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To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and \u03b1\u2010synuclein in animals with low VMAT2 expression. Conversely, animals that overexpress VMAT2 show better protection for dopamine neurons. Based on these findings, this study used histone deacetylase inhibitors (HDACi) to increase VMAT2 expression, reduce dopamine\u2010induced oxidative stress, and evaluate the resulting behavioral improvements in a 1\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine (MPTP)\u2010induced PD animal model. LMK\u2010235 not only increased VMAT2 expression at various concentrations in the SH\u2010SY5Y cell line differentiated into dopaminergic cells but also demonstrated effective cytoprotective properties in several toxicity assays. It significantly raised VMAT2 expression in both the striatum and the ventral tegmental area of an MPTP\u2010induced PD model, supporting its role in reversing behavioral abnormalities linked to PD. In addition to these results, coadministration of LMK\u2010235 with L\u2010DOPA, a standard therapy for PD, restored typical behavioral patterns, highlighting the potential of HDACi in alleviating PD symptoms. The expression of VMAT2 induced by LMK\u2010235, an inhibitor of Class IIa histone deacetylases primarily found in the nervous system, aids in sequestering dopamine into vesicles, potentially enhancing cell survival by inhibiting dopamine oxidation. Additionally, upregulation of VMAT2 has been shown to offer effective protection against MPTP\u2010induced toxicity and significantly improve behavioral abnormalities associated with PD. Coadministration with L\u2010DOPA produced the most notable improvement in behavioral outcomes. Altogether, these findings suggest that the overexpression of VMAT2 may offer a promising strategy for developing treatments for PD by mitigating dopaminergic neuron death resulting from dopamine oxidation.<\/jats:p>","DOI":"10.1002\/prp2.70057","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T04:54:55Z","timestamp":1736830495000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>HDAC4<\/scp>\/5 Inhibitor, <scp>LMK<\/scp>\u2010235 Improves Animal Voluntary Movement in <scp>MPTP<\/scp>\u2010Induced Parkinson's Disease Model"],"prefix":"10.1002","volume":"13","author":[{"given":"Heejin","family":"Lee","sequence":"first","affiliation":[{"name":"New Drug Development Center  Daegu Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun\u2010Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Salk Institute for Biological Studies  La Jolla 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