Abstract Background and Purpose Parkinson's disease (PD), characterized by motor dysfunction and dopaminergic neuron loss in the substantia nigra, is frequently complicated by depression (depression‐associated PD, DPD), affecting 40–50% of patients and accelerating disease progression. This study investigated neuroprotective effects in a chronic MPTP‐induced mouse model of DPD. Experimental Approach 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‐depressive groups, followed by 14‐day treatment with SVHRSP or vehicle. Key Results Post‐treatment 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‐maze, passive‐avoidance and novel‐object‐recognition 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‐95). 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‐HT 2C receptor levels and normalized stress‐axis glucocorticoid receptor (GR) expression. Molecular docking simulations revealed strong binding affinities between SVHRSP and CREB/Akt. Conclusion and Implications The results indicate that SVHRSP mitigates motor deficits, depressive symptoms and cognitive impairments in MPTP‐induced DPD mice by suppressing CREB‐Akt‐mediated neuroinflammation and modulating synaptic plasticity. The multitarget mechanism of SVHRSP underscores its potential as a novel therapeutic candidate for DPD.
Iqbal et al. (Wed,) studied this question.