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.

Center for Nanomedicine Department of Ophthalmology Wilmer Eye Institute Johns Hopkins University School of Medicine Baltimore MD 21231 USA

Center 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

Department of Psychiatry and Behavioral Sciences 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; Lieber Institute for Brain Development Johns Hopkins Medical Campus Baltimore MD 21205 USA

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague 160 00 Czech Republic

Johns Hopkins Drug Discovery Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Johns 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

Johns 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 and Therapeutics Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Johns 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 and 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

Johns 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

Johns 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 Prague 160 00 Czech Republic

Lieber Institute for Brain Development Johns Hopkins Medical Campus Baltimore MD 21205 USA

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Hasin D.S., Sarvet A.L., Meyers J.L., Saha T.D., Ruan W.J., Stohl M., et al. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatr. 2018;75(4):336–346. PubMed PMC

Kessler R.C., Berglund P., Demler O., Jin R., Koretz D., Merikangas K.R., et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R) JAMA. 2003;289(23):3095–3105. PubMed

Hodes G.E., Kana V., Menard C., Merad M., Russo S.J. Neuroimmune mechanisms of depression. Nat Neurosci. 2015;18(10):1386–1393. PubMed PMC

Mathew S.J. Treatment-resistant depression: recent developments and future directions. Depress Anxiety. 2008;25(12):989–992. PubMed PMC

Otte C., Gold S.M., Penninx B.W., Pariante C.M., Etkin A., Fava M., et al. Major depressive disorder. Nat Rev Dis Primers. 2016;2 PubMed

Akil H., Gordon J., Hen R., Javitch J., Mayberg H., McEwen B., et al. Treatment resistant depression: a multi-scale, systems biology approach. Neurosci Biobehav Rev. 2018;84:272–288. PubMed PMC

Malhi G.S., Mann J.J. Depression. Lancet. 2018;392(10161):2299–2312. PubMed

Lieblich S.M., Castle D.J., Pantelis C., Hopwood M., Young A.H., Everall I.P. High heterogeneity and low reliability in the diagnosis of major depression will impair the development of new drugs. BJPsych Open. 2015;1(2):e5–e7. PubMed PMC

Krystal J.H., Sanacora G., Duman R.S. Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry. 2013;73(12):1133–1141. PubMed PMC

Murrough J.W., Abdallah C.G., Mathew S.J. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16(7):472–486. PubMed

Reus G.Z., de Moura A.B., Silva R.H., Resende W.R., Quevedo J. Resilience dysregulation in major depressive disorder: focus on glutamatergic imbalance and microglial activation. Curr Neuropharmacol. 2017 PubMed PMC

Kim J.S., Schmid-Burgk W., Claus D., Kornhuber H.H. Increased serum glutamate in depressed patients. Arch Psychiatr Nervenkr. 1982;232(4):299–304. PubMed

Umehara H., Numata S., Watanabe S.Y., Hatakeyama Y., Kinoshita M., Tomioka Y., et al. Altered KYN/TRP, Gln/Glu, and Met/methionine sulfoxide ratios in the blood plasma of medication-free patients with major depressive disorder. Sci Rep. 2017;7(1):4855. PubMed PMC

Levine J., Panchalingam K., Rapoport A., Gershon S., McClure R.J., Pettegrew J.W. Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatr. 2000;47(7):586–593. PubMed

Hashimoto K., Bruno D., Nierenberg J., Marmar C.R., Zetterberg H., Blennow K., et al. Abnormality in glutamine-glutamate cycle in the cerebrospinal fluid of cognitively intact elderly individuals with major depressive disorder: a 3-year follow-up study. Transl Psychiatr. 2016;6 PubMed PMC

Taylor R., Neufeld R.W., Schaefer B., Densmore M., Rajakumar N., Osuch E.A., et al. Functional magnetic resonance spectroscopy of glutamate in schizophrenia and major depressive disorder: anterior cingulate activity during a color-word Stroop task. NPJ Schizophrenia. 2015;1 PubMed PMC

Haroon E., Fleischer C.C., Felger J.C., Chen X., Woolwine B.J., Patel T., et al. Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol Psychiatr. 2016;21(10):1351–1357. PubMed PMC

Milak M.S., Proper C.J., Mulhern S.T., Parter A.L., Kegeles L.S., Ogden R.T., et al. A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder. Mol Psychiatr. 2016;21(3):320–327. PubMed PMC

Quiroz J.A., Tamburri P., Deptula D., Banken L., Beyer U., Rabbia M., et al. Efficacy and safety of basimglurant as adjunctive therapy for major depression: a randomized clinical trial. JAMA Psychiatr. 2016;73(7):675–684. PubMed

