Effects of Apamin on MPP + -Induced Calcium Overload and Neurotoxicity by Targeting CaMKII/ERK/p65/STAT3 Signaling Pathways in Dopaminergic Neuronal Cells

• Published in: International journal of molecular sciences Vol. 23; no. 23; p. 15255
• Main Authors: Park, Jihyun, Jang, Kyung Mi, Park, Kwan-Kyu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 03.12.2022; MDPI
• Subjects: 1-Methyl-4-phenylpyridinium - toxicity; Animals; apamin; Apamin - pharmacology; Apoptosis; Ca2+/calmodulin-dependent protein kinase II; Calcium (mitochondrial); Calcium - metabolism; Calcium antagonists; Calcium homeostasis; Calcium ions; Calcium signalling; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cell Line, Tumor; Cytotoxicity; Dopamine receptors; Dopaminergic Neurons - metabolism; Extracellular signal-regulated kinase; Homeostasis; Humans; Inflammation; Mitochondria; Morphology; MPP; Neuroblastoma - metabolism; Neurons; Neuroprotective Agents - pharmacology; Neurotoxicity; Neurotoxicity Syndromes - pathology; NF-kappa B - metabolism; NF-κB protein; Overloading; oxidant stress; Oxidative Stress; Parkinson Disease - metabolism; Parkinson's disease; Pathogenesis; Phosphorylation; Potassium channels (calcium-gated); Proteins; Rats; ROS; Signal Transduction; SK channel; Stat3 protein; apoptosis; oxidant stress; SK channel; Parkinson’s disease; apamin; ROS
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232315255

Parkinson's disease (PD), a neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons. The pathogenesis of PD is associated with several factors including oxidative stress, inflammation, and mitochondrial dysfunction. Ca signaling plays a vital role in neuronal signaling and altered Ca homeostasis has been implicated in many neuronal diseases including PD. Recently, we reported that apamin (APM), a selective antagonist of the small-conductivity Ca -activated K (SK) channel, suppresses neuroinflammatory response. However, the mechanism(s) underlying the vulnerability of DA neurons were not fully understood. In this study, we investigated whether APM affected 1-methyl-4-phenyl pyridinium (MPP )-mediated neurotoxicity in SH-SY5Y cells and rat embryo primary mesencephalic neurons. We found that APM decreased Ca overload arising from MPP -induced neurotoxicity response through downregulating the level of CaMKII, phosphorylation of ERK, and translocation of nuclear factor NFκB/signal transducer and activator of transcription (STAT)3. Furthermore, we showed that the correlation of MPP -mediated Ca overload and ERK/NFκB/STAT3 in the neurotoxicity responses, and dopaminergic neuronal cells loss, was verified through inhibitors. Our findings showed that APM might prevent loss of DA neurons via inhibition of Ca -overload-mediated signaling pathway and provide insights regarding the potential use of APM in treating neurodegenerative diseases.