Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

Crockett, Elahé T; Galligan, James J.; Uhal, Bruce D.; Harkema, Jack; Roth, Robert A.; Pandya, Kinnari

doi:10.1186/1472-6890-6-3

Cited by 42 publications

(39 citation statements)

References 52 publications

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“…Fujiki et al (9) demonstrated the neuroprotective effects of donepezil, a nicotinic acetylcholine receptor activator, after cerebral infarction in rats, an effect that was prevented by coinjection with mecamylamine, a nAChR antagonist, indicating that protection was mediated by nAChR activation (9). Crockett et al (7) showed the protection of early phase hepatic I/R injury by cholinergic agonists. Finally, our laboratory (38) and Sadis et al (29) have shown that nAChR stimulation with cholinergic agonists protects the rat and mouse, respectively, from renal I/R injury.…”

Section: Discussionmentioning

confidence: 98%

Nicotinic acetylcholine receptor expression and regulation in the rat kidney after ischemia-reperfusion injury

Yeboah

Xue²,

Javdan³

et al. 2008

American Journal of Physiology-Renal Physiology

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The cholinergic anti-inflammatory pathway is a mechanism whereby local inflammation is modulated by the brain via the vagus nerve and nicotinic acetylcholine receptors (nAChRs). The nAChR family are ligand-gated ion channels that consist of many different subtypes formed by the specific assembly of five polypeptide subunits including alpha1-10, beta1-4, gamma, delta, and epsilon. The alpha7 receptor (alpha7nAChR) mediates the anti-inflammatory effects of cholinergic stimulation. We recently demonstrated that cholinergic agonists attenuate renal ischemia-reperfusion (I/R) injury in rats. We also showed that tubular epithelial cells express functional nAChRs in vitro. The current studies report the expression, localization, and regulation of the alpha7nAChR in the rat kidney after I/R injury. We also examined, in this model, potential interactions between cholinergic stimulation and the STAT3 pathway, a key signaling cascade that has been linked to alpha7nAChR activation. RT-PCR and immunohistochemistry showed constitutive expression of many nAChR subunits. Immunohistochemistry localized basal alpha7nAChR expression to the endothelium of cortical peritubular capillaries, and its distribution was upregulated after I/R injury. Western blotting also showed an increase in alpha7nAChR subunit protein after renal I/R injury. Interestingly, pretreatment with nicotine, which improves the outcome after renal I/R injury, reduced the alpha7nAChR protein after I/R injury. Finally, we found that I/R injury stimulated the STAT3 pathway, whereas pretreatment with nicotine downregulated its activation. These results suggest that the alpha7nAChR plays an important role in the pathophysiology of renal I/R injury.

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Section: Discussionmentioning

confidence: 98%

Nicotinic acetylcholine receptor expression and regulation in the rat kidney after ischemia-reperfusion injury

Yeboah

Xue²,

Javdan³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…29 Cholinergic agonists (including nicotine and GTS-21) produce effects similar to the electrical stimulation of the vagus nerve. [30][31][32][33][34] In this study, we investigated the effects of pharmacologic cholinergic stimulation in both normal and vagotomized rats after a standardized renal I/R injury. 16,35,36 …”

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confidence: 99%

Cholinergic agonists attenuate renal ischemia–reperfusion injury in rats

Yeboah

Xue

Duan

et al. 2008

Kidney International

130

116

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Inflammation plays a significant role in the pathophysiology of renal ischemia-reperfusion injury. Local inflammation is modulated by the brain via the vagus nerve and nicotinic acetylcholine receptors such that electrical or pharmacologic stimulation of this cholinergic anti-inflammatory pathway results in suppression of proinflammatory cytokine production. We examined the effects of cholinergic stimulation using agonists, nicotine or GTS-21, given before or after bilateral renal ischemia-reperfusion injury in rats. Pretreatment of rats with either agonist significantly attenuated renal dysfunction and tubular necrosis induced by renal ischemia. Similarly, tumor necrosis factor-alpha protein expression and leukocyte infiltration of the kidney were markedly reduced following treatment with cholinergic agonists. We found functional nicotinic acetylcholine receptors were present on rat proximal tubule epithelial cells. Cholinergic stimulation significantly decreased tubular necrosis in vagotomized rats after injury, implying an intact vagus nerve is not required for this renoprotective effect.