Sanacora G., Zarate C.A., Krystal J.H., Manji H.K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7(5):426–437. PubMed PMC

Jaso B.A., Niciu M.J., Iadarola N.D., Lally N., Richards E.M., Park M., et al. Therapeutic modulation of glutamate receptors in major depressive disorder. Curr Neuropharmacol. 2017;15(1):57–70. PubMed PMC

Lener M.S., Niciu M.J., Ballard E.D., Park M., Park L.T., Nugent A.C., et al. Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine. Biol Psychiatr. 2017;81(10):886–897. PubMed PMC

Zarate C.A., Jr., Singh J.B., Carlson P.J., Brutsche N.E., Ameli R., Luckenbaugh D.A., et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatr. 2006;63(8):856–864. PubMed

Murrough J.W., Iosifescu D.V., Chang L.C., Al Jurdi R.K., Green C.E., Perez A.M., et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatr. 2013;170(10):1134–1142. PubMed PMC

Singh J.B., Fedgchin M., Daly E.J., De Boer P., Cooper K., Lim P., et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatr. 2016;173(8):816–826. PubMed

Setiawan E., Wilson A.A., Mizrahi R., Rusjan P.M., Miler L., Rajkowska G., et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatr. 2015;72(3):268–275. PubMed PMC

Raison C.L., Rutherford R.E., Woolwine B.J., Shuo C., Schettler P., Drake D.F., et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatr. 2013;70(1):31–41. PubMed PMC

Shelton R.C., Claiborne J., Sidoryk-Wegrzynowicz M., Reddy R., Aschner M., Lewis D.A., et al. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatr. 2011;16(7):751–762. PubMed PMC

Haroon E., Miller A.H., Sanacora G. Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacology. 2017;42(1):193–215. PubMed PMC

Miller A.H., Raison C.L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22–34. PubMed PMC

Takeuchi H., Jin S., Wang J., Zhang G., Kawanokuchi J., Kuno R., et al. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem. 2006;281(30):21362–21368. PubMed

Potter M.C., Figuera-Losada M., Rojas C., Slusher B.S. Targeting the glutamatergic system for the treatment of HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol : Off J Soc NeuroImmune Pharmacol. 2013;8(3):594–607. PubMed PMC

Maezawa I., Jin L.W. Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J Neurosci. 2010;30(15):5346–5356. PubMed PMC

Werner P., Pitt D., Raine C.S. Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann Neurol. 2001;50(2):169–180. PubMed

Pitt D., Werner P., Raine C.S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med. 2000;6(1):67–70. PubMed

Thomas A.G., O'Driscoll C.M., Bressler J., Kaufmann W., Rojas C.J., Slusher B.S. Small molecule glutaminase inhibitors block glutamate release from stimulated microglia. Biochem Biophys Res Commun. 2014;443(1):32–36. PubMed PMC

Zhu X., Nedelcovych M.T., Thomas A.G., Hasegawa Y., Moreno-Megui A., Coomer W., et al. JHU-083 selectively blocks glutaminase activity in brain CD11b(+) cells and prevents depression-associated behaviors induced by chronic social defeat stress. Neuropsychopharmacology. 2019;44(4):683–694. PubMed PMC

Ji C., Tang Y., Zhang Y., Li C., Liang H., Ding L., et al. Microglial glutaminase 1 deficiency mitigates neuroinflammation associated depression. Brain Behav Immun. 2022;99:231–245. PubMed

Nagy C., Maitra M., Tanti A., Suderman M., Theroux J.F., Davoli M.A., et al. Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons. Nat Neurosci. 2020;23(6):771–781. PubMed

Lemberg K.M., Vornov J.J., Rais R., Slusher B.S. We're not "DON" yet: optimal dosing and prodrug delivery of 6-Diazo-5-oxo-L-norleucine. Mol Cancer Ther. 2018;17(9):1824–1832. PubMed PMC

Magill G.B., Myers W.P., Reilly H.C., Putnam R.C., Magill J.W., Sykes M.P., et al. Pharmacological and initial therapeutic observations on 6-diazo-5-oxo-1-norleucine (DON) in human neoplastic disease. Cancer. 1957;10(6):1138–1150. PubMed

Earhart R.H., Amato D.J., Chang A.Y., Borden E.C., Shiraki M., Dowd M.E., et al. Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas. Invest New Drugs. 1990;8(1):113–119. PubMed

Rahman A., Smith F.P., Luc P.T., Woolley P.V. Phase I study and clinical pharmacology of 6-diazo-5-oxo-L-norleucine (DON) Invest New Drugs. 1985;3(4):369–374. PubMed

