Bumetanide induces post-traumatic microglia–interneuron1 contact to promote neurogenesis and recovery

 Hell, your doctor should  have done something with bumetanide over a decade ago.

 

• bumetanide (5 posts to February 2012)

   

   

Bumetanide induces post-traumatic microglia–interneuron1 contact to promote neurogenesis and recovery

Benoit Dehapiot,3 Li Tian,4 Florence Molinari,5 Jerome Laurin,1 François Guillemot,6 Christian4
A. Hübner,7 Christophe Pellegrino1 and Claudio Rivera1,2

Abstract

Although the Na-K-Cl cotransporter (NKCC1) inhibitor bumetanide has prominent positive effects
on the pathophysiology of many neurological disorders, the mechanism of action is obscure.
Attention for elucidating the role of Nkcc1 has been mainly focused on neurons. Recent single cell mRNA sequencing analysis has demonstrated that the major cellular populations expressing NKCC1 in the cortex are non-neuronal. We used a combination of conditional transgenic animals, in vivo electrophysiology, two-photon imaging, cognitive behavioral tests and flow cytometry to investigate the role of Nkcc1 inhibition by bumetanide in a mouse model of controlled cortical impact (CCI). Here, we found that bumetanide rescues parvalbumin-positive interneurons by increasing interneuron-microglia contacts shortly after injury. The longitudinal phenotypic changes of microglia were significantly modified by bumetanide, including an increase in the expression of microglial-derived Bdnf. These effects were accompanied by the prevention of CCI-induced decrease in hippocampal neurogenesis. Treatment with bumetanide during the first week post-CCI resulted in significant recovery of working and episodic memory as well as changes in theta band oscillations one month later. These results disclose a novel mechanism for the neuroprotective action of bumetanide mediated by an acceleration of microglial activation dynamics that leads to an increase of parvalbumininterneuron survival following CCI, possibly resulting from increased microglial Bdnf expression and contact with interneurons. Salvage of interneurons may normalize ambient gamma-aminobutyric acid (GABA), resulting in the preservation of adult neurogenesis processes as well as contributing to bumetanide-mediated improvement of cognitive performance.

Role of SPAK-NKCC1 Signaling Cascade in the Choroid Plexus Blood-CSF Barrier Damage After Stroke

What will your doctors and hospital do to get this testing(Pharmacological blockade of the SPAK-NKCC1 pathway protected the ChP barrier integrity) done in humans? If nothing you don't have a functioning stroke hospital.

Role of SPAK-NKCC1 Signaling Cascade in theChoroid Plexus Blood-CSF Barrier Damage After Stroke

Jun Wang, Ruijia Liu, Md Nabiul Hasan, Sydney Fischer, Matt Como, Victoria M Fiesler, Gulnaz Begum, Yang Chen, Mohammad Iqbal H. Bhuiyan, Shuying Dong, Eric Li, Kristopher T Kahle, Jinwei Zhang, Xianming Deng, Arohan R Subramanya, Yan Yin, Dandan Sun

DOI:

10.21203/rs.3.rs-1189368/v1

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LICENSE:

This work is licensed under a CC BY 4.0 License. Read Full License

Background: 

The mechanisms underlying dysfunction of choroid plexus (ChP) blood-cerebrospinal fluid (CSF) barrier and lymphocyte invasion in neuroinflammatory responses to stroke are not well understood. In this study, we investigated whether stroke damaged the blood-CSF barrier integrity due to dysregulation of major ChP ion transport system Na+-K+-Cl- cotransporter (NKCC1) and regulatory Ste20-related proline-alanine-rich kinase (SPAK). 

Methods: 

Sham or ischemic stroke was induced in C57Bl/6J mice. Changes of the SPAK-NKCC1 complex and tight junction proteins (TJs) in the ChP were quantified by immunofluorescence staining and immunoblotting. Immune cell infiltration in the ChP was assessed by flow cytometry and immunostaining. Cultured ChP epithelium cells (CPECs) and cortical neurons were used to evaluate H2O2-mediated oxidative stress in stimulating the SPAK-NKCC1 complex and cellular damage. In vivo or in vitro pharmacological blockade of the ChP SPAK-NKCC1 cascade with SPAK inhibitor ZT-1a or NKCC1 inhibitor bumetanide were examined. 

Results: 

Ischemic stroke stimulated activation of the CPECs apical membrane SPAK-NKCC1 complex, NF-κB, and MMP9, which was associated with loss of the blood-CSF barrier integrity and increased immune cell infiltration into the ChP. Oxidative stress directly activated SPAK-NKCC1 pathway and resulted in apoptosis, neurodegeneration, and NKCC1-mediated ion influx. Pharmacological blockade of the SPAK-NKCC1 pathway protected the ChP barrier integrity, attenuated ChP immune cell infiltration or neuronal death. 

