The chemotherapy agent doxorubicin induces CNS expression of Ascl1, a regulator of adult neurogenesis and differentiation

 Do you really think your stroke medical 'professionals' have seen this and initiated research into human stroke subjects? I don't!

Do you prefer your doctor and hospital incompetence being NOT KNOWING. Or NOT DOING?

The chemotherapy agent doxorubicin induces CNS expression of Ascl1, a regulator of adult neurogenesis and differentiation

• Christi Anne S. Ng,
• Morgan Pedus,
• Madeline F. Lee,
• Lawrence F. Kromer,
• Jeanne Mandelblatt &
• G. William Rebeck 

Scientific Reports volume 15, Article number: 9725 (2025) Cite this article

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Abstract

Cancer-related cognitive impairment (CRCI) is a common side effect of cancer and its treatments. Cancer chemotherapy has been associated with hippocampal dysfunction and memory impairment. We investigated the effects of one chemotherapy agent, doxorubicin, on the transcription factor Ascl1 and proliferation of stem cells in the brain. We used an inducible mouse model designed to express TdTomato in Ascl1-lineage cells. Five to six-month-old Ascl1-CreERT2:ROSA mice were treated peripherally with a single dose of either doxorubicin (10 mg/kg) or DMSO control (n = 9 per group, n = 4–5 per sex). We analyzed brains of mice that had been exposed to doxorubicin for 2 weeks and had induced Ascl1 expression after the first week. We used immunostaining of neurogenesis stage specific markers to evaluate the doxorubicin effects on neuronal differentiation in the dentate gyrus of the hippocampus. Overall, doxorubicin significantly increased Ascl1 expression by 81% at this time point. As measured by Ascl1 double stains with Sox2, GFAP, and NeuroD1, doxorubicin-treated mice experienced an increase in Ascl1-mediated neural proliferation compared to control. A similar significant increase in the number of Ascl1-expressing cells (by 146%) after doxorubicin treatment was observed in the gray matter of the cerebral cortex. Thus, rather than leading to the loss of developing neurons, we found that a single dose of doxorubicin increased their appearance and progression, suggesting that hippocampal losses from chemotherapies may require greater and more sustained damage.

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

I got nothing out of this so your doctor can contact the two given email addresses to see what needs to be done to followup research in humans and create a stroke protocol for this. No followup, they need to be fired. Dead wood needs to be removed.  

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

Kyung-Min Noh, Jee-Yeon Hwang, Antonia Follenzi, Rodoniki Athanasiadou, Takahiro Miyawaki, John M. Greally, Michael V. L. Bennett, and R. Suzanne Zukin

PNAS February 27, 2012. 201121568; published ahead of print February 27, 2012. https://doi.org/10.1073/pnas.1121568109

1. Contributed by Michael V. L. Bennett, January 15, 2012 (sent for review December 22, 2011)

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Abstract

Dysregulation of the transcriptional repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor is important in a broad range of diseases, including cancer, diabetes, and heart disease. The role of REST-dependent epigenetic modifications in neurodegeneration is less clear. Here, we show that neuronal insults trigger activation of REST and CoREST in a clinically relevant model of ischemic stroke and that REST binds a subset of “transcriptionally responsive” genes (gria2, grin1, chrnb2, nefh, nfκb2, trpv1, chrm4, and syt6), of which the AMPA receptor subunit GluA2 is a top hit. Genes with enriched REST exhibited decreased mRNA and protein. We further show that REST assembles with CoREST, mSin3A, histone deacetylases 1 and 2, histone methyl-transferase G9a, and methyl CpG binding protein 2 at the promoters of target genes, where it orchestrates epigenetic remodeling and gene silencing. RNAi-mediated depletion of REST or administration of dominant-negative REST delivered directly into the hippocampus in vivo prevents epigenetic modifications, restores gene expression, and rescues hippocampal neurons. These findings document a causal role for REST-dependent epigenetic remodeling in the neurodegeneration associated with ischemic stroke and identify unique therapeutic targets for the amelioration of hippocampal injury and cognitive deficits.

• chromatin remodeling
• global ischemia
• CA1
• synaptic plasticity

Footnotes

• ↵¹K.-M.N. and J.-Y.H. contributed equally to this work.
• ↵²To whom correspondence may be addressed. E-mail: michael.bennett@einstein.yu.edu or suzanne.zukin@einstein.yu.edu.

Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System

We need this. What is your doctor doing to accomplish this in your recovery? ANYTHING AT ALL? 

Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System

Xueting Luo³

,

Marcio Ribeiro

,

Eric R. Bray

,

Do-Hun Lee

,

Benjamin J. Yungher

,

Saloni T. Mehta

,

Kinjal A. Thakor

,

Francisca Diaz

,

Jae K. Lee

,

Carlos T. Moraes

,

John L. Bixby

,

Vance P. Lemmon

,

Kevin K. Park

³Present address: Department of Ophthalmology, Shanghai First People’s Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Fundus Disease, 100 Hai Ning Road, Shanghai 200080, China

Publication stage: In Press Corrected Proof

Open Access

DOI: http://dx.doi.org/10.1016/j.celrep.2016.03.029

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Highlights

• •STAT3 shifts to distinct cellular regions in CNS neurons upon cytokine stimulation
• •STAT3′s transcriptional activity and mitochondrial localization co-induce regeneration
• •MEK enhances STAT3 functions and localization and potentiates axon regeneration
• •Modulation of STAT3, MEK, and PTEN promotes extensive axon growth and sprouting

Summary

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor central to axon regrowth with an enigmatic ability to act in different subcellular regions independently of its transcriptional roles. However, its roles in mature CNS neurons remain unclear. Here, we show that along with nuclear translocation, STAT3 translocates to mitochondria in mature CNS neurons upon cytokine stimulation. Loss- and gain-of-function studies using knockout mice and viral expression of various STAT3 mutants demonstrate that STAT3′s transcriptional function is indispensable for CNS axon regrowth, whereas mitochondrial STAT3 enhances bioenergetics and further potentiates regrowth. STAT3′s localization, functions, and growth-promoting effects are regulated by mitogen-activated protein kinase kinase (MEK), an effect further enhanced by Pten deletion, leading to extensive axon regrowth in the mouse optic pathway and spinal cord. These results highlight CNS neuronal dependence on STAT3 transcriptional activity, with mitochondrial STAT3 providing ancillary roles, and illustrate a critical contribution for MEK in enhancing diverse STAT3 functions and axon regrowth.

The Expression of FOXJ1 in Neurogenesis after Transient Focal Cerebral Ischemia

Your researcher should be able to match this up with all the other neurogenesis factors and translate that into a stroke protocol.

The Expression of FOXJ1 in Neurogenesis after Transient Focal Cerebral Ischemia

Authors

Yabo Huang¹, Zheng Xu¹, Jie Cao¹, Haibo Cao¹, Shiming Zhang¹

¹Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou, China

Abstract

Objective and Background: FOXJ1 is a member of the Forkhead/winged-helix (Fox) family of transcription factors, which is required for the differentiation of the cells acting as adult neural stem cells which participate in neurogenesis and give rise to neurons, astrocytes, oligodendrocytes. The expression pattern of FOXJ1 in the brain after cerebral ischemia has so far not been described. In the current study, we investigated the expression pattern of FOXJ1 in the rat brain after cerebral ischemia by animal model. Methods: We performed a middle cerebral artery occlusion (MCAO) model in adult rats and investigated the expression of FOXJ1 in the brain by Western blotting and immunochemistry; double immunofluorescence staining was used to analyze FOXJ1's co-expression with Ki67. Results: Western blot analysis showed that the expression of FOXJ1 was lower than normal and sham-operated brain after cerebral ischemia, but the level of FOXJ1 gradually increased from Day 1 to Day 14. Immuohistochemical staining suggested that the immunostaining of FOXJ1 deposited strongly in the ipsilateral and contralateral hemisphere in the cortical penumbra (CP). There was no FOXJ1 expression in the ischemic core (IC). The positive cells in the cortical penumbra might migrat to the ischemic core. In addition, double immunofluorescence staining revealed that FOXJ1 was co-expressed with mAP-2 and gFAP, and Ki67 had the colocalization with NeuN, GFAP, and FOXJ1. Conclusions: All our findings suggest that FOXJ1 plays an important role on neuronal production and neurogenesis in the adult brain after cerebral ischemia.