Harding J.J., Telli M., Munster P., Voss M.H., Infante J.R., DeMichele A., et al. A phase I dose-escalation and expansion study of telaglenastat in patients with advanced or metastatic solid tumors. Clin Cancer Res. 2021;27(18):4994–5003. PubMed PMC

Gross M.I., Demo S.D., Dennison J.B., Chen L., Chernov-Rogan T., Goyal B., et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13(4):890–901. PubMed

Guo Y., Johnson M.A., Mehrabian Z., Mishra M.K., Kannan R., Miller N.R., et al. Dendrimers target the ischemic lesion in rodent and primate models of nonarteritic anterior ischemic optic neuropathy. PLoS One. 2016;11(4) PubMed PMC

Kannan S., Dai H., Navath R.S., Balakrishnan B., Jyoti A., Janisse J., et al. Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. Sci Transl Med. 2012;4(130) PubMed PMC

Nino D.F., Zhou Q., Yamaguchi Y., Martin L.Y., Wang S., Fulton W.B., et al. Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain. Sci Transl Med. 2018;10(471) PubMed PMC

Kambhampati S.P., Bhutto I.A., Wu T., Ho K., McLeod D.S., Lutty G.A., et al. Systemic dendrimer nanotherapies for targeted suppression of choroidal inflammation and neovascularization in age-related macular degeneration. J Contr Release : Off J Contr Release Soc. 2021;335:527–540. PubMed

Menjoge A.R., Kannan R.M., Tomalia D.A. Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications. Drug Discov Today. 2010;15(5-6):171–185. PubMed

Inapagolla R., Guru B.R., Kurtoglu Y.E., Gao X., Lieh-Lai M., Bassett D.J., et al. In vivo efficacy of dendrimer-methylprednisolone conjugate formulation for the treatment of lung inflammation. Int J Pharm. 2010;399(1-2):140–147. PubMed

Kambhampati S.P., Kannan R.M. Dendrimer nanoparticles for ocular drug delivery. J Ocul Pharmacol Ther. 2013;29(2):151–165. PubMed

Nance E., Kambhampati S.P., Smith E.S., Zhang Z., Zhang F., Singh S., et al. Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome. J Neuroinflamm. 2017;14(1):252. PubMed PMC

Nance E., Zhang F., Mishra M.K., Zhang Z., Kambhampati S.P., Kannan R.M., et al. Nanoscale effects in dendrimer-mediated targeting of neuroinflammation. Biomaterials. 2016;101:96–107. PubMed PMC

Turk B.R., Nemeth C.L., Marx J.S., Tiffany C., Jones R., Theisen B., et al. Dendrimer-N-acetyl-L-cysteine modulates monophagocytic response in adrenoleukodystrophy. Ann Neurol. 2018;84(3):452–462. PubMed PMC

Zhang F., Nance E., Alnasser Y., Kannan R., Kannan S. Microglial migration and interactions with dendrimer nanoparticles are altered in the presence of neuroinflammation. J Neuroinflamm. 2016;13(1):65. PubMed PMC

Kambhampati S.P., Clunies-Ross A.J., Bhutto I., Mishra M.K., Edwards M., McLeod D.S., et al. Systemic and intravitreal delivery of dendrimers to activated microglia/macrophage in ischemia/reperfusion mouse retina. Investig Ophthalmol Vis Sci. 2015;56(8):4413–4424. PubMed PMC

Mishra M.K., Beaty C.A., Lesniak W.G., Kambhampati S.P., Zhang F., Wilson M.A., et al. Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest. ACS Nano. 2014;8(3):2134–2147. PubMed PMC

Sharma A., Porterfield J.E., Smith E., Sharma R., Kannan S., Kannan R.M. Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model. J Contr Release : Off J Contr Release Soc. 2018;283:175–189. PubMed PMC

Sharma R., Kim S.Y., Sharma A., Zhang Z., Kambhampati S.P., Kannan S., et al. Activated microglia targeting dendrimer-minocycline conjugate as therapeutics for neuroinflammation. Bioconjug Chem. 2017;28(11):2874–2886. PubMed PMC

Gusdon A.M., Faraday N., Aita J.S., Kumar S., Mehta I., Choi H.A., et al. Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase2a clinical trial. Sci Transl Med. 2022;14(654) PubMed

Khoury E.S., Sharma A., Ramireddy R.R., Thomas A.G., Alt J., Fowler A., et al. Dendrimer-conjugated glutaminase inhibitor selectively targets microglial glutaminase in a mouse model of Rett syndrome. Theranostics. 2020;10(13):5736–5748. PubMed PMC