Conclusion: 

Stroke-induced pathological stimulation of the SPAK-NKCC1 cascade caused CPECs damage and disruption of TJs at the blood-CSF barrier. The ChP SPAK-NKCC1 complex emerged as a therapeutic target for attenuating ChP dysfunction and lymphocyte invasion after stroke.

KEYWORDS

bumetanide, choroid plexus, H2O2, Na+-K+-Cl- cotransporter, SPAK, ZT-1a

Repurposed drug reverses signs of Alzheimer's in mice, human cells

You'll want your doctors and stroke hospital to be closely following this so as soon as it is proven protocols are written and implemented in your hospital. If your hospital doesn't have a dedicated research analyst whose only job is to follow and implement research then you don't have a functioning stroke hospital. You'll have to ask your doctor if this works for non-APOE4-related Alzheimer’s disease.

Hell your doctor should have been using bumetanide for 9 years already.

• bumetanide (2 posts to February 2012)

Your risk of dementia, has your doctor told you of this?

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

 

Repurposed drug reverses signs of Alzheimer's in mice, human cells

The Scientist|October 13, 2021

Bumetanide, a drug already approved to treat swelling associated with conditions such as heart failure, improved performance on cognitive tests and reduced the buildup of amyloid plaques in mice with an Alzheimer’s-like condition, researchers report. Furthermore, in cultured human neurons derived from stem cells, bumetanide reversed gene expression changes associated with Alzheimer’s, and the electronic health records of millions of patients point to a link between the drug and reduced odds of being diagnosed with the disease.

On the basis of these results, published this week (October 10) in Nature Aging, Gladstone Institutes neurobiologist and study coauthor Yadong Huang tells STAT that he and his team are now pursuing a clinical trial to test the drug in human patients with at least one copy of the APOE4 variant, a well-known risk factor for the disease.

Bumetanide blocks ion channels in the cell membrane, thereby altering salt balances and reducing water retention, but how this mechanism might affect neural function is not known. “The mechanism of the drug is well-known, but what the authors haven’t addressed is how that mechanism is related to what they think might happen if they were to give this drug to Alzheimer’s patients,” Johns Hopkins University neurologist Shilpa Kadam, who was not involved in the study, tells STAT.

While bumetanide did shrink amyloid plaques in a mouse model of Alzheimer’s, the drug is not thought to target these protein aggregations directly as many experimental Alzheimer’s drugs have. Many such drugs have failed, and one that was recently approved, Biogen’s Aduhelm, has been mired in controversy, with some questioning its efficacy and the legitimacy of its regulatory review.

The new study supports a growing body of evidence that amyloid plaques are but one piece of the puzzle. In Alzheimer’s patients with at least one copy of APOE4, nearly 2,000 genes showed altered expression compared with healthy controls, Huang and his colleagues found. These included genes involved with circadian rhythms, morphine addiction, and the neurotransmitter GABA.

“There are many cellular and molecular changes in Alzheimer’s disease patients besides plaques, but we usually don’t talk about them,” Huang tells STAT. He adds that “patients may have different underlying cellular mechanisms that lead to their neurodegeneration,” and thus may require different treatments. “More and more people are accepting this concept, but it’s definitely still an emerging idea.”

Jeffrey Cummings, director of the Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada Las Vegas, tells STATthat the new study reveals “a repertoire of pathways that have not been adequately investigated,” but notes that bumetanide can cause dehydration and electrolyte imbalances. “This drug’s relationship to Alzheimer’s disease is not quite proven and its side effect profile is undesirable in older people,” he says.

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Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease

You'll want your doctors and stroke hospital to be closely following this so as soon as it is proven protocols are written and implemented in your hospital. If your hospital doesn't have a dedicated research analyst whose only job is to follow and implement research then you don't have a functioning stroke hospital. You'll have to ask your doctor if this works for non-APOE4-related Alzheimer’s disease.

Hell your doctor should have been using bumetanide for 9 years already.

• bumetanide (2 posts to February 2012)

Your risk of dementia, has your doctor told you of this?

