{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T02:01:27Z","timestamp":1774922487163,"version":"3.50.1"},"reference-count":121,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>In contemporary aging societies, preventing and ameliorating mental and physical frailty is essential. Kampo formulas, including ninjinyoeito (NYT) and juzentaihoto (JTT), have been used traditionally to treat frailty in the elderly. NYT has been reported to alleviate psychological frailty such as depression and anxiety. This study aimed to clarify the mechanisms underlying the effects of these two Kampo formulas in the early stages of neurodegeneration associated with psychiatric disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Genes affected by Kampo formulas were comprehensively investigated by administering JTT or NYT to senescence accelerated mouse prone 8 (SAMP8) mice, from 7\u00a0weeks, and by RNA sequencing of the hippocampus at 19\u00a0weeks when depression and anxiety behaviors typically emerge. Additionally, we examined the impact of these Kampo formulas on neuroinflammation induced by lipopolysaccharide (LPS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The two Kampo formulas alleviated the depressive-like behavior of SAMP8 mice, as demonstrated by the restoration of microglial cell activation, DNA repair, stress-responsive transcription factor expression, and nervous system development-related gene expression. However, the NYT-administrated group presented a greater number of recovered genes than did the JTT-administrated group, and NYT additionally suggests that the potential inhibition of age-related mitochondrial dysfunction and increased oxidative stress. The administration of LPS resulted in elevated expression levels of immune and inflammation-related genes and increased astrocyte activity in SAMP8 mice. JTT mitigated these effects by suppressing the expression of the LPS receptor TLR4 and its downstream target NF-\u03baB. In contrast to JTT, NYT maintained and increased the expression of genes associated with neuroprotective functions in microglia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The two Kampo formulas exerted neuroprotective effects by enhancing neural and glial stress responses in the early stages of neurodegeneration. Under condition of acute inflammation, JTT and NYT alleviated neuronal damage via the suppression of microglial activity and the enhancement of microglial neuroprotection, respectively. These findings provide novel insights into the mechanism of action of NYT, which has been reported to ameliorate psychological frailty associated with aging, and further suggest that JTT may exert effects against inflammatory neurodegeneration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1600176","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T05:28:13Z","timestamp":1761283693000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Distinct neuroprotective and anti-inflammatory effects of Kampo formulas ninjinyoeito and juzentaihoto in depression-like SAMP8 mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Akiko","family":"Maruko","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenshiro","family":"Oshima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinori","family":"Nishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinori","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norihiro","family":"Okada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1002\/glia.23324","article-title":"CXCL12-mediated feedback from granule neurons regulates generation and positioning of new neurons in the dentate gyrus","volume":"66","author":"Abe","year":"2018","journal-title":"Glia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.3390\/brainsci11111373","article-title":"TLR-mediated signal transduction and neurodegenerative disorders","volume":"11","author":"Adhikarla","year":"2021","journal-title":"Brain Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1111\/neup.12373","article-title":"SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: toshio Takeda's legacy and future directions","volume":"37","author":"Akiguchi","year":"2017","journal-title":"Neuropathology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.51010\/sjms.39.1_1","article-title":"Effect of ninjin\u2019yoeito on lipopolysaccharide-induced depressive-like behavior and glial activation in the hippocampus","volume":"39","author":"Alim","year":"2022","journal-title":"Shimane J. Med. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"13537","DOI":"10.1523\/JNEUROSCI.3457-10.2010","article-title":"NMDA-mediated regulation of DSCAM dendritic local translation is lost in a mouse model of Down's syndrome","volume":"30","author":"Alves-Sampaio","year":"2010","journal-title":"J. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1007\/s12603-011-0110-9","article-title":"Physical frailty predicts future cognitive decline - a four-year prospective study in 2737 cognitively normal older adults","volume":"15","author":"Auyeung","year":"2011","journal-title":"J. Nutr. Health Aging"},{"key":"B7","doi-asserted-by":"publisher","first-page":"149245","DOI":"10.1016\/j.brainres.2024.149245","article-title":"Novel insights into the role of TREM2 in cerebrovascular diseases","volume":"1846","author":"Awuah","year":"2025","journal-title":"Brain Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2030","DOI":"10.1016\/j.neurobiolaging.2009.11.022","article-title":"Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats","volume":"32","author":"Bachstetter","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"B9","doi-asserted-by":"publisher","first-page":"11351","DOI":"10.1074\/jbc.M111.272427","article-title":"Nurr1 protein is required for N-Methyl-d-aspartic acid (NMDA) receptor-mediated neuronal survival","volume":"287","author":"Barneda-Zahonero","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e431","DOI":"10.1371\/journal.pone.0000431","article-title":"CRE\/CREB-driven up-regulation of gene expression by chronic social stress in CRE-luciferase transgenic mice: reversal by antidepressant treatment","volume":"2","author":"Boer","year":"2007","journal-title":"PLoS One"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"B12","doi-asserted-by":"publisher","first-page":"934 e7","DOI":"10.1016\/j.neurobiolaging.2013.09.017","article-title":"Heterozygous TREM2 mutations in frontotemporal dementia","volume":"35","author":"Borroni","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"B13","volume-title":"The inflamed mind: a radical new approach to depression","author":"Bullmore","year":"2018"},{"key":"B14","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1038\/s41583-018-0057-5","article-title":"Microglial signatures and their role in health and disease","volume":"19","author":"Butovsky","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1016\/j.physbeh.2007.03.023","article-title":"Age-related changes in anxiety are task-specific in the senescence-accelerated prone mouse 8","volume":"91","author":"Chen","year":"2007","journal-title":"Physiol. Behav."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1038\/s41398-017-0028-z","article-title":"Novel schizophrenia risk factor pathways regulate FEZ1 to advance oligodendroglia development","volume":"7","author":"Chen","year":"2017","journal-title":"Transl. Psychiatry"},{"key":"B17","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.arr.2013.10.002","article-title":"The behavioral, pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an alzheimer's disease animal model","volume":"13","author":"Cheng","year":"2014","journal-title":"Ageing Res. Rev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"652","DOI":"10.14336\/AD.2019.0118","article-title":"Emerging roles of complement protein C1q in neurodegeneration","volume":"10","author":"Cho","year":"2019","journal-title":"Aging Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e47866","DOI":"10.7554\/eLife.47866","article-title":"Elevating acetyl-CoA levels reduces aspects of brain aging","volume":"8","author":"Currais","year":"2019","journal-title":"Elife"},{"key":"B20","doi-asserted-by":"publisher","first-page":"145824","DOI":"10.1016\/j.gene.2021.145824","article-title":"A role for zinc transporter gene SLC39A12 in the nervous system and beyond","volume":"799","author":"Davis","year":"2021","journal-title":"Gene"},{"key":"B21","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.molimm.2019.10.008","article-title":"Recombinant C1q variants modulate macrophage responses but do not activate the classical complement pathway","volume":"117","author":"Espericueta","year":"2020","journal-title":"Mol. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e101174","DOI":"10.15252\/embj.2018101174","article-title":"Decreased synthesis of ribosomal proteins in tauopathy revealed by non-canonical amino acid labelling","volume":"38","author":"Evans","year":"2019","journal-title":"EMBO J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/j.tins.2019.07.002","article-title":"Anxiety and brain mitochondria: a bidirectional crosstalk","volume":"42","author":"Filiou","year":"2019","journal-title":"Trends Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s12974-017-0814-9","article-title":"Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain","volume":"14","author":"Fonseca","year":"2017","journal-title":"J. Neuroinflammation"},{"key":"B25","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.jep.2012.10.051","article-title":"Magnolol inhibits lipopolysaccharide-induced inflammatory response by interfering with TLR4 mediated NF-\u03baB and MAPKs signaling pathways","volume":"145","author":"Fu","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2341","DOI":"10.1038\/sj.npp.1301649","article-title":"Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system","volume":"33","author":"Godbout","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.3390\/ijms22041636","article-title":"Microglia and neuroinflammation: what place for P2RY12?","volume":"22","author":"G\u00f3mez Morillas","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"135561","DOI":"10.1016\/j.neulet.2020.135561","article-title":"Ginsenoside Rb1 exerts antidepressant-like effects via suppression inflammation and activation of AKT pathway","volume":"744","author":"Guo","year":"2021","journal-title":"Neurosci. Lett."