 2023

Preprint

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Microglia are the resident immune cells of the central nervous system (CNS) and are important regulators of normal brain functions. In CNS demyelinating diseases like multiple sclerosis (MS), the functions of these cells are of particular interest. Here we probed the impact of microRNA (miRNA)-mediated post-transcriptional gene regulation using a mouse model lacking microglia/macrophage-specific Dicer expression during demyelination and remyelination. Conditional Dicer ablation and loss of miRNAs in adult microglia led to extensive demyelination and impaired myelin processing. Interestingly, demyelination was accompanied by increased apoptosis of mature oligodendrocytes (OLs) and arresting OL progenitor cells (OPCs) in the precursor stage. At the transcriptional level, Dicer-deficient microglia led to downregulation of microglial homeostatic genes, increased cell proliferation, and a shift towards a disease-associated phenotype. Loss of remyelination efficiency in these mice was accompanied by stalling of OPCs in the precursor stage. Collectively, these results highlight a new role of microglial miRNAs in promoting a pro-regenerative phenotype in addition to promoting OPC maturation and differentiation during demyelination and remyelination.

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“…MS (16,17). Previous CPZ studies have demonstrated memory impairment and depression like-symptoms following a CPZ diet of 5-6 weeks (18)(19)(20). Hence, strategies that promote intrinsic repair of myelin may help restore brain function and consequently alleviate depression and improve cognition in animal models, and ultimately, patients with MS.…”

Section: Low-field Magnetic Stimulation Improved Cuprizone-induced Depression-like Symptoms and Demyelination In Female Micementioning

confidence: 99%

Low‑field magnetic stimulation improved cuprizone‑induced depression‑like symptoms and demyelination in female mice

et al. 2022

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Depression is a common and disabling comorbidity of multiple sclerosis (MS), with currently no clear guidelines for treatment. Low-field magnetic stimulation (LFMS), a novel non-invasive neuromodulation intervention, has been previously demonstrated to rapidly alleviate mood disorders. The aim of the present study was to investigate the effects of LFMS on depression-like behaviors and demyelination in a well-established mouse model of MS. C57BL/6 female mice were fed a 0.2% cuprizone (CPZ) diet for 3 or 6 weeks to induce acute demyelination. During this time, the mice were treated with either sham or LFMS for 20 min/day, 5 days/week. After 3 or 6 weeks of treatment, behavior was assessed with the open field task, Y-maze and the forced swim test. The prefrontal cortex and hippocampus were then collected to perform immunohistochemistry and western blot analysis to verify myelination status. The CPZ diet did not cause significant locomotor deficits; however, working memory, measured using the Y maze, depression-like behavior and adaptive learning, assayed using the forced swim test, were significantly impaired in these animals. LFMS treatment demonstrated a significant antidepressant-like effect and markedly attenuated the CPZ-induced demyelination in the prefrontal cortex after 3-and 6-weeks of treatment, as observed by changes in myelin basic protein immunostaining and western blot analysis. Therefore, the results of the present study indicated that LFMS may be a promising therapy for demyelinating diseases due to the improvement of depressive symptoms via regulation of myelination in cortical areas.

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Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

Cited by 11 publications

References 67 publications

HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies

HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies

Dicer deficiency in microglia leads to accelerated demyelination and failed remyelination

Low‑field magnetic stimulation improved cuprizone‑induced depression‑like symptoms and demyelination in female mice

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