{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:30:03Z","timestamp":1780075803806,"version":"3.54.0"},"reference-count":75,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bulgarian National Science Fund","award":["KP-06-H81\/7"],"award-info":[{"award-number":["KP-06-H81\/7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It is widely accepted that chronic inflammation constitutes a significant mechanism that promotes the biological aging process. The pineal gland is regarded as being closely related to the control of the \u201clife clock\u201d. The present study aimed to determine the inflammation associated with pinealectomy in the rat hippocampus and to investigate the extent to which age stage impacts the severity of this inflammation. We evaluated the expression of the Akt\/NF-kB signaling pathway in neurons and gliosis level in the dorsal hippocampus (dHipp) of rats subjected to sham surgery or pinealectomy at 3, 14, or 18 months of age. The assessment was conducted using immunohistochemistry. Removal of the pineal gland resulted in significant, region-specific increases in NF-kB expression in neurons of the dHipp in the youngest and middle-aged groups. However, the change in expression of the phosphorylated form of Akt (pAkt1) in neurons went in the opposite direction in these two age groups, and there were also regional differences. Pinealectomy triggered microgliosis in both young and old rats, but middle-aged rats were resistant to microglia activation. Conversely, astrogliosis was observed in young adult and middle-aged groups with melatonin deficiency in certain regions of the dHipp. It is noteworthy that young adult rats demonstrated the highest degree of vulnerability to inflammation associated with the loss of melatonin as a hormone. In contrast, middle-aged rats with pinealectomy exhibited a complex and partial adaptive response. These findings emphasize the dynamic and age-dependent nature of neuroinflammation following pinealectomy, underscoring the developmental stage as a critical determinant of inflammatory susceptibility.<\/jats:p>","DOI":"10.3390\/ijms26168093","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T07:41:45Z","timestamp":1755848505000},"page":"8093","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pinealectomy-Induced Neuroinflammation Varies with Age in Rats"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1745-7755","authenticated-orcid":false,"given":"Dimitrinka","family":"Atanasova","sequence":"first","affiliation":[{"name":"Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"},{"name":"Department of Anatomy, Faculty of Medicine, Trakia University, 6003 Stara Zagora, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desislava","family":"Krushovlieva","sequence":"additional","affiliation":[{"name":"Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7701-940X","authenticated-orcid":false,"given":"Pavel","family":"Rashev","sequence":"additional","affiliation":[{"name":"Institute of Biology and Immunology of Reproduction \u201cAcad. Kiril Bratanov\u201d, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1416-1457","authenticated-orcid":false,"given":"Milena","family":"Mourdjeva","sequence":"additional","affiliation":[{"name":"Institute of Biology and Immunology of Reproduction \u201cAcad. Kiril Bratanov\u201d, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Despina","family":"Pupaki","sequence":"additional","affiliation":[{"name":"Institute of Biology and Immunology of Reproduction \u201cAcad. Kiril Bratanov\u201d, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1640-5099","authenticated-orcid":false,"given":"Jana","family":"Tchekalarova","sequence":"additional","affiliation":[{"name":"Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12979-022-00277-w","article-title":"NF-\u03baB, a Culprit of Both Inflamm-Ageing and Declining Immunity?","volume":"19","author":"Songkiatisak","year":"2022","journal-title":"Immun. Ageing"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"362","DOI":"10.2174\/1574888X15666200213105155","article-title":"Stem Cell Aging in Lifespan and Disease: A State-of-the-Art Review","volume":"15","author":"Sameri","year":"2020","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Garc\u00eda, V.A., Alameda, J.P., Page, A., and Casanova, M.L. (2021). Role of NF-\u03baB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models. Cells, 10.","DOI":"10.3390\/cells10081906"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e12989","DOI":"10.1111\/acel.12989","article-title":"Aging-induced Akt Activation Involves in Aging-related Pathologies and A\u03b2-induced Toxicity","volume":"18","author":"Chen","year":"2019","journal-title":"Aging Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/(SICI)1097-0029(19981001)43:1<24::AID-JEMT4>3.0.CO;2-P","article-title":"Glial Reaction in Aging and Alzheimer\u2019s Disease","volume":"43","author":"Unger","year":"1998","journal-title":"Microsc. Res. Tech."