},{"key":"B29","doi-asserted-by":"publisher","first-page":"427","DOI":"10.3233\/JAD-2010-1381","article-title":"The therapeutic effects of the herbal medicine, juzen-taiho-to, on amyloid-beta burden in a mouse model of alzheimer's disease","volume":"20","author":"Hara","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/1742-2094-5-15","article-title":"Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia","volume":"5","author":"Henry","year":"2008","journal-title":"J. Neuroinflammation"},{"key":"B31","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nrn3689","article-title":"Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases","volume":"15","author":"Hetz","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1089\/acm.2020.0083","article-title":"Usefulness of ninjin'yoeito for chronic obstructive pulmonary disease patients with frailty","volume":"26","author":"Hirai","year":"2020","journal-title":"J. Altern. Complement. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.ceb.2015.02.004","article-title":"Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system","volume":"32","author":"Hol","year":"2015","journal-title":"Curr. Opin. Cell Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"444","DOI":"10.3390\/biom10030444","article-title":"Pro-resolving effect of ginsenosides as an anti-inflammatory mechanism of Panax ginseng","volume":"10","author":"Im","year":"2020","journal-title":"Biomolecules"},{"key":"B35","doi-asserted-by":"publisher","first-page":"10014","DOI":"10.3390\/molecules180810014","article-title":"Antianxiety-like effects of chimpi (dried citrus peels) in the elevated open-platform test","volume":"18","author":"Ito","year":"2013","journal-title":"Molecules"},{"key":"B36","doi-asserted-by":"publisher","first-page":"111109","DOI":"10.1016\/j.exger.2020.111109","article-title":"Neuroinflammaging underlies emotional disturbances and circadian rhythm disruption in young male senescence-accelerated mouse prone 8 mice","volume":"142","author":"Ito","year":"2020","journal-title":"Exp. Gerontol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"109","DOI":"10.18632\/aging.203811","article-title":"Kampo formulas alleviate aging-related emotional disturbances and neuroinflammation in male senescence-accelerated mouse prone 8 mice","volume":"14","author":"Ito","year":"2022","journal-title":"Aging (Albany NY)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.reth.2021.07.002","article-title":"Combination therapy of Juzentaihoto and mesenchymal stem cells attenuates liver damage and regresses fibrosis in mice","volume":"18","author":"Iwasawa","year":"2021","journal-title":"Regen. Ther."},{"key":"B39","doi-asserted-by":"publisher","first-page":"108852","DOI":"10.1016\/j.exer.2021.108852","article-title":"Microglia-derived TNF-\u03b1 mediates M\u00fcller cell activation by activating the TNFR1-NF-\u03baB pathway","volume":"214","author":"Ji","year":"2022","journal-title":"Exp. Eye Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"688703","DOI":"10.3389\/fpsyt.2021.688703","article-title":"Protective effects and mechanism of Radix polygalae against neurological diseases as well as effective substance","volume":"12","author":"Jiang","year":"2021","journal-title":"Front. Psychiatry"},{"key":"B41","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1007\/s00401-019-01970-9","article-title":"Tau drives translational selectivity by interacting with ribosomal proteins","volume":"137","author":"Koren","year":"2019","journal-title":"Acta Neuropathol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"26357","DOI":"10.1074\/jbc.M112.446138","article-title":"Myocilin mediates myelination in the peripheral nervous system through ErbB2\/3 signaling","volume":"288","author":"Kwon","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"B45","doi-asserted-by":"publisher","first-page":"a001651","DOI":"10.1101\/cshperspect.a001651","article-title":"The nuclear factor NF-\u03baB pathway in inflammation","volume":"1","author":"Lawrence","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"7448","DOI":"10.1128\/MCB.23.21.7448-7459.2003","article-title":"XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response","volume":"23","author":"Lee","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.14670\/HH-18-345","article-title":"Mitochondrial support and local translation of mitochondrial proteins in synaptic plasticity and function","volume":"36","author":"Liang","year":"2021","journal-title":"Histol. Histopathol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2013","journal-title":"Bioinformatics"},{"key":"B50","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"B51","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1620\/tjem.215.43","article-title":"Juzen-taiho-to, an herbal medicine, activates and enhances phagocytosis in microglia\/macrophages","volume":"215","author":"Liu","year":"2008","journal-title":"Tohoku J. Exp. Med."