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

 

Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease

 

• Alice Taubes,
• Phil Nova,
• […]
• Yadong Huang 

Nature Aging volume 1, pages 932–947 (2021)Cite this article

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Abstract

The evident genetic, pathological and clinical heterogeneity of Alzheimer’s disease (AD) poses challenges for traditional drug development. We conducted a computational drug-repurposing screen for drugs to treat apolipoprotein E4 (APOE4)-related AD. We first established APOE genotype-dependent transcriptomic signatures of AD by analyzing publicly available human brain databases. We then queried these signatures against the Connectivity Map database, which contains transcriptomic perturbations of more than 1,300 drugs, to identify those that best reverse APOE genotype-specific AD signatures. Bumetanide was identified as a top drug for APOE4-related AD. Treatment of APOE4-knock-in mice without or with amyloid β (Aβ) accumulation using bumetanide rescued electrophysiological, pathological or cognitive deficits. Single-nucleus RNA sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in APOE4 induced pluripotent stem cell (iPSC)-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 years in two electronic health record databases, suggesting the effectiveness of bumetanide in preventing AD.

Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia

We will never know if this might help stroke survivors because we have no fucking stroke leaders that followup promising research with human clinical trials. You'll be screwed forever until we destroy the existing stroke leadership.

Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia

Wang-shu Xu¹, Xuan Sun², Cheng-guang Song³, Xiao-peng Mu⁴, Wen-ping Ma⁵, Xing-hu Zhang⁶, Chuan-sheng Zhao M.D. ^4
1 Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province; Neuroinfection and Neuroimmunology Center, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
² Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
³ Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang; Department of Neurology, Benxi Central Hospital of China Medical University, Benxi, Liaoning Province, China
⁴ Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
⁵ Department of Medical Genetics, School of Basic Medicine, Peking University, Beijing, China
⁶ Neuroinfection and Neuroimmunology Center, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Date of Acceptance	25-Feb-2016
Date of Web Publication	1-Jun-2016

Correspondence Address:
Chuan-sheng Zhao
Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province
China

Source of Support: None, Conflict of Interest: None
DOI: 10.4103/1673-5374.182700

Abstract

Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic stage of cerebral ischemia. We established a rat model of cerebral ischemia by injecting endothelin-1 in the left cortical motor area and left corpus striatum. Seven days later, bumetanide 200 µg/kg/day was injected into the lateral ventricle for 21 consecutive days with a mini-osmotic pump. Results demonstrated that the number of neuroblasts cells and the total length of dendrites increased, escape latency reduced, and the number of platform crossings increased in the rat hippocampal dentate gyrus in the chronic stage of cerebral ischemia. These findings suggest that bumetanide promoted neural precursor cell regeneration, dendritic development and the recovery of cognitive function, and protected brain tissue in the chronic stage of ischemia.

Keywords: nerve regeneration; cerebral ischemia; bumetanide; Na ⁺ -K ⁺ -2Cl^- cotransporter 1; hippocampal dentate gyrus; neurogenesis; neural precursor cells; dendritic development; cognitive function; neural regeneration

How to cite this article: Xu Ws, Sun X, Song Cg, Mu Xp, Ma Wp, Zhang Xh, Zhao Cs. Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia. Neural Regen Res 2016;11:745-51

The Loop Diuretic Bumetanide Blocks Posttraumatic p75NTR Upregulation and Rescues Injured Neurons

We will never know if this might help stroke survivors because we have no fucking stroke leaders that followup promising research with human clinical trials. You'll be screwed forever until we destroy the existing stroke leadership.

 

 The Loop Diuretic Bumetanide Blocks Posttraumatic p75NTR Upregulation and Rescues Injured Neurons

Abstract

Injured neurons become dependent on trophic factors for survival. However, application of trophic factors to the site of injury is technically extremely challenging. Novel approaches are needed to circumvent this problem. Here, we unravel the mechanism of the emergence of dependency of injured neurons on brain-derived neurotrophic factor (BDNF) for survival. Based on this mechanism, we propose the use of the diuretic bumetanide to prevent the requirement for BDNF and consequent neuronal death in the injured areas. Responses to the neurotransmitter GABA change from hyperpolarizing in intact neurons to depolarizing in injured neurons. We show in vivo in rats and ex vivo in mouse organotypic slice cultures that posttraumatic GABA_A-mediated depolarization is a cause for the well known phenomenon of pathological upregulation of pan-neurotrophin receptor p75^NTR. The increase in intracellular Ca²⁺ triggered by GABA-mediated depolarization activates ROCK (Rho kinase), which in turn leads to the upregulation of p75^NTR. We further show that high levels of p75^NTR and its interaction with sortilin and proNGF set the dependency on BDNF for survival. Thus, application of bumetanide prevents p75^NTR upregulation and neuronal death in the injured areas with reduced levels of endogenous BDNF.