Membrane permeabilization by non-steroidal anti-inflammatory drugs

Tomisato, Wataru; Tanaka, Ken Ichiro; Katsu, Takashi; Kakuta, Hiroki; Sasaki, Kenji; Tsutsumi, Shinji; Hoshino, Tatsuya; Aburaya, Mayuko; Li, Daiwei; Tsuchiya, Tomofusa; Suzuki, Keitarou; Yokomizo, Kazumi; Mizushima, Tohru

doi:10.1016/j.bbrc.2004.08.205

Cited by 88 publications

(116 citation statements)

References 41 publications

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“…[30][31][32] However, it has been reported that NSAIDs induce necrosis and apoptosis in cultured gastric mucosal cells and in the gastric mucosa in a manner independent of COX inhibition, [33][34][35][36][37] and that the total inhibition of PG production in the stomach causes very little gastric damage in rats. 38) Therefore it is now believed that the inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side effects of NSAIDs, 39) and it is assumed that other mechanisms in addition to PG deficiency are involved in the gastric ulcerogenicity of NSAIDs.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Mizushima et al clearly showed that the primary targets of NSAIDs in the induction of necrosis and apoptosis are the cytoplasmic membranes. 33,35) In addition, Kato et al reported that excessive NO production via iNOS is related to an increased ulcerogenic response to NSAIDs including loxoprofen and indomethacin. 11,40) We show that the expression of iNOS mRNA and NO production in the gastric mucosa of normal and AA rats are increased by the administration of loxoprofen, and that these increases are significantly higher than those that occur in normal rats administered loxoprofen.…”

Section: Discussionmentioning

confidence: 99%

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Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Nagai

Takeda

Itanami

et al. 2012

Biological & Pharmaceutical Bulletin

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Non-steroidal anti-inflammatory drugs (NSAIDs) comprise one of the most frequently used classes of medicines in the world; however, NSAIDs have significant side effects, such as gastroenteropathy, and rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAID-induced gastric lesions as compared to patients with other diseases. In Asian countries, loxoprofen has been used clinically for many years as a standard NSAID. We demonstrate the preventive effect of the co-administration of water containing magnesium ion (magnesium water, 1-200 µg/kg) on the ulcerogenic response to loxoprofen in adjuvant-induced arthritis (AA) rats. Oral administration of loxoprofen (100 mg/kg) caused hemorrhagic lesions in the gastric mucosa of AA rats 14 d after adjuvant injection, and, following loxoprofen administration, the lesion score of AA rats was significantly higher than that of normal rats. The expression of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in the gastric mucosa of AA rats were also increased by the administration of loxoprofen, and the increase in lesions and NO were prevented by the administration of aminoguanidine, an iNOS inhibitor. The co-administration of magnesium water decreased the ulcerogenic response to loxoprofen in AA rats. In addition, the co-administration of magnesium water attenuated the increase in iNOS mRNA expression and NO production in AA rats receiving loxoprofen. These results suggest that the oral co-administration of magnesium water to AA rats has a potent preventive effect on the ulcerogenic response to loxoprofen, probably by inhibiting the rise in iNOS and NO levels in the gastric mucosa.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Nagai

Takeda

Itanami

et al. 2012

Biological & Pharmaceutical Bulletin

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“…Therefore, membrane permeabilization induced by palytoxin occurred after the increase of intracellular Ca 2ϩ concentration (65). Several other molecules such as epidermal growth factor (EGF) (55,86) or nonsteroidal anti-inflammatory drugs (NSAIDs) are also known to increase intracellular Ca 2ϩ as well as membrane permeabilization (77), leading to apoptosis (35). NSAIDs were able to raise intracellular Ca 2ϩ and permeabilize the cell membrane to calcein (77).…”

Section: Discussionmentioning

confidence: 99%

“…Although the P2X 7 itself is considered as a nonselective large pore, some groups have had difficulty in detecting it in cells expressing the heterologous P2X 7 receptor, suggesting that the pore-forming molecule might be a distinct entity (11,14,77). Similarly, some cell types present a native P2 receptor that shares most of the P2X 7 receptor pharmacological features but fail to permeabilize (43,62).…”

