Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

Abstract

Manganese (Mn) plays a critical role in individual growth and development, yet excessive exposure can result in neurotoxicity, especially cognitive impairment. Neuronal apoptosis is considered as one of the mechanisms of Mn‐induced neurotoxicity. Recent evidence suggests that cAMP‐PKA‐CREB signaling regulates apoptosis and is associated with cognitive function. However, whether this pathway participates in Mn‐induced neurotoxicity is not completely understood. To fill this gap, in vitro cultures of PC12 cells were exposed to 0, 400, 500, and 600 μmol/L Mn for 24 hours, respectively. Another group of cells were pretreated with 10.0 μmol/L rolipram (a phosphodiesterase‐4 [PDE4] inhibitor) for 1 hour followed by 500 μmol/L Mn exposure for 24 hours. Flow cytometry, immunofluorescence staining, enzyme‐linked immunosorbent assay, and Western blot analysis were used to detect the apoptosis rate, protein levels of PDE4, cAMP signaling, and apoptosis‐associated proteins, respectively. We found that Mn exposure significantly inhibited cAMP signaling and protein expression of Bcl‐2, while increasing apoptosis rate, protein levels of PDE4, Bax, activated caspase‐3, and activated caspase‐8 in PC12 cells. Pretreatment of rolipram ameliorated Mn‐induced deficits in cAMP signaling and apoptosis. These findings demonstrate that cAMP‐PKA‐CREB signaling pathway‐induced apoptosis is involved in Mn‐induced neurotoxicity.

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

“…Alteration of cAMP/PKA/MAPK/CREB pathway was also shown to play a significant role in Mn-induced apoptosis in PC12 cell line (0–600 μM Mn for 24 h) through down-regulation of BDNF expression and Bcl-2 levels [ 137 ]. This pathway may be also modulated by alterations of intracellular Ca 2+ levels and subsequent increase in MAPK and CREB phosphorylation in response to an increase in Ca 2+ levels induced by Mn exposure in PC12 cells (0–500 μM for 0–24 h) [ 138 ].…”

“…The impact of Mn on p53 signaling may be also mediated by Mn-dependent modulation of ataxia telangiectasia mutated (ATM) kinase [ 71 ]. In turn, Mn may decrease anti-apoptotic effects of Bcl2 and BDNF through inhibiting CREB phosphorylation and subsequent down-regulation of Bcl2 and BDNF expression [ 137 ]. It has been also demonstrated that mitochondrial pathway of apoptosis may be also aggravated by Mn-induced alteration of mitofusin 2 (Mfn2) expression, a protein involved in mitochondrial fusion and functioning [ 134 ].…”

rTMS alleviates AD-induced cognitive impairment by inhibitng apoptosis in SAMP8 mouse

“…rTMS is a magnetic stimulation method that has attracted the most attention in clinical medicine and neuroscience. Cotelli and Manenti et al [ 21 ] used high-frequency rTMS to treat the dorsolateral prefrontal cortex in patients with AD and found that patients' naming ability was improved. In addition, high frequency rTMS has been found to have facilitate neurons that stimulate cortical nerve excitation [ 22 ].…”

Potential contribution of ryanodine receptor 2 upregulation to cGMP/PKG signaling‐induced cone degeneration in cyclic nucleotide‐gated channel deficiency

“…Thus, the upregulation of CREB in CNG channel deficiency is likely a consequence of both elevated cGMP/PKG signaling and enhanced RyR2 function/ER calcium dysregulation. CREB signaling has been shown to have pro‐survival effects and anti‐survival effects . Alterations of CREB activity have been implicated in human neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and in animal models of retinal degeneration .…”