{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:00:51Z","timestamp":1785438051403,"version":"3.56.0"},"reference-count":29,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["25-25-00048"],"award-info":[{"award-number":["25-25-00048"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["25-25-00048"],"award-info":[{"award-number":["25-25-00048"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathophysiology"],"abstract":"<jats:p>Background\/Objectives. Parkinson\u2019s disease (PD) is a multifactorial neurodegenerative disorder characterized by dopaminergic neuron loss, \u03b1-synuclein pathology, neuroinflammation, and cognitive decline. Synaptamide (N-Docosahexaenoylethanolamine (DHEA)) is an endogenous lipid mediator with documented anti-inflammatory and neurogenic properties, but its effects in PD models remain unexplored. This study aimed to evaluate the neuroprotective potential of synaptamide in a subchronic MPTP-induced mouse model of PD. Methods. Male C57BL\/6 mice received MPTP (30 mg\/kg\/day, i.p., 5 days) with or without synaptamide (10 mg\/kg\/day, s.c., 13 days). Behavioral tests (open field, Y-maze, elevated plus maze, novel object recognition (NOR)) were performed, followed by immunohistochemical analysis of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra, and Western blotting for \u03b1-synuclein, p-\u03b1-synuclein, TH, and IL1\u03b2 in brain homogenates and serum. In vitro Neuro-2a cells were co-treated with MPP+ (100 \u00b5M) and synaptamide (0.1\u201310 \u00b5M) for cytotoxicity assessment (MTS assay). Results. Synaptamide (10 \u00b5M) significantly attenuated MPP+-induced cytotoxicity in Neuro-2a cells. In vivo, MPTP caused a marked loss of TH+-neurons in the substantia nigra, which was prevented by synaptamide treatment. Importantly, this subchronic MPTP model recapitulates early biochemical alterations (e.g., \u03b1-synuclein phosphorylation at Ser129) rather than mature Lewy body pathology, a limitation that should be considered when interpreting these findings. Although no motor deficits or anxiety-like behavior were observed, the NOR test revealed MPTP-induced long-term memory impairment, which was fully restored by synaptamide. Conclusions. These findings suggest that synaptamide may exert effects on pathological processes associated with PD, warranting further investigation into its potential role in combination or supportive therapy for this disease.<\/jats:p>","DOI":"10.3390\/pathophysiology33030042","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:37:55Z","timestamp":1782391075000},"page":"42","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuroprotective Potential of Synaptamide in MPTP-Induced Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"33","author":[{"given":"Igor","family":"Manzhulo","sequence":"first","affiliation":[{"name":"A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str., 17, Vladivostok 690041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7496-9517","authenticated-orcid":false,"given":"Yuliya","family":"Kipryushina","sequence":"additional","affiliation":[{"name":"A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str., 17, Vladivostok 690041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1373-3471","authenticated-orcid":false,"given":"Ekaterina","family":"Gromova","sequence":"additional","affiliation":[{"name":"A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str., 17, Vladivostok 690041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Manzhulo","sequence":"additional","affiliation":[{"name":"A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str., 17, Vladivostok 690041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Milkina","sequence":"additional","affiliation":[{"name":"A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str., 17, Vladivostok 690041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0059-1061","authenticated-orcid":false,"given":"Darya","family":"Ivashkevich","sequence":"additional","affiliation":[{"name":"A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str., 17, Vladivostok 690041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Macedo, V.F.B., Macedo, V.K.B., de Miranda Coelho, J.A.P., and de Melo Barboza, A.M. (2025). Parkinson\u2019s disease physiopathology-beyond the \u03b1-synuclein aggregation: A narrative review. Front. Aging Neurosci., 17.","DOI":"10.3389\/fnagi.2025.1664269"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100274","DOI":"10.1016\/j.mocell.2025.100274","article-title":"Current therapeutic strategies in Parkinson\u2019s disease: Future perspectives","volume":"48","author":"Kim","year":"2025","journal-title":"Mol. Cells"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Khan, M.S., Nasiripour, S., and Bopassa, J.C. (2025). Parkinson Disease Signaling Pathways, Molecular Mechanisms, and Potential Therapeutic Strategies: A Comprehensive Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136416"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.neuron.2016.03.038","article-title":"Understanding Dopaminergic Cell Death Pathways in Parkinson Disease","volume":"90","author":"Michel","year":"2016","journal-title":"Neuron"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s40035-023-00378-6","article-title":"Role of dopamine in the pathophysiology of Parkinson\u2019s disease","volume":"12","author":"Zhou","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s10571-025-01544-2","article-title":"Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson\u2019s Disease","volume":"45","author":"Yaribash","year":"2025","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pitton Rissardo, J., McGarry, A., Shi, Y., Fornari Caprara, A.L., and Kannarkat, G.T. (2025). Alpha-Synuclein Neurobiology in Parkinson\u2019s Disease: A Comprehensive Review of Its Role, Mechanisms, and Therapeutic Perspectives. Brain Sci., 15.","DOI":"10.3390\/brainsci15121260"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Blesa, J., and Przedborski, S. (2014). Parkinson\u2019s disease: Animal models and dopaminergic cell vulnerability. Front. Neuroanat., 8.","DOI":"10.3389\/fnana.2014.00155"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Tanaka, M. (2025). Parkinson\u2019s Disease: Bridging Gaps, Building Biomarkers, and Reimagining Clinical Translation. Cells, 14.","DOI":"10.20944\/preprints202506.2099.v2"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Cuenca-Bermejo, L., Pizzichini, E., Gon\u00e7alves, V.C., Guill\u00e9n-D\u00edaz, M., Aguilar-Mo\u00f1ino, E., S\u00e1nchez-Rodrigo, C., Gonz\u00e1lez-Cuello, A.