},{"key":"B52","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1620\/tjem.233.113","article-title":"Juzen-Taiho-to, an herbal medicine, promotes the differentiation of transplanted bone marrow cells into microglia in the mouse brain injected with fibrillar amyloid \u03b2","volume":"233","author":"Liu","year":"2014","journal-title":"Tohoku J. Exp. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"967825","DOI":"10.3389\/fnagi.2022.967825","article-title":"TREM2 improves neurological dysfunction and attenuates neuroinflammation, TLR signaling and neuronal apoptosis in the acute phase of intracerebral hemorrhage","volume":"14","author":"Liu","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"B54","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.jad.2021.07.012","article-title":"Do depressive symptoms link chronic diseases to cognition among older adults? Evidence from the health and retirement study in the United States","volume":"294","author":"Lu","year":"2021","journal-title":"J. Affect Disord."},{"key":"B55","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.brainresbull.2018.11.017","article-title":"Fractalkine\/CX3CR1 is involved in the cross-talk between neuron and glia in neurological diseases","volume":"146","author":"Luo","year":"2019","journal-title":"Brain Res. Bull."},{"key":"B56","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.bbi.2019.06.035","article-title":"CREB deletion increases resilience to stress and downregulates inflammatory gene expression in the hippocampus","volume":"81","author":"Manners","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"B57","doi-asserted-by":"publisher","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet. J."},{"key":"B58","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.jneuroim.2013.02.008","article-title":"Suppressed pro-inflammatory response of microglia in CX3CR1 knockout mice","volume":"257","author":"Mattison","year":"2013","journal-title":"J. Neuroimmunol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.15252\/embr.201743922","article-title":"TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury","volume":"18","author":"Mazaheri","year":"2017","journal-title":"EMBO Rep."},{"key":"B60","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.bbi.2015.07.024","article-title":"Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress","volume":"55","author":"Milior","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"B61","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1083\/jcb.201606052","article-title":"Merlin controls the repair capacity of schwann cells after injury by regulating Hippo\/YAP activity","volume":"216","author":"Mindos","year":"2017","journal-title":"J. Cell Biol."},{"key":"B62","unstructured":"The Japanese pharmacopoeia\n          \n          \n          2021"},{"key":"B63","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"B64","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1254\/fpj.153.179","article-title":"The senescence-accelerated mouse as a model for geriatrics and aging biology","volume":"153","author":"Mori","year":"2019","journal-title":"Nihon Yakurigaku Zasshi"},{"key":"B65","doi-asserted-by":"publisher","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"B66","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.biopsych.2018.09.026","article-title":"The role of dendritic brain-derived neurotrophic factor transcripts on altered inhibitory circuitry in depression","volume":"85","author":"Oh","year":"2019","journal-title":"Biol. Psychiatry"},{"key":"B67","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3233\/ADR-170026","article-title":"A possibility of simultaneous treatment with the multicomponent drug, ninjin'yoeito, for anorexia, apathy, and cognitive dysfunction in frail alzheimer's disease patients: an open-label pilot study","volume":"1","author":"Ohsawa","year":"2017","journal-title":"J. Alzheimers Dis. Rep."},{"key":"B68","doi-asserted-by":"publisher","first-page":"145752","DOI":"10.1016\/j.gene.2021.145752","article-title":"Intron retention as a new pre-symptomatic marker of aging and its recovery to the normal state by a traditional Japanese multi-herbal medicine","volume":"794","author":"Okada","year":"2021","journal-title":"Gene"},{"key":"B69","doi-asserted-by":"publisher","first-page":"1450708","DOI":"10.3389\/fpsyt.2024.1450708","article-title":"Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention","volume":"15","author":"Okada","year":"2024","journal-title":"Front. Psychiatry"},{"key":"B70","doi-asserted-by":"publisher","first-page":"107","DOI":"10.3233\/ADR-220074","article-title":"Frailty improvement by multicomponent drug, ninjin'Yoeito, in mild cognitive impairment and mild alzheimer's disease patients: an open-label exploratory study (FRAMINGO)","volume":"7","author":"Okahara","year":"2023","journal-title":"J. Alzheimers Dis. Rep."