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“…Moreover, dimethylphenylpiperazinium (DMPP), a synthetic nicotinic acetylcholine receptor (nAChR) agonist, reduces airway inflammation as well as the increase in airway resistance in a mouse model of asthma (2). Finally, both nAChR agonists nicotine and DMPP have protective effects on early phase hepatic ischemia-reperfusion injury (6,27).…”

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confidence: 99%

Dimethyphenylpiperazinium, a nicotinic receptor agonist, downregulates inflammation in monocytes/macrophages through PI3K and PLC chronic activation

Blanchet¹,

Israël-Assayag²,

Daleau³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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. Dimethyphenylpiperazinium, a nicotinic receptor agonist, downregulates inflammation in monocytes/macrophages through PI3K and PLC chronic activation. Am J Physiol Lung Cell Mol Physiol 291: L757-L763, 2006. First published June 16, 2006 doi:10.1152/ajplung.00409.2005.-Activation of nicotinic acetylcholine receptors (nAChRs) on inflammatory cells induces anti-inflammatory effects. The intracellular mechanisms that regulate this effect are still poorly understood. In neuronal cells, nAChRs are associated with phosphatidylinositol 3-kinase (PI3K). This enzyme, which can activate phospholipase C (PLC), is also present in monocytes. The aim of this study was to assess the role of these proteins in the signaling pathways involved in the anti-inflammatory effect of dimethylphenylpiperazinium (DMPP), a synthetic nAChR agonist, on monocytes and macrophages. The results indicate that PI3K is associated with ␣3, -4, and -5 nAChR subunits in monocytes. The PI3K inhibitors wortmannin and LY294002 abrogated the inhibitory effect of DMPP on LPS-induced TNF release by monocytes. Treatment with DMPP for 24 and 48 h provoked a mild PLC phosphorylation, which was blocked by the nAChR antagonist mecamylamine and reversed by PI3K inhibitors. Treatment of monocytes and alveolar macrophages with DMPP reduced the inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium mobilization induced by platelet-activating factor (PAF), an effect that was reversed by mecamylamine in alveolar macrophages. DMPP did not have any effect on PAF receptor expression. DMPP also inhibited the thapsigargin-provoked calcium release, indicating that the endoplasmic reticulum calcium stores might be depleted by treatment with the nAChR agonist. Taken together, these results suggest that PI3K and PLC activation is involved in the anti-inflammatory effect of DMPP. PLC limited, but constant activation could induce, the depletion of intracellular calcium stores, leading to the anti-inflammatory effect of DMPP.phosphatidylinositol 3-kinase; intracellular calcium; nicotinic acetylcholine receptors; phospholipase C NICOTINIC RECEPTOR AGONISTS show anti-inflammatory properties in vivo. Studies have demonstrated that administration of nicotine has anti-inflammatory effects in a mouse model of hypersensitivity pneumonitis, reduces the incidence of type 1 (autoimmune) diabetes and ulcerative colitis (1,21,24), and improves survival in experimental sepsis (27). Moreover, dimethylphenylpiperazinium (DMPP), a synthetic nicotinic acetylcholine receptor (nAChR) agonist, reduces airway inflammation as well as the increase in airway resistance in a mouse model of asthma (2). Finally, both nAChR agonists nicotine and DMPP have protective effects on early phase hepatic ischemia-reperfusion injury (6, 27).These effects are further supported by in vitro studies showing that nicotine reduces the production of IL-1 by macrophages (22), TNF expression and IFN-␥ and IL-10 mRNA production by alveolar macrophages (AM) (1). Nicotine also has inhibitory effects on the express...

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Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

Cited by 42 publications

References 52 publications

Nicotinic acetylcholine receptor expression and regulation in the rat kidney after ischemia-reperfusion injury

Nicotinic acetylcholine receptor expression and regulation in the rat kidney after ischemia-reperfusion injury

Cholinergic agonists attenuate renal ischemia–reperfusion injury in rats

Dimethyphenylpiperazinium, a nicotinic receptor agonist, downregulates inflammation in monocytes/macrophages through PI3K and PLC chronic activation

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