Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa

Hