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The present study evaluated the alpha-lipoic acid (ALA) neuroprotective potential against TiO\u2082-NP-induced cognitive and molecular impairments in male Sprague\u2013Dawley rats. Twenty-four rats were allocated into four groups: negative control, TiO\u2082-NPs (150\u00a0mg\/kg, i.p.), ALA (50\u00a0mg\/kg, orally), and TiO\u2082-NPs\u2009+\u2009ALA. Treatments were administered on alternate days for 28\u00a0days. Neurobehavioral tests, including the open field test (OFT), elevated plus maze (EPM), novel object recognition test (NORT), and Morris water maze (MWM), revealed that TiO\u2082-NPs impaired memory and increased anxiety-like behavior, while ALA co-treatment significantly restored behavioral performance. TiO\u2082-NPs exposure significantly decreased antioxidant enzymes (SOD, CAT, GSH), increased lipid peroxidation (MDA), elevated proinflammatory cytokines (TNF-\u03b1, IL-6), and apoptotic marker (caspase-3), and reduced neurotransmitter levels (GABA and dopamine). ALA administration reversed these alterations, indicating antioxidant, anti-inflammatory, and neuroprotective effects. Gene expression analysis showed TiO\u2082-NPs upregulated BAX, NF-\u03baB, APP, and MAPT and downregulated BCL-2 and Nrf2, consistent with neurodegenerative and apoptotic signaling. ALA co-treatment normalized these gene expressions. Histopathological analysis confirmed structural damage in the cerebrum and cerebellum after TiO\u2082-NPs exposure, which ALA markedly improved. These findings suggest that ALA offers significant neuroprotection against TiO\u2082-NP-induced toxicity via its antioxidant, anti-inflammation, and anti-apoptosis properties, and supports being a potential protective agent against nanoparticle-induced neurodegeneration.<\/jats:p>","DOI":"10.1007\/s12011-025-04672-4","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T17:00:40Z","timestamp":1748883640000},"page":"172-188","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Neuroprotective Effects of Alpha-Lipoic Acid Against\u00a0Behavioral Toxicity,\u00a0Oxidative and Inflammatory Damage Caused by Titanium Dioxide Nanoparticles"],"prefix":"10.1007","volume":"204","author":[{"given":"Mahmoud A.","family":"Khedr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"El-Kazaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashed R.","family":"Rashed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossam G.","family":"Tohamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Shukry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira A.","family":"Goma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"4672_CR1","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.colsurfb.2017.08.003","volume":"159","author":"I Takeuchi","year":"2017","unstructured":"Takeuchi I, Suzuki T, Makino K (2017) Skin permeability and transdermal delivery route of 50-nm indomethacin-loaded PLGA nanoparticles. 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