p42/44 MAPK is an essential effector for purine nucleoside-mediated neuroprotection of hypoxic PC12 cells and primary cerebellar granule neurons

Tomaselli, Bettina; Nedden, Stephanie zur; Podhraski, Valerie; Baier‐Bitterlich, Gabriele

doi:10.1016/j.mcn.2008.05.004

Cited by 18 publications

(51 citation statements)

References 32 publications

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“…It is likely that inosine in food is transported to the brain, activates adenosine receptors and functions as a neuromodulator. Previous studies using cell culture systems indicated that inosine increases cell proliferation and the growth of dendrites in PC12 cells and primary cultured cells from the cerebellum and the spinal cord132627. We also confirmed that the addition of inosine to primary cultured neocortical neurons significantly improved cell viability and neurite outgrowth in a dose-dependent manner (Figure 1a–e).…”

Section: Discussionsupporting

confidence: 86%

“…We observed that the addition of inosine immediately increased the phosphorylation of MAPK (Figure 1h, i). Several findings have demonstrated that the linkage of adenosine receptors to the p42/44 MAPK pathway apparently plays a pivotal role in inosine-mediated cellular protection1326. Inhibitory effects of adenosine receptor antagonists on phosphorylation of MAPK (Figure 1j) further supported previous findings.…”

Section: Discussionsupporting

confidence: 84%

“…Moreover, inosine increases the rates of glycogenolysis and gluconeogenesis via A 3 receptor on hepatocytes12. The binding of inosine to the receptors activates intracellular signaling responses including the mitogen-activated protein kinase (MAPK) pathway, which is essential for inosine-mediated neuroprotection13.…”

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confidence: 99%

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Oral administration of inosine produces antidepressant-like effects in mice

Muto

Lee

et al. 2014

Sci Rep

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Inosine, a breakdown product of adenosine, has recently been shown to exert immunomodulatory and neuroprotective effects. We show here that the oral administration of inosine has antidepressant-like effects in two animal models. Inosine significantly enhanced neurite outgrowth and viability of primary cultured neocortical neurons, which was suppressed by adenosine A1 and A2A receptor agonists. Oral administration of inosine to mice transiently increased its concentration in the brain and enhanced neuronal proliferation in the dentate gyrus, accompanied by phosphorylation of mitogen-activated protein kinase and increase in transcript level of brain-derived neurotrophic factor. In stress models, oral inosine prevented an increase in immobility time in forced swim test after chronically unexpected stress and mitigated a reduction in sucrose preference after chronic social defeat stress. These results indicate that oral administration of inosine has the potential to prevent depressive disorder via adenosine receptors.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 84%

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Oral administration of inosine produces antidepressant-like effects in mice

Muto

Lee

et al. 2014

Sci Rep

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“…The accumulation of adenosine during these pathologies protects the brain from injury [1] . In the extracellular space, adenosine modifies cell functioning by acting on adenosine receptors (A 1 R, A 2a R, A 2b R, A 3 R) [2,3] . The activation of adenosine A 1 receptor (A 1 R) is known to mediate neuronal and myocardial protection [1] .…”

Section: Introductionmentioning

confidence: 99%

Adenosine A1 receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro

et al. 2009

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Aim: To understand the mechanism of the transactivation of the epidermal growth factor receptor (EGFR) mediated by the adenosine A 1 receptor (A 1 R). Methods: Primary cultured rat cortical neurons subjected to oxygen-glucose deprivation (OGD) and HEK293/A 1 R cells were treated with the A 1 R-specific agonist N 6 -cyclopentyladenosine (CPA). Phospho-EGFR, Akt, and ERK1/2 were observed by Western blot. An interaction between EGFR and A 1 R was detected using immunoprecipitation and immunocytochemistry. Results: The A 1 R agonist CPA causes protein kinase B (Akt) activation and protects primary cortical neurons from oxygen-glucose deprivation (OGD) insult. A 1 R and EGFR co-localize in the membranes of neurons and form an immunocomplex. A 1 R stimulation induces significant EGFR phosphorylation via a PI3K and Src kinase signaling pathway; this stimulation provides a neuroprotective effect in cortical neurons. CPA leads to sustained phosphorylation of extracellularly regulated kinases 1 and 2 (ERK1/2) in cortical neurons, but only to transient phosphorylation in HEK 293/A 1 R cells. The response to the A 1 R agonist is mediated primarily through EGFR transactivation that is dependent on pertussis toxin (PTX)-sensitive G i protein and metalloproteases in HEK 293/A 1 R. Conclusion: A 1 R-mediated EGFR transactivation confers a neuroprotective effect in primary cortical neurons. PI3 kinase and Src kinase play pivotal roles in this response.

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“…Numerous authors, (see reviews [72-74]) have proposed adenosine and its receptors as targets for therapeutic approaches in stroke and related disorders. We have previously studied neuronal signaling in hypoxia and observed a protective capacity of the purine nucleosides adenosine, guanosine and inosine in both PC12 cells [22, 71, 75, 76] and in primary cerebellar granule neurons [71, 77-79]; see also our latest review: [70], which was inhibited by adenosine receptor (ADORA) antagonists, as reviewed [70]. …”

Section: Role Of Pkn1 In Hypoxic Neuronsmentioning

confidence: 99%

Protein Kinase C-Related Kinase (PKN/PRK). Potential Key-Role for PKN1 in Protection of Hypoxic Neurons

Thauerer¹,

Nedden²,

Baier‐Bitterlich

2014

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Serine/threonine protein kinase C-related kinase (PKN/PRK) is a family of three isoenzymes (PKN1, PKN2, PKN3), which are widely distributed in eukaryotic organisms and share the same overall domain structure. The Nterminal region encompasses a conserved repeated domain, termed HR1a-c as well as a HR2/C2 domain. The serine/threonine kinase domain is found in the C-terminal region of the protein and shows high sequence homology to other members of the PKC superfamily. In neurons, PKN1 is the most abundant isoform and has been implicated in a variety of functions including cytoskeletal organization and neuronal differentiation and its deregulation may contribute to neuropathological processes such as amyotrophic lateral sclerosis and Alzheimer’s disease. We have recently identified a candidate role of PKN1 in the regulation of neuroprotective processes during hypoxic stress. Our key findings were that: 1) the activity of PKN1 was significantly increased by hypoxia (1% O2) and neurotrophins (nerve growth factor and purine nucleosides); 2) Neuronal cells, deficient of PKN1 showed a decrease of cell viability and neurite formation along with a disturbance of the F-actinassociated cytoskeleton; 3) Purine nucleoside-mediated neuroprotection during hypoxia was severely hampered in PKN1 deficient neuronal cells, altogether suggesting a potentially critical role of PKN1 in neuroprotective processes. This review gives an up-to-date overview of the PKN family with a special focus on the neuroprotective role of PKN1 in hypoxia.

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p42/44 MAPK is an essential effector for purine nucleoside-mediated neuroprotection of hypoxic PC12 cells and primary cerebellar granule neurons

Cited by 18 publications

References 32 publications

Oral administration of inosine produces antidepressant-like effects in mice

Oral administration of inosine produces antidepressant-like effects in mice

Adenosine A1 receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro

Protein Kinase C-Related Kinase (PKN/PRK). Potential Key-Role for PKN1 in Protection of Hypoxic Neurons

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