},{"key":"B71","doi-asserted-by":"publisher","first-page":"7300","DOI":"10.18632\/aging.204284","article-title":"Age-related metabolic and neurodegenerative changes in SAMP8 mice","volume":"14","author":"Pacesova","year":"2022","journal-title":"Aging (Albany NY)"},{"key":"B72","doi-asserted-by":"publisher","first-page":"4342","DOI":"10.1038\/s41598-019-40690-8","article-title":"Rg6, a rare ginsenoside, inhibits systemic inflammation through the induction of interleukin-10 and microRNA-146a","volume":"9","author":"Paik","year":"2019","journal-title":"Sci. Rep."},{"key":"B73","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.nbd.2007.07.001","article-title":"Reduced CXCL12\/CXCR4 results in impaired learning and is downregulated in a mouse model of alzheimer disease","volume":"28","author":"Parachikova","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"B74","first-page":"S216","article-title":"Review: the role of inflammation in depression","volume":"25","author":"Patel","year":"2013","journal-title":"Psychiatr. Danub"},{"key":"B75","doi-asserted-by":"publisher","first-page":"2839","DOI":"10.2174\/1381612043383638","article-title":"The role of STATs in inflammation and inflammatory diseases","volume":"10","author":"Pfitzner","year":"2004","journal-title":"Curr. Pharm. Des."},{"key":"B76","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.brainres.2004.05.048","article-title":"Antisense directed at the abeta region of APP decreases brain oxidative markers in aged senescence accelerated mice","volume":"1018","author":"Poon","year":"2004","journal-title":"Brain Res."},{"key":"B77","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3390\/genes8010002","article-title":"Regulation and function of Cdt1; A key factor in cell proliferation and genome stability","volume":"8","author":"Pozo","year":"2016","journal-title":"Genes (Basel)"},{"key":"B78","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.omtm.2019.05.008","article-title":"Differential uptake of NAGLU-IGF2 and unmodified NAGLU in cellular models of sanfilippo syndrome type B","volume":"14","author":"Prill","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"B79","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.cell.2018.12.013","article-title":"Spatially stable mitochondrial compartments fuel local translation during plasticity","volume":"176","author":"Rangaraju","year":"2019","journal-title":"Cell"},{"key":"B80","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1126\/science.aag2590","article-title":"How neuroinflammation contributes to neurodegeneration","volume":"353","author":"Ransohoff","year":"2016","journal-title":"Science"},{"key":"B81","doi-asserted-by":"publisher","first-page":"101122","DOI":"10.1016\/j.yfrne.2024.101122","article-title":"Cholecystokinin (CCK): a neuromodulator with therapeutic potential in Alzheimer's and parkinson's disease","volume":"73","author":"Reich","year":"2024","journal-title":"Front. Neuroendocrinol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"e202302111","DOI":"10.26508\/lsa.202302111","article-title":"FAM111A regulates replication origin activation and cell fitness","volume":"6","author":"Rios-Szwed","year":"2023","journal-title":"Life Sci. Alliance"},{"key":"B83","doi-asserted-by":"publisher","first-page":"R25","DOI":"10.1186\/gb-2010-11-3-r25","article-title":"A scaling normalization method for differential expression analysis of RNA-seq data","volume":"11","author":"Robinson","year":"2010","journal-title":"Genome Biol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2009","journal-title":"Bioinformatics"},{"key":"B85","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.phrs.2015.10.022","article-title":"Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: restorative effect of pharmacological intervention","volume":"103","author":"Rossetti","year":"2016","journal-title":"Pharmacol. Res."},{"key":"B86","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s41419-022-04602-5","article-title":"CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response","volume":"13","author":"Ruan","year":"2022","journal-title":"Cell Death Dis."},{"key":"B87","doi-asserted-by":"publisher","first-page":"113506","DOI":"10.1016\/j.expneurol.2020.113506","article-title":"TREM2 overexpression rescues cognitive deficits in APP\/PS1 transgenic mice by reducing neuroinflammation via the JAK\/STAT\/SOCS signaling pathway","volume":"336","author":"Ruganzu","year":"2021","journal-title":"Exp. Neurol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"732360","DOI":"10.3389\/fncel.2021.732360","article-title":"Neuromodulation of hippocampal-prefrontal cortical synaptic plasticity and functional connectivity: implications for neuropsychiatric disorders","volume":"15","author":"Ruggiero","year":"2021","journal-title":"Front. Cell Neurosci."