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.neuropharm.2014.10.028","article-title":"Microglial Priming and Enhanced Reactivity to Secondary Insult in Aging, and Traumatic CNS Injury, and Neurodegenerative Disease","volume":"96","author":"Norden","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4688","DOI":"10.18632\/aging.102863","article-title":"ATM Is a Key Driver of NF-\u03baB-Dependent DNA-Damage-Induced Senescence, Stem Cell Dysfunction and Aging","volume":"12","author":"Zhao","year":"2020","journal-title":"Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/s41419-021-03465-6","article-title":"Neuroinflammation Induces Synaptic Scaling through IL-1\u03b2-Mediated Activation of the Transcriptional Repressor REST\/NRSF","volume":"12","author":"Buffolo","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5061","DOI":"10.1073\/pnas.88.11.5061","article-title":"cAMP Response Element-Binding Protein Is Activated by Ca2+\/Calmodulin- as Well as cAMP-Dependent Protein Kinase","volume":"88","author":"Dash","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ahmad, M.A., Kareem, O., Khushtar, M., Akbar, M., Haque, M.R., Iqubal, A., Haider, M.F., Pottoo, F.H., Abdulla, F.S., and Al-Haidar, M.B. (2022). Neuroinflammation: A Potential Risk for Dementia. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020616"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mart\u00edn Gim\u00e9nez, V.M., De Las Heras, N., Lahera, V., Tresguerres, J.A.F., Reiter, R.J., and Manucha, W. (2022). Melatonin as an Anti-Aging Therapy for Age-Related Cardiovascular and Neurodegenerative Diseases. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.888292"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/j.exger.2004.04.012","article-title":"Melatonin, Human Aging, and Age-Related Diseases","volume":"39","author":"Karasek","year":"2004","journal-title":"Exp. Gerontol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S0531-5565(98)00054-0","article-title":"Age-Related Changes in Melatonin Levels in Humans and Its Potential Consequences for Sleep Disorders","volume":"33","author":"Waldhauser","year":"1998","journal-title":"Exp. Gerontol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Begemann, K., Rawashdeh, O., Olejniczak, I., Pilorz, V., De Assis, L.V.M., Osorio-Mendoza, J., and Oster, H. (2025). Endocrine Regulation of Circadian Rhythms. npj Biol. Timing Sleep., 2.","DOI":"10.1038\/s44323-025-00024-6"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/jnc.15286","article-title":"A Multi-level Assessment of the Bidirectional Relationship between Aging and the Circadian Clock","volume":"157","author":"Buijink","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1600-079X.2008.00604.x","article-title":"Decreased MT1 and MT2 Melatonin Receptor Expression in Extrapineal Tissues of the Rat during Physiological Aging","volume":"46","author":"Lardone","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8638","DOI":"10.3390\/ijms14048638","article-title":"Melatonin: Buffering the Immune System","volume":"14","author":"Lardone","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1089\/jir.1990.10.403","article-title":"Interferon-\u03b3 Modulates Melatonin Production in Rat Pineal Glands in Organ Culture","volume":"10","author":"Withyachumnarnkul","year":"1990","journal-title":"J. Interferon Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1600-079X.2007.00487.x","article-title":"Pineal Melatonin and the Innate Immune Response: The TNF-\u03b1 Increase after Cesarean Section Suppresses Nocturnal Melatonin Production","volume":"43","author":"Pontes","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1002\/jnr.24220","article-title":"The Neuroprotective Role of Melatonin in Neurological Disorders","volume":"96","author":"Alghamdi","year":"2018","journal-title":"J. Neurosci. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/jpi.12090","article-title":"Melatonin and the Theories of Aging: A Critical Appraisal of Melatonin\u2019s Role in Antiaging Mechanisms","volume":"55","author":"Hardeland","year":"2013","journal-title":"J. Pineal Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Won, E., Na, K.-S., and Kim, Y.-K. (2021). Associations between Melatonin, Neuroinflammation, and Brain Alterations in Depression. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010305"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6251","DOI":"10.2147\/JIR.S334423","article-title":"Melatonin as a Potential Regulator of Oxidative Stress, and Neuroinflammation: Mechanisms and Implications for the Management of Brain Injury-Induced Neurodegeneration","volume":"14","author":"Ikram","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Rehman, S., Ikram, M., Ullah, N., Alam, S., Park, H., Badshah, H., Choe, K., and Ok Kim, M. (2019). Neurological Enhancement Effects of Melatonin against Brain Injury-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration via AMPK\/CREB Signaling. Cells, 8.","DOI":"10.3390\/cells8070760"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113786","DOI":"10.1016\/j.physbeh.2022.113786","article-title":"Metabolic Footprint in Young, Middle-Aged and Elderly Rats with Melatonin Deficit","volume":"250","author":"Tchekalarova","year":"2022","journal-title":"Physiol. Behav."