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

Abstract

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. Ca2+ signaling plays a vital role in neuronal signaling and altered Ca2+ homeostasis has been implicated in many neuronal diseases including PD. Recently, we reported that apamin (APM), a selective antagonist of the small-conductivity Ca2+-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 Ca2+ 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 Ca2+ 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 Ca2+-overload-mediated signaling pathway and provide insights regarding the potential use of APM in treating neurodegenerative diseases.

Protective Effects of Apamin on Acetaminophen-Induced Hepatotoxicity in Mice

“…Consistent with our findings, APM protected macrophages from apoptosis evoked by oxidized low-density lipoprotein [46]. APM prevents loss of dopaminergic neurons through inhibiting the caspase-dependent mitochondrial apoptotic pathway [47]. Apoptosis can also be triggered by oxidative stress [5].…”

Progesterone exerts a neuroprotective action in a Parkinson’s disease human cell model through membrane progesterone receptor α (mPRα/PAQR7)

“…Activation of both signaling pathways has been recently reported to be beneficial in different PD models (53-58). Our results also support the neuroprotective role of the ERK signaling pathway, whereas in several other studies the ERK pathway was also linked to possible worsening of PD damage by increasing oxidative stress and inflammation (59,60). P4 treatment was not effective in activating these pathways in the striatum in an in vivo mouse model (20).…”

Protective effect of Tat fused HPCA protein on neuronal cell death caused by ischemic injury

“…Furthermore, the role of Tat-HPCA in reducing oxidative stress and DNA fragmentation was evaluated by inducing oxidative stress with H 2 O 2 and measuring ROS production and DNA fragmentation through DCF-DA and TUNEL staining, respectively. Tat-HPCA treatment significantly reduced ROS production and DNA fragmentation, consistent with observed inhibition of neuronal cell death [ [33] , [34] , [35] ]. These findings demonstrate that Tat-HPCA protein can reduce oxidative stress and prevent cell death caused by oxidative stress by inhibiting ROS levels within cells.…”