},{"key":"B89","doi-asserted-by":"publisher","first-page":"e99669","DOI":"10.15252\/embj.201899669","article-title":"Nuclear import of the DSCAM-cytoplasmic domain drives signaling capable of inhibiting synapse formation","volume":"38","author":"Sachse","year":"2019","journal-title":"EMBO J."},{"key":"B90","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1097\/MCO.0000000000000336","article-title":"Anorexia of aging and its role for frailty","volume":"20","author":"Sanford","year":"2017","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"B91","doi-asserted-by":"publisher","first-page":"617438","DOI":"10.1093\/ecam\/neq001","article-title":"Administration of chinpi, a component of the herbal medicine ninjin-youei-to, reverses age-induced demyelination","volume":"2011","author":"Sato","year":"2011","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"B92","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1002\/jnr.23161","article-title":"Alterations in local thyroid hormone signaling in the hippocampus of the SAMP8 mouse at younger ages: association with delayed myelination and behavioral abnormalities","volume":"91","author":"Sawano","year":"2013","journal-title":"J. Neurosci. Res."},{"key":"B93","doi-asserted-by":"publisher","first-page":"987","DOI":"10.4103\/1673-5374.324835","article-title":"Axonal protein synthesis in central nervous system regeneration: is building an axon a local matter?","volume":"17","author":"Schaeffer","year":"2022","journal-title":"Neural Regen. Res."},{"key":"B94","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1002\/hipo.20805","article-title":"GSK3\u03b2 overexpression induces neuronal death and a depletion of the neurogenic niches in the dentate gyrus","volume":"21","author":"Sirerol-Piquer","year":"2011","journal-title":"Hippocampus"},{"key":"B95","doi-asserted-by":"publisher","first-page":"2113","DOI":"10.1093\/brain\/aww101","article-title":"The unfolded protein response: mechanisms and therapy of neurodegeneration","volume":"139","author":"Smith","year":"2016","journal-title":"Brain"},{"key":"B96","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1016\/s0531-5565(03)00185-2","article-title":"Aging and molecular chaperones","volume":"38","author":"Soti","year":"2003","journal-title":"Exp. Gerontol."},{"key":"B97","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/BF00428203","article-title":"The tail suspension test: a new method for screening antidepressants in mice","volume":"85","author":"Steru","year":"1985","journal-title":"Psychopharmacology"},{"key":"B98","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A., Gene set Enrich. analysis A knowledge-based approach interpreting genome-wide Expr. profiles"},{"key":"B99","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1111\/j.1532-5415.1991.tb04460.x","article-title":"Senescence-accelerated mouse (SAM): a novel murine model of accelerated senescence","volume":"39","author":"Takeda","year":"1991","journal-title":"J. Am. Geriatrics Soc."},{"key":"B100","first-page":"1347","article-title":"Ninjinyoeito actions on mitochondria amount in the in vitro system","volume":"46","author":"Takeda","year":"2018","journal-title":"Jpn. Pharmacol. Ther."},{"key":"B101","doi-asserted-by":"publisher","first-page":"8293","DOI":"10.1523\/JNEUROSCI.0799-12.2012","article-title":"Semaphorin 4D\/Plexin-B1-mediated M-Ras GAP activity regulates actin-based dendrite remodeling through lamellipodin","volume":"32","author":"Tasaka","year":"2012","journal-title":"J. Neurosci."},{"key":"B102","doi-asserted-by":"publisher","first-page":"573966","DOI":"10.3389\/fnagi.2021.573966","article-title":"Motor dyscoordination and alteration of functional correlation between DGK\u03b3 and PKC\u03b3 in senescence-accelerated mouse prone 8 (SAMP8)","volume":"13","author":"Tsumagari","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"B103","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/j.jamda.2017.02.004","article-title":"Association of social frailty with both cognitive and physical deficits among older people","volume":"18","author":"Tsutsumimoto","year":"2017","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"B104","doi-asserted-by":"publisher","first-page":"146496","DOI":"10.1016\/j.gene.2022.146496","article-title":"Intron retention is a stress response in sensor genes and is restored by Japanese herbal medicines: a basis for future clinical applications","volume":"830","author":"Vu","year":"2022","journal-title":"Gene"},{"key":"B105","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1083\/jcb.149.2.263","article-title":"Ephrin-A5 induces collapse of growth cones by activating rho and rho kinase","volume":"149","author":"Wahl","year":"2000","journal-title":"J. Cell Biol."