Tolperisone hydrochloride improves motor functions in Parkinson’s disease via MMP-9 inhibition and by downregulating p38 MAPK and ERK1/2 signaling cascade

• Published in: Biomedicine & pharmacotherapy 2024-05, Vol.174, p.116438-116438, Article 116438
• Main Authors: Zaman, Bushra, Mostafa, Irona, Hassan, Tazree, Ahmed, Shamim, Esha, Nusrat Jahan Ikbal, Chowdhury, Fowzia Afsana, Bosu, Tory, Chowdhury, Humayra Noor, Mallick, Anup, Islam, MM Shanjid, Sharmin, Ayesha, Uddin, Kabir M., Hossain, Md. Mainul, Rahman, Mahbubur
• Format: Article
• Language: English
• Subjects: Animals; Down-Regulation - drug effects; ERK1/2; Male; MAP Kinase Signaling System - drug effects; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors - pharmacology; Mice; Mice, Inbred C57BL; MMP-9; Motor Activity - drug effects; Motor function; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson's disease; Rotenone - pharmacology; tolperisone hydrochloride
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2024.116438

The mitogen-activated protein kinase (MAPK) signaling pathway, particularly the p38 MAPK and ERK1/2, has been implicated in the pathogenesis of Parkinson's disease (PD). Recent studies have shown that MAPK signaling pathway can influence the expression of matrix metalloproteinase 9 (MMP-9), known for its involvement in various physiological and pathological processes, including neurodegenerative diseases. This study explores the modulation of MMP-9 expression via the MAPK/ERK signaling cascade and its potential therapeutic implications in the context of PD-associated motor dysfunction. Here, tolperisone hydrochloride (TL), a muscle relaxant that blocks voltage-gated sodium and calcium channels, was used as a treatment to observe its effect on MAPK signaling and MMP-9 expression. Rotenone (RT) exposure in mice resulted in a significant reduction in substantia nigra and primary motor cortex neurons, which were further evidenced by impairments in motor function. When TL was administered, neuron count was restored (89.0 ± 4.78 vs 117.0 ± 4.46/mm2), and most of the motor dysfunction was alleviated. Mechanistically, TL reduced the protein expression of phospho-p38MAPK (1.06 fold vs 1.00 fold) and phospho-ERK1/2 (1.16 fold vs 1.02 fold), leading to the inhibition of MAPK signaling, as well as reduced MMP-9 concentrations (2.76 ± 0.10 vs 1.94 ± 0.10 ng/mL) in the process of rescuing RT-induced neuronal cell death and motor dysfunction. Computational analysis further revealed TL’s potential inhibitory properties against MMP-9 along with N and L-type calcium channels. These findings shed light on TL's neuroprotective effects via MMP-9 inhibition and MAPK signaling downregulation, offering potential therapeutic avenues for PD-associated motor dysfunction. [Display omitted] •Rotenone (RT) induces neuronal death in the striatum and motor cortex, leading to motor dysfunction.•Tolpersione hydrochloride (TL) restores RT-induced cytochrome-c release and prevents subsequent neuronal apoptosis.•Treatment with TL leads to improved motor coordination, balance, and muscle strength.•TL exerts its neuroprotective effect by inhibiting MMP-9 and downregulating MAPK/ERK signaling.