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tchekalarova, J., Nenchovska, Z., Kortenska, L., Uzunova, V., Georgieva, I., and Tzoneva, R. (2022). Impact of Melatonin Deficit on Emotional Status and Oxidative Stress-Induced Changes in Sphingomyelin and Cholesterol Level in Young Adult, Mature, and Aged Rats. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052809"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12993-024-00229-y","article-title":"The Role of Melatonin Deficiency Induced by Pinealectomy on Motor Activity and Anxiety Responses in Young Adult, Middle-Aged and Old Rats","volume":"20","author":"Tchekalarova","year":"2024","journal-title":"Behav. Brain Funct."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/j.1749-6632.1994.tb23084.x","article-title":"The Pineal Gland as Ontogenetic Scanner of Reproduction, Immunity, and Aging The Aging Clock","volume":"741","author":"Pierpaoli","year":"1994","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1089\/109454501750225668","article-title":"The Pineal Aging and Death Program. I. Grafting of Old Pineals in Young Mice Accelerates Their Aging","volume":"4","author":"Pierpaoli","year":"2001","journal-title":"J. Anti Aging Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1196\/annals.1356.008","article-title":"The Pineal Aging and Death Program: Life Prolongation in Pre-aging Pinealectomized Mice","volume":"1057","author":"Pierpaoli","year":"2005","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1096\/fj.01-0409fje","article-title":"Loss in Oxidative Stress Tolerance with Aging Linked to Reduced Extracellular Signal-regulated Kinase and Akt Kinase Activities","volume":"16","author":"Ikeyama","year":"2002","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/cdd.2008.171","article-title":"Regional Hippocampal Differences in AKT Survival Signaling across the Lifespan: Implications for CA1 Vulnerability with Aging","volume":"16","author":"Jackson","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.3233\/JAD-150926","article-title":"Brain-Specific Basal and Novelty-Induced Alternations in PI3K-Akt and MAPK\/ERK Signaling in a Middle-Aged A\u03b2PP\/PS1 Mouse Model of Alzheimer\u2019s Disease","volume":"51","author":"Guillot","year":"2016","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8120","DOI":"10.1074\/jbc.RA119.012425","article-title":"Phosphorylation-Dependent Substrate Selectivity of Protein Kinase B (AKT1)","volume":"295","author":"Balasuriya","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1101\/lm.1067808","article-title":"Role of the Phosphoinositide 3-Kinase-Akt-Mammalian Target of the Rapamycin Signaling Pathway in Long-Term Potentiation and Trace Fear Conditioning Memory in Rat Medial Prefrontal Cortex","volume":"15","author":"Sui","year":"2008","journal-title":"Learn. Mem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5888","DOI":"10.1523\/JNEUROSCI.0782-06.2006","article-title":"Long-Term Potentiation Enhances Neurogenesis in the Adult Dentate Gyrus","volume":"26","author":"Davis","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1089\/neu.2007.0369","article-title":"Simvastatin-Mediated Upregulation of VEGF and BDNF, Activation of the PI3K\/Akt Pathway, and Increase of Neurogenesis Are Associated with Therapeutic Improvement after Traumatic Brain Injury","volume":"25","author":"Wu","year":"2008","journal-title":"J. Neurotrauma"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1111\/jnc.15441","article-title":"Akt3-mTOR Regulates Hippocampal Neurogenesis in Adult Mouse","volume":"159","author":"Zhang","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.bbrc.2008.11.010","article-title":"Age-Related Decrease in Constructive Activation of Akt\/PKB in SAMP10 Hippocampus","volume":"378","author":"Nie","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1000543","DOI":"10.4172\/2155-9899.1000543","article-title":"Brain Inflammaging: Roles of Melatonin, Circadian Clocks and Sirtuins","volume":"9","author":"Hardeland","year":"2018","journal-title":"J. Clin. Cell Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3263","DOI":"10.1111\/bph.13950","article-title":"Melatonin Receptors: Molecular Pharmacology and Signalling in the Context of System Bias","volume":"175","author":"Cecon","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.4103\/1673-5374.387973","article-title":"Melatonin Improves Synapse Development by PI3K\/Akt Signaling in a Mouse Model of Autism Spectrum Disorder","volume":"19","author":"Wang","year":"2024","journal-title":"Neural Regen. