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Current monoamine oxidase inhibitors have limited cognitive benefits and disease-modifying properties. A new nanotherapeutic, combining chitosan nanoparticles, propargylamino-1-(4-methylthiophenyl) propane (PAMTP), and L-tyrosine (En@PAMTP_Tyr), was developed. En@PAMTP_Tyr nanoparticles were ~140 nm in diameter, with a zeta potential of +27 mV and entrapment efficiencies of 73.45% for PAMTP and 90.85% for L-tyrosine. Drug release was pH-sensitive, favoring acidity. Intraperitoneal administration of En@PAMTP_Tyr reduced anhedonia, despair, cognitive deficits, and neuromuscular weakness, with efficacy matching or exceeding that of selegiline. In treated rats\u2019 hippocampal tissue, En@PAMTP_Tyr increased superoxide dismutase and glutathione, normalized MAO and acetylcholinesterase activities, and corrected CUSD-induced TNF-\u03b1 and IL-10 changes, showing antioxidant and anti-inflammatory effects. Histological analyses revealed that En@PAMTP_Tyr preserved CA1 pyramidal neurons, reduced \u03b2-amyloid levels, restored tau protein, and improved brain-derived neurotrophic factor levels, indicating reduced neurodegeneration. Molecular docking studies showed that PAMTP had high affinity for monoamine oxidase and acetylcholinesterase, supporting its role as an MAO-B inhibitor and cholinergic modulator. These findings suggest that En@PAMTP_Tyr is a promising nanoplatform for targeting MAO-B in depression, addressing mood, cognitive function, oxidative stress, inflammation, and Alzheimer-like pathology in the hippocampus.<\/jats:p>","DOI":"10.3390\/biom16060871","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"871","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chitosan Nanoparticles Co-Encapsulating Selegiline Analogue and L-Tyrosine Mitigate Depression-Related Pathology and Cognitive Decline in Rats"],"prefix":"10.3390","volume":"16","author":[{"given":"Wesam","family":"Abd El-Fattah","sequence":"first","affiliation":[{"name":"Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), P.O. Box 5701, Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7552-4146","authenticated-orcid":false,"given":"Ahlem","family":"Guesmi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), P.O. Box 5701, Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2410-5275","authenticated-orcid":false,"given":"Naoufel Ben","family":"Hamadi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), P.O. 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