mentioning

confidence: 99%

Pharmacological properties of a pore induced by raising intracellular Ca²⁺

Faria¹,

Reis²,

Casabulho³

et al. 2009

American Journal of Physiology-Cell Physiology

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-Recent studies on the P2X 7 receptor in 2BH4 cells and peritoneal macrophages have demonstrated that the raise in intracellular Ca 2ϩ concentration induces a pore opening similar to P2X 7 receptor pore. Herein, we have investigated whether the pore activated by the elevation of intracellular Ca 2ϩ concentration is associated to P2X 7 receptor. Using patch clamp in cell attached, whole cell configuration, and dye uptake, we measured the pore opening in cell types that express the P2X 7 receptor (2BH4 cells and peritoneal macrophages) and in cells that do not express this receptor . In 2BH4 cells, the stimulation with ionomycin (5-10 M) increased intracellular free Ca 2ϩ concentration and induced pore formation with conductance of 421 Ϯ 14 pS, half-time (t 1 ⁄2) for ethidium bromide uptake of 118 Ϯ 17 s, and t 1 ⁄2 for Lucifer yellow of 122 Ϯ 11 s. P2X 7 receptor antagonists did not block these effects. Stimulation of HEK-293 and IT45-RI cells resulted in pore formation with properties similar to those found for 2BH4 cells. Connexin hemichannel inhibitors (carbenoxolone and heptanol) also did not inhibit the pore-induced effect following the increase in intracellular Ca 2ϩ concentration. However, 5-(N,N-hexamethylene)-amiloride, a P2X 7 receptor pore blocker, inhibited the induced pore. Moreover, intracellular signaling modulators, such as calmodulin, phospholipase C, mitogen-activated protein kinase, and cytoskeleton components were important for the pore formation. Additionally, we confirmed the results obtained for electrophysiology by using the flow cytometry, and we discarded the possibility of cellular death induced by raising intracellular Ca 2ϩ at the doses used by using lactate dehydrogenase release assay. In conclusion, increased concentration in intracellular Ca ϩ2 induces a novel membrane pore pharmacologically different from the P2X 7 associated pore and hemigap-junction pore.P2X 7 receptor; pore formation; second messenger P2X RECEPTORS are members of a family of P2 receptors with seven subtypes (P2X 1 -P2X 7 ) that induce an increase in intracellular Ca 2ϩ concentration when activated. Among the P2X receptors, P2X 7 subtype is the most divergent component of this family in terms of pharmacological properties, molecular structure, and function (54). This receptor forms a nonselective cation channel upon low ATP concentration, whereas at high ATP concentration, this receptor induces a pore formation that allows the flux of molecules of up to 900 Da and may lead to cell death. Although P2X 7 receptor is associated with expression of both functional channels and large pores, the structure of the large pore-forming subunits and whether the channel and the large pore are the same structure are still not known.From a physiological point of view, P2X 7 is mainly expressed in the immune system found in all cells of this system studied so far. The activation of P2X 7 receptor has several effects in the immune system such as release of mature interleukin-␤ and other pro-inflammatory cytokines (interleukin-18,...

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“…Walter et al [32] showed that CLX is localized at the interfacial region of 1-palmitoyl-2-oleoylsn-glycero-3-phosphocholine (POPC) -cholesterol membranes using small angle X-ray diffraction. In other studies, using fluorescence anisotropy technique, CLX has been shown to decrease membrane fluidity in a mouse neuroblastoma cell line N2a [10] and decrease in membrane fluidity in egg phosphatidylcholine model membranes [27]. In our previous study, using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC), we have found that CLX exerts opposing effects on membrane order in a concentration dependent manner and it decreases the fluidity of the membrane at all concentrations.…”

Section: Introductionmentioning

confidence: 86%

Effects of the non-steroidal anti-inflammatory drug celecoxib on cholesterol containing distearoyl phosphatidylcholine membranes

2011

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Abstract.The effects of different concentrations of celecoxib on the acyl chain order, dynamics and the hydration status of the head group and interfacial region of model membranes containing DSPC and cholesterol were investigated in detail using Fourier transform infrared spectroscopy. Our results reveal that regardless of the presence of cholesterol, celecoxib is able to alter the physical properties of membranes. It exerts opposing effects on membrane order at high and low concentrations and decreases membrane fluidity in the presence of cholesterol. An evidence of phase separation has also been observed. The decrease in membrane fluidity supports the hypothesis that celecoxib may induce changes in the activity of membrane bound enzymes through modulating physical properties of the membrane thereby contributing to its anticancer activity. A possible change in the location of celecoxib in DSPC membranes when cholesterol is present has also been proposed. These results clarify, to a certain extent, the molecular interactions of celecoxib with membrane systems and may additionally contribute to a better understanding of COX-2 independent mechanisms of celecoxib action.

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Membrane permeabilization by non-steroidal anti-inflammatory drugs

Cited by 88 publications

References 41 publications

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Pharmacological properties of a pore induced by raising intracellular Ca²⁺

Effects of the non-steroidal anti-inflammatory drug celecoxib on cholesterol containing distearoyl phosphatidylcholine membranes

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Membrane permeabilization by non-steroidal anti-inflammatory drugs

Cited by 88 publications

References 41 publications

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Pharmacological properties of a pore induced by raising intracellular Ca2+

Effects of the non-steroidal anti-inflammatory drug celecoxib on cholesterol containing distearoyl phosphatidylcholine membranes

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Pharmacological properties of a pore induced by raising intracellular Ca²⁺