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.redox.2017.04.006","article-title":"Particular Phosphorylation of PI3K\/Akt on Thr308 via PDK-1 and PTEN Mediates Melatonin\u2019s Neuroprotective Activity after Focal Cerebral Ischemia in Mice","volume":"12","author":"Kilic","year":"2017","journal-title":"Redox Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"17590914211022888","DOI":"10.1177\/17590914211022888","article-title":"Melatonin Protects Against Ischemic Brain Injury by Modulating PI3K\/AKT Signaling Pathway via Suppression of PTEN Activity","volume":"13","author":"Ran","year":"2021","journal-title":"ASN Neuro"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1016\/j.biocel.2013.05.037","article-title":"NF-\u03baB: Emerging Roles in Hippocampal Development and Function","volume":"45","author":"Crampton","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bortolotto, V., Cuccurazzu, B., Canonico, P.L., and Grilli, M. (2014). NF-\u03baB Mediated Regulation of Adult Hippocampal Neurogenesis: Relevance to Mood Disorders and Antidepressant Activity. BioMed Res. Int., 2014.","DOI":"10.1155\/2014\/612798"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0006-8993(96)00310-1","article-title":"Enhancement of Immunoreactivity for NF-\u03baB in the Hippocampal Formation and Cerebral Cortex of Alzheimer\u2019s Disease","volume":"735","author":"Terai","year":"1996","journal-title":"Brain Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Yin, C., Zhang, M., Cheng, L., Ding, L., Lv, Q., Huang, Z., Zhou, J., Chen, J., Wang, P., and Zhang, S. (2024). Melatonin Modulates TLR4\/MyD88\/NF-\u03baB Signaling Pathway to Ameliorate Cognitive Impairment in Sleep-Deprived Rats. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1430599"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/j.1600-079X.2006.00407.x","article-title":"One Molecule, Many Derivatives: A Never-ending Interaction of Melatonin with Reactive Oxygen and Nitrogen Species?","volume":"42","author":"Tan","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jneuroim.2005.05.002","article-title":"Anti-Inflammatory Actions of Melatonin and Its Metabolites, N1-Acetyl-N2-Formyl-5-Methoxykynuramine (AFMK) and N1-Acetyl-5-Methoxykynuramine (AMK), in Macrophages","volume":"165","author":"Mayo","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1034\/j.1600-079X.2002.02113.x","article-title":"Several Antioxidant Pathways Are Involved in Astrocyte Protection by Melatonin","volume":"33","author":"Sainz","year":"2002","journal-title":"J. Pineal Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"43","DOI":"10.2119\/molmed.2008.00117","article-title":"Melatonin: An Established Antioxidant Worthy of Use in Clinical Trials","volume":"15","author":"Korkmaz","year":"2009","journal-title":"Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1007\/s10753-023-01822-5","article-title":"Melatonin-Driven NLRP3 Inflammation Inhibition Via Regulation of NF-\u03baB Nucleocytoplasmic Transport: Implications for Postoperative Cognitive Dysfunction","volume":"46","author":"Zhu","year":"2023","journal-title":"Inflammation"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.3324\/haematol.2012.066175","article-title":"The PI3K\/Akt Signaling Pathway Regulates the Expression of Hsp70, Which Critically Contributes to Hsp90-Chaperone Function and Tumor Cell Survival in Multiple Myeloma","volume":"98","author":"Chatterjee","year":"2013","journal-title":"Haematologica"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Lyu, Q., Wawrzyniuk, M., Rutten, V.P.M.G., Van Eden, W., Sijts, A.J.A.M., and Broere, F. (2020). Hsp70 and NF-kB Mediated Control of Innate Inflammatory Responses in a Canine Macrophage Cell Line. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186464"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Moniruzzaman, M., Ghosal, I., Das, D., and Chakraborty, S.B. (2018). Melatonin Ameliorates H2O2-Induced Oxidative Stress through Modulation of Erk\/Akt\/NFkB Pathway. Biol. Res., 51.","DOI":"10.1186\/s40659-018-0168-5"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"105960","DOI":"10.1016\/j.neuint.2025.105960","article-title":"Age-Related Memory Decline Is Accelerated by Pinealectomy in Young Adult and Middle-Aged Rats via BDNF\/ERK\/CREB Signalling in the Hippocampus 2024","volume":"185","author":"Tchekalarova","year":"2025","journal-title":"Neurochem. Int."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Tchekalarova, J., Ivanova, P., Krushovlieva, D., Kortenska, L., and Angelova, V.T. (2024). Protective Effect of the Novel Melatonin Analogue Containing Donepezil Fragment on Memory Impairment via MT\/ERK\/CREB Signaling in the Hippocampus in a Rat Model of Pinealectomy and Subsequent A\u03b21-42 Infusion. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202401.1555.v1"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e279","DOI":"10.1038\/oncsis.2016.81","article-title":"ERK-Mediated NF-\u03baB Activation through ASIC1 in Response to Acidosis","volume":"5","author":"Chen","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6413","DOI":"10.4049\/jimmunol.1001829","article-title":"The Role of the Transcription Factor CREB in Immune Function","volume":"185","author":"Wen","year":"2010","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Hiramoto, K., Imai, M., Tanaka, S., and Ooi, K. (2023). Dementia Is Induced via the AGEs\/Iba1\/iNOS Pathway in Aged KK-Ay\/Tajcl Mice. Life, 13.","DOI":"10.3390\/life13071540"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.3892\/mmr.2020.11216","article-title":"Age-dependent Alterations in the Immunoreactivity of Macrophage Inflammatory Protein-3\u03b1 and Its Receptor CCR6 in the Gerbil Hippocampus","volume":"22","author":"Ahn","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Song, C., Suo, Z., Wang, Z., Cao, J., Dong, Y., and Chen, Y. (2024). Melatonin Modulates Neuroinflammatory Response and Microglial Activation in Mice Exposed to Dim Blue Light at Night. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1416350"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s41398-024-02887-y","article-title":"Melatonin Alleviates Chronic Stress-Induced Hippocampal Microglia Pyroptosis and Subsequent Depression-like Behaviors by Inhibiting Cathepsin B\/NLRP3 Signaling Pathway in Rats","volume":"14","author":"Gao","year":"2024","journal-title":"Transl. Psychiatry"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Merlo, S., Luaces, J.P., Spampinato, S.F., Toro-Urrego, N., Caruso, G.I., D\u2019Amico, F., Capani, F., and Sortino, M.A. (2020). SIRT1 Mediates Melatonin\u2019s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence. Biomolecules, 10.","DOI":"10.3390\/biom10030364"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Arioz, B.I., Tastan, B., Tarakcioglu, E., Tufekci, K.U., Olcum, M., Ersoy, N., Bagriyanik, A., Genc, K., and Genc, S. (2019). Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1\/Nrf2 Pathway. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01511"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.neuron.2024.12.010","article-title":"Astrocytes in Aging","volume":"113","author":"Allen","year":"2025","journal-title":"Neuron"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.immuni.2017.06.006","article-title":"Reactive Astrocytes: Production, Function, and Therapeutic Potential","volume":"46","author":"Liddelow","year":"2017","journal-title":"Immunity"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13195-016-0206-x","article-title":"Protective Effect of Melatonin on Soluble A\u03b21\u201342-Induced Memory Impairment, Astrogliosis, and Synaptic Dysfunction via the Musashi1\/Notch1\/Hes1 Signaling Pathway in the Rat Hippocampus","volume":"8","author":"Zhang","year":"2016","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"G\u00e1ll, Z., Boros, B., Kelemen, K., Urkon, M., Zolcseak, I., M\u00e1rton, K., and Kolcsar, M. (2024). Melatonin Improves Cognitive Dysfunction and Decreases Gliosis in the Streptozotocin-Induced Rat Model of Sporadic Alzheimer\u2019s Disease. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1447757"},{"key":"ref_71","first-page":"83","article-title":"Rapid pinealectomy in hamsters and other small rodents","volume":"24","author":"Hoffman","year":"1965","journal-title":"Anat. Record."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.bbr.2015.12.043","article-title":"Consequences of Long-Term Treatment with Agomelatine on Depressive-like Behavior and Neurobiological Abnormalities in Pinealectomized Rats","volume":"302","author":"Tchekalarova","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"105599","DOI":"10.1016\/j.yhbeh.2024.105599","article-title":"Inhibition of Hippocampal Melatonin Synthesis by siRNA Induced Learning and Memory Deficits in Male Rats","volume":"164","author":"Ghorbandaiepour","year":"2024","journal-title":"Horm. Behav."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"55","DOI":"10.32794\/mr112500120","article-title":"Melatonin Synthesized by Activated Microglia Orchestrates the Progression of Microglia from a Pro-Inflammatory to a Recovery\/Repair Phenotype","volume":"5","author":"Souza","year":"2022","journal-title":"Melatonin Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/j.1600-079X.2007.00466.x","article-title":"Cultured Rat Cortical Astrocytes Synthesize Melatonin: Absence of a Diurnal Rhythm","volume":"43","author":"Liu","year":"2007","journal-title":"J. Pineal Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8093\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:56Z","timestamp":1760034776000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8093"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":75,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26168093"],"URL":"https:\/\/doi.org\/10.3390\/ijms26168093","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]}}}