},{"key":"B106","article-title":"Chapter eight - the synthesis and secretion of inhibins","volume-title":"Vitamins and Hormones","author":"Walton","year":"2011"},{"key":"B107","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.celrep.2019.06.054","article-title":"Deficiency in BDNF\/TrkB neurotrophic activity stimulates \u03b4-Secretase by upregulating C\/EBP\u03b2 in alzheimer's disease","volume":"28","author":"Wang","year":"2019","journal-title":"Cell Rep."},{"key":"B108","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s12974-022-02492-0","article-title":"Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression","volume":"19","author":"Wang","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"B109","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.neuroscience.2018.03.034","article-title":"The role of depressive subtypes within the neuroinflammation hypothesis of major depressive disorder","volume":"403","author":"Woelfer","year":"2019","journal-title":"Neuroscience"},{"key":"B110","doi-asserted-by":"publisher","first-page":"114510","DOI":"10.1016\/j.expneurol.2023.114510","article-title":"Experimental upregulation of developmentally downregulated ribosomal protein large subunits 7 and 7A promotes axon regeneration after injury in vivo","volume":"368","author":"Xing","year":"2023","journal-title":"Exp. Neurol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.phymed.2007.08.006","article-title":"Effect of ninjin-yoei-to (Rensheng-Yangrong-Tang) on olfactory behavior after olfactory nerve transection","volume":"15","author":"Yamasaki","year":"2008","journal-title":"Phytomedicine"},{"key":"B112","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.bbr.2016.04.026","article-title":"Early onset of behavioral alterations in senescence-accelerated mouse prone 8 (SAMP8)","volume":"308","author":"Yanai","year":"2016","journal-title":"Behav. Brain Res."},{"key":"B113","doi-asserted-by":"publisher","first-page":"690","DOI":"10.3389\/fphar.2020.00690","article-title":"Neuroprotective effect of catalpol via anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms","volume":"11","author":"Yang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B114","doi-asserted-by":"publisher","first-page":"1181973","DOI":"10.3389\/fimmu.2023.1181973","article-title":"Lipopolysaccharide-induced depression-like model in mice: meta-analysis and systematic evaluation","volume":"14","author":"Yin","year":"2023","journal-title":"Front. Immunol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"e2416305","DOI":"10.1001\/jamanetworkopen.2024.16305","article-title":"Bidirectional associations of depressive symptoms and cognitive function over time","volume":"7","author":"Yin","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"B116","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/j.tins.2015.08.001","article-title":"Depression as a microglial disease","volume":"38","author":"Yirmiya","year":"2015","journal-title":"Trends Neurosci."},{"key":"B117","doi-asserted-by":"publisher","first-page":"766267","DOI":"10.3389\/fnagi.2021.766267","article-title":"Aged microglia in neurodegenerative diseases: microglia lifespan and culture methods","volume":"13","author":"Yoo","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"B118","doi-asserted-by":"publisher","first-page":"2602","DOI":"10.1100\/2011\/625690","article-title":"The DNA replication stress hypothesis of alzheimer's disease","volume":"11","author":"Yurov","year":"2011","journal-title":"Scientific World Journal"},{"key":"B119","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1186\/s12974-021-02185-0","article-title":"Ginsenoside Rb1 induces a pro-neurogenic microglial phenotype via PPAR\u03b3 activation in male mice exposed to chronic mild stress","volume":"18","author":"Zhang","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"B120","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.jclinepi.2023.05.005","article-title":"Exploring the concept of psychological frailty in older adults: a systematic scoping review","volume":"159","author":"Zhao","year":"2023","journal-title":"J. Clin. Epidemiol."},{"key":"B121","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.bbi.2020.11.007","article-title":"Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala","volume":"91","author":"Zheng","year":"2021","journal-title":"Brain Behav. Immun."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1600176\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T05:28:16Z","timestamp":1761283696000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1600176\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,24]]},"references-count":121,"alternative-id":["10.3389\/fphar.2025.1600176"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1600176","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,24]]},"article-number":"1600176"}}