Evidence map›Paper›PMID 41015675›Full record

ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2025

Inhibition of microglial glutaminase alleviates chronic stress-induced neurobehavioral and cognitive deficits.

Meixiang Huang, Yannan Li, Ajit G Thomas, Anjali Sharma, Wathsala Liyanage, Tomáš Tichý, Lukáš Tenora, Yu Su, Jisu Ha, Niyada Hin and 8 more

Abstract read
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In one paragraph

Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

  1. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Meixiang HuangJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yannan LiDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ajit G ThomasJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Anjali SharmaCenter for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Wathsala LiyanageCenter for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Tomáš TichýInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic (ASCR), Prague 160 00, Czech Republic.
Lukáš TenoraJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic (ASCR), Prague 160 00, Czech Republic.
Yu SuJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jisu HaLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA.
Niyada HinJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mizuho ObayashiDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Pavel MajerInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic (ASCR), Prague 160 00, Czech Republic.
Rangaramanujam M KannanCenter for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Takashi TsukamotoJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Pharmacology & Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Gianluca UrsiniDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA.
Rana RaisJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Pharmacology & Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Barbara S SlusherJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Pharmacology & Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: bslusher@jhmi.edu.
Xiaolei ZhuJohns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: xzhu31@jhmi.edu.

Funding

The role of microglial glutaminase in HIV-induced sleep deficitsR01HL180044 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI Xiaolei Zhu · 2025 to 2026
$1.4M
Microglia-targeted glutaminase inhibition forthe treatment of chronic stress-associated depressionR56MH135895 · NIMH · JOHNS HOPKINS UNIVERSITY · PI ZHU, XIAOLEI · 2024 to 2025
$1.1M
Exploring a natural product to modulate aberrant gut bacterial-fungal interactions as pathological mechanisms underlying HIV-associated depressionK01AT010984 · NCCIH · JOHNS HOPKINS UNIVERSITY · PI ZHU, XIAOLEI · 2020 to 2024
$676k
NCCIH NIH HHS K01 AT010984NHLBI NIH HHS R01 HL180044NIMH NIH HHS R56 MH135895
6 · The paper itself

Abstract

Major depressive disorder (MDD) is a prevalent and debilitating psychiatric condition with significant societal and economic impacts. Many patients are resistant to current antidepressant therapies, underscoring the need for novel treatments targeting underlying mechanisms. We previously discovered that glutaminase (GLS1), an enzyme converting glutamine to glutamate, is upregulated specifically in activated microglia in mice exposed to Chronic Social Defeat Stress (CSDS). Importantly, GLS1 mRNA was also upregulated in microglia within postmortem brain tissue of MDD patients, highlighting a potential role for microglial GLS1 in MDD pathophysiology. However, existing GLS1 inhibitors lack brain penetrance and/or cause gastrointestinal toxicities, limiting their translational potential. To address this, we utilized a hydroxyl-terminated poly(amidoamine) dendrimer nanoparticle system to selectively target microglial GLS1. Using structurally distinct GLS1 inhibitors, we synthesized two hydroxyl-dendrimer-GLS1 inhibitor conjugates: dendrimer-TTM020 (D-TTM020) and dendrimer-JHU29 (D-JHU29). In the murine CSDS model, we evaluated their microglial target engagement, safety, and efficacy using immunofluorescence, GLS1 activity assays, gastrointestinal histopathology, and a battery of behavioral tests. Using a Cy5 fluorescently labeled hydroxyl-dendrimer (D-Cy5), we confirmed that systemically administered D-Cy5 crossed the blood-brain barrier and was selectively engulfed by activated microglia in mice after CSDS. D-TTM020 and D-JHU29 attenuated CSDS-induced microglial GLS1 activity elevation without affecting non-microglial cells. Furthermore, D-TTM020 and D-JHU29 both alleviated CSDS-induced social avoidance, and D-TTM020 additionally reduced anxiety-like behavior and improved recognition memory. Both conjugates were well tolerated, with no overt or gastrointestinal toxicities. Collectively, these findings suggest that microglia-targeted GLS1 inhibition is a promising therapeutic approach for chronic stress-associated depression.

Indexed as

Cognitive DysfunctionEnzyme InhibitorsGlutaminaseMicrogliaStress, PsychologicalAnimalsMaleMiceMice, Inbred C57BLSocial DefeatEnzyme InhibitorsGLS1 protein, mouseGlutaminaseChronic social defeat stressDendrimerDepressionGlutaminaseMicroglia

Identifiers

PMID41015675
PMCPMC12664560

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.