-M., Fern\u00e1ndez-Villalba, E., and Herrero, M.T. (2021). A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094341"},{"key":"ref_11","first-page":"422","article-title":"MPTP-induced mouse model of Parkinson\u2019s disease: A promising direction of therapeutic strategies","volume":"21","author":"Mustapha","year":"2021","journal-title":"Bosn. J. Basic Med. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/aps.2017.49","article-title":"Reassessment of subacute MPTP-treated mice as animal model of Parkinson\u2019s disease","volume":"38","author":"Zhang","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.mam.2018.03.004","article-title":"N-Docosahexaenoylethanolamine: A neurotrophic and neuroprotective metabolite of docosahexaenoic acid","volume":"64","author":"Kim","year":"2018","journal-title":"Mol. Asp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"110094","DOI":"10.1016\/j.neuropharm.2024.110094","article-title":"Anti-inflammatory and anti-apoptotic activity of synaptamide improves the morphological state of neurons in traumatic brain injury","volume":"258","author":"Manzhulo","year":"2024","journal-title":"Neuropharmacology"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Tyrtyshnaia, A., Manzhulo, O., and Manzhulo, I. (2023). Synaptamide Ameliorates Hippocampal Neurodegeneration and Glial Activation in Mice with Traumatic Brain Injury. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210014"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Saramowicz, K., Siwecka, N., Galita, G., Kucharska-Lusina, A., Rozp\u0119dek-Kami\u0144ska, W., and Majsterek, I. (2023). Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson\u2019s Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010360"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/jnc.15699","article-title":"Neurochemical, histological, and behavioral profiling of the acute, sub-acute, and chronic MPTP mouse model of Parkinson\u2019s disease","volume":"164","author":"Santoro","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15333175251346292","DOI":"10.1177\/15333175251346292","article-title":"Restoration of Memory Along With Neurogenic Enhancement by Therapeutic Botulinum Neurotoxin in a Preclinical Model of Parkinson\u2019s Disease","volume":"40","author":"Joseph","year":"2025","journal-title":"Am. J. Alzheimers Dis. Other Demen."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tyrtyshnaia, A.A., Egorova, E.L., Starinets, A.A., Ponomarenko, A.I., Ermolenko, E.V., and Manzhulo, I.V. (2020). N-Docosahexaenoylethanolamine Attenuates Neuroinflammation and Improves Hippocampal Neurogenesis in Rats with Sciatic Nerve Chronic Constriction Injury. Mar. Drugs, 18.","DOI":"10.3390\/md18100516"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"651","DOI":"10.2147\/NDT.S235562","article-title":"Phosphorylation of Tau and \u03b1-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson\u2019s Disease","volume":"16","author":"Hu","year":"2020","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/S0306-4522(01)00295-0","article-title":"Mouse model of Parkinsonism: A comparison between subacute MPTP and chronic MPTP\/probenecid treatment","volume":"106","author":"Petroske","year":"2001","journal-title":"Neuroscience"},{"key":"ref_22","first-page":"19","article-title":"MPTP mouse models of Parkinson\u2019s disease: An update","volume":"1","author":"Meredith","year":"2011","journal-title":"J. Park. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/s41531-025-01167-w","article-title":"\u03b1-synuclein in Parkinson\u2019s disease: A central point of convergence with depression","volume":"11","author":"Yusuf","year":"2025","journal-title":"NPJ Park. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5055","DOI":"10.1074\/jbc.M110.178905","article-title":"Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and alpha-synuclein mutations promote Tau protein phosphorylation at Ser262 and destabilize microtubule cytoskeleton in vitro","volume":"286","author":"Qureshi","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"22398","DOI":"10.1038\/srep22398","article-title":"Gene dysregulation is restored in the Parkinson\u2019s disease MPTP neurotoxic mice model upon treatment of the therapeutic drug Cu (II)(atsm)","volume":"6","author":"Cheng","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8581","DOI":"10.1038\/s41598-024-59090-8","article-title":"Plasminogen degrades \u03b1-synuclein, Tau and TDP-43 and decreases dopaminergic neurodegeneration in mouse models of Parkinson\u2019s disease","volume":"14","author":"Guo","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.chemphyslip.2017.11.002","article-title":"N-Docosahexaenoylethanolamine (synaptamide): Carbon-14 radiolabeling and metabolic studies","volume":"210","author":"Sonti","year":"2018","journal-title":"Chem. Phys. Lipids"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ponomarenko, A., Tyrtyshnaia, A., Ivashkevich, D., Ermolenko, E., Dyuizen, I., and Manzhulo, I. (2022). Synaptamide Modulates Astroglial Activity in Mild Traumatic Brain Injury. Mar. Drugs, 20.","DOI":"10.3390\/md20080538"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1007\/s40120-025-00793-z","article-title":"Neuroprotection in Parkinson Disease","volume":"14","author":"Bandmann","year":"2025","journal-title":"Neurol. Ther."}],"container-title":["Pathophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1873-149X\/33\/3\/42\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T14:33:41Z","timestamp":1782398021000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1873-149X\/33\/3\/42"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":29,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["pathophysiology33030042"],"URL":"https:\/\/doi.org\/10.3390\/pathophysiology33030042","relation":{},"ISSN":["1873-149X"],"issn-type":[{"value":"1873-149X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}