Sakamoto S., Mallah D., Medeiros D.J., Dohi E., Imai T., Rose I.V.L., et al. Alterations in circulating extracellular vesicles underlie social stress-induced behaviors in mice. FEBS Open Bio. 2021;11(10):2678–2692. PubMed PMC

Zhu X., Sakamoto S., Ishii C., Smith M.D., Ito K., Obayashi M., et al. Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses. Nat Immunol. 2023;24(4):625–636. PubMed PMC

Nie X., Kitaoka S., Tanaka K., Segi-Nishida E., Imoto Y., Ogawa A., et al. The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation. Neuron. 2018;99(3):464–479 e7. PubMed

Golden S.A., Covington H.E., 3rd, Berton O., Russo S.J. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6(8):1183–1191. PubMed PMC

Sharma A., Liaw K., Sharma R., Spriggs T., Appiani La Rosa S., Kannan S., et al. Dendrimer-mediated targeted delivery of rapamycin to tumor-associated macrophages improves systemic treatment of glioblastoma. Biomacromolecules. 2020;21(12):5148–5161. PubMed

Sharma K., Schmitt S., Bergner C.G., Tyanova S., Kannaiyan N., Manrique-Hoyos N., et al. Cell type- and brain region-resolved mouse brain proteome. Nat Neurosci. 2015;18(12):1819–1831. PubMed PMC

Nedelcovych M.T., Kim B.H., Zhu X., Lovell L.E., Manning A.A., Kelschenbach J., et al. Glutamine antagonist JHU083 normalizes aberrant glutamate production and cognitive deficits in the EcoHIV murine model of HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol : Off J Soc NeuroImmune Pharmacol. 2019 PubMed PMC

Hasegawa Y., Kim J., Ursini G., Jouroukhin Y., Zhu X., Miyahara Y., et al. Microglial cannabinoid receptor type 1 mediates social memory deficits in mice produced by adolescent THC exposure and 16p11.2 duplication. Nat Commun. 2023;14(1):6559. PubMed PMC

Huang M., Tallon C., Zhu X., Huizar K.D.J., Picciolini S., Thomas A.G., et al. Microglial-targeted nSMase2 inhibitor fails to reduce tau propagation in PS19 mice. Pharmaceutics. 2023;15(9) PubMed PMC

Wolf F.A., Angerer P., Theis F.J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 2018;19(1):15. PubMed PMC

Wolock S.L., Lopez R., Klein A.M. Scrublet: computational identification of cell doublets in single-cell transcriptomic data. Cell Syst. 2019;8(4):281–291 e9. PubMed PMC

Hao Y., Hao S., Andersen-Nissen E., Mauck W.M., 3rd, Zheng S., Butler A., et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184(13):3573–3587 e29. PubMed PMC

Korsunsky I., Millard N., Fan J., Slowikowski K., Zhang F., Wei K., et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods. 2019;16(12):1289–1296. PubMed PMC

Shukla K., Ferraris D.V., Thomas A.G., Stathis M., Duvall B., Delahanty G., et al. Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors. J Med Chem. 2012;55(23):10551–10563. PubMed PMC

Tallon C., Bell B.J., Sharma A., Pal A., Malvankar M.M., Thomas A.G., et al. Dendrimer-conjugated nSMase2 inhibitor reduces Tau propagation in mice. Pharmaceutics. 2022;14(10) PubMed PMC

Iezzi R., Guru B.R., Glybina I.V., Mishra M.K., Kennedy A., Kannan R.M. Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration. Biomaterials. 2012;33(3):979–988. PubMed

Lesniak W.G., Mishra M.K., Jyoti A., Balakrishnan B., Zhang F., Nance E., et al. Biodistribution of fluorescently labeled PAMAM dendrimers in neonatal rabbits: effect of neuroinflammation. Mol Pharm. 2013;10(12):4560–4571. PubMed PMC

Hollinger K.R., Zhu X., Khoury E.S., Thomas A.G., Liaw K., Tallon C., et al. Glutamine antagonist JHU-083 normalizes aberrant hippocampal glutaminase activity and improves cognition in APOE4 mice. J Alzheimers Dis. 2020 PubMed PMC

Krishnan V., Han M.H., Graham D.L., Berton O., Renthal W., Russo S.J., et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131(2):391–404. PubMed

Tran I., Gellner A.K. Long-term effects of chronic stress models in adult mice. J Neural Transm (Vienna) 2023;130(9):1133–1151. PubMed PMC

Perna S., Alalwan T.A., Alaali Z., Alnashaba T., Gasparri C., Infantino V., et al. The role of glutamine in the complex interaction between gut microbiota and Health: a narrative review. Int J Mol Sci. 2019;20(20) PubMed PMC

Rao R., Samak G. Role of glutamine in protection of intestinal epithelial tight junctions. J Epithel Biol Pharmacol. 2012;5(Suppl 1-M7):47–54. PubMed PMC

Kim M.H., Kim H. The roles of glutamine in the intestine and its implication in intestinal diseases. Int J Mol Sci. 2017;18(5) PubMed PMC

Arteaga Cabeza O., Zhang Z., Smith Khoury E., Sheldon R.A., Sharma A., Zhang F., et al. Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury. Neurobiol Dis. 2021;148 PubMed PMC

Yin N., Yan E., Duan W., Mao C., Fei Q., Yang C., et al. The role of microglia in chronic pain and depression: innocent bystander or culprit? Psychopharmacology (Berl) 2021;238(4):949–958. PubMed

Brisch R., Wojtylak S., Saniotis A., Steiner J., Gos T., Kumaratilake J., et al. The role of microglia in neuropsychiatric disorders and suicide. Eur Arch Psychiatr Clin Neurosci. 2021 PubMed PMC

Jia X., Gao Z., Hu H. Microglia in depression: current perspectives. Sci China Life Sci. 2021;64(6):911–925. PubMed

Brites D., Fernandes A. Neuroinflammation and depression: microglia activation, extracellular microvesicles and microRNA dysregulation. Front Cell Neurosci. 2015;9:476. PubMed PMC

Deng S.L., Chen J.G., Wang F. Microglia: a central player in depression. Curr Med Sci. 2020;40(3):391–400. PubMed

Sakamoto S., Zhu X., Hasegawa Y., Karma S., Obayashi M., Alway E., et al. Inflamed brain: targeting immune changes and inflammation for treatment of depression. Psychiatr Clin Neurosci. 2021;75(10):304–311. PubMed PMC

Han Q.Q., Shen S.Y., Chen X.R., Pilot A., Liang L.F., Zhang J.R., et al. Minocycline alleviates abnormal microglial phagocytosis of synapses in a mouse model of depression. Neuropharmacology. 2022;220 PubMed

Stein D.J., Vasconcelos M.F., Albrechet-Souza L., Cereser K.M.M., de Almeida R.M.M. Microglial over-activation by social defeat stress contributes to anxiety- and depressive-like behaviors. Front Behav Neurosci. 2017;11:207. PubMed PMC

Alnasser Y., Kambhampati S.P., Nance E., Rajbhandari L., Shrestha S., Venkatesan A., et al. Preferential and increased uptake of hydroxyl-terminated PAMAM dendrimers by activated microglia in rabbit brain mixed glial culture. Molecules. 2018;23(5) PubMed PMC

Sharma A., Sharma R., Zhang Z., Liaw K., Kambhampati S.P., Porterfield J.E., et al. Dense hydroxyl polyethylene glycol dendrimer targets activated glia in multiple CNS disorders. Sci Adv. 2020;6(4) PubMed PMC

Menard C., Pfau M.L., Hodes G.E., Kana V., Wang V.X., Bouchard S., et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20(12):1752–1760. PubMed PMC

Ding L., Xu X., Li C., Wang Y., Xia X., Zheng J.C. Glutaminase in microglia: a novel regulator of neuroinflammation. Brain Behav Immun. 2021;92:139–156. PubMed

Chen W., Zhang Y., Zhai X., Xie L., Guo Y., Chen C., et al. Microglial phagocytosis and regulatory mechanisms after stroke. J Cerebr Blood Flow Metabol : Off J Int Soc Cereb Blood Flow Metabol. 2022;42(9):1579–1596. PubMed PMC

Miao J., Chen L., Pan X., Li L., Zhao B., Lan J. Microglial metabolic reprogramming: emerging insights and therapeutic strategies in neurodegenerative diseases. Cell Mol Neurobiol. 2023;43(7):3191–3210. PubMed PMC

Zhang G.Q., Xi C., Ju N.T., Shen C.T., Qiu Z.L., Song H.J., et al. Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer. J Endocrinol Investig. 2024;47(8):1953–1969. PubMed PMC

Liaw K., Zhang F., Mangraviti A., Kannan S., Tyler B., Kannan R.M. Dendrimer size effects on the selective brain tumor targeting in orthotopic tumor models upon systemic administration. Bioeng Transl Med. 2020;5(2) PubMed PMC

Zhang F., Trent Magruder J., Lin Y.A., Crawford T.C., Grimm J.C., Sciortino C.M., et al. Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model. J Contr Release : Off J Contr Release Soc. 2017;249:173–182. PubMed PMC