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This study investigated neuroprotective effects in a chronic MPTP\u2010induced mouse model of DPD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>We established a chronic PD model induced by MPTP, with motor deficits assessed via rotarod and gait analysis. Depressive phenotypes were confirmed by tail suspension, sucrose preference and forced swim tests. Mice were categorized into DPD and non\u2010depressive groups, followed by 14\u2010day treatment with SVHRSP or vehicle.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Post\u2010treatment behavioural evaluations demonstrated that SVHRSP significantly ameliorated depressive symptoms, as evidenced by increased sucrose preference, reduced immobility in the forced swim test and restored cognitive performance in the Y\u2010maze, passive\u2010avoidance and novel\u2010object\u2010recognition tests. Molecular analyses demonstrated that SVHRSP enhanced neuroprotection by normalizing the phosphorylated Akt and CREB levels, reducing neuroinflammatory markers (IBA1, GFAP and cytokines) and modulating synaptic proteins (NR2B and PSD\u201095). Immunofluorescence further corroborated these findings, confirming reduced NR2B and NR1 expression and preserved neuronal integrity. SVHRSP downregulated Nav1.6 ion channel expression and restored 5\u2010HT\n                      <jats:sub>2C<\/jats:sub>\n                      receptor levels and normalized stress\u2010axis glucocorticoid receptor (GR) expression. Molecular docking simulations revealed strong binding affinities between SVHRSP and CREB\/Akt.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>The results indicate that SVHRSP mitigates motor deficits, depressive symptoms and cognitive impairments in MPTP\u2010induced DPD mice by suppressing CREB\u2010Akt\u2010mediated neuroinflammation and modulating synaptic plasticity. The multitarget mechanism of SVHRSP underscores its potential as a novel therapeutic candidate for DPD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70364","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:29:26Z","timestamp":1770856166000},"page":"2820-2836","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protective effect of scorpion\u2010venom heat\u2010resistant peptide (SVHRSP) against depression associated with Parkinson's disease via suppression of CREB\u2010Akt pathway\u2010mediated inflammation"],"prefix":"10.1111","volume":"183","author":[{"given":"Muhammad Khalid","family":"Iqbal","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases Dalian Medical University  Dalian Liaoning China"},{"name":"National\u2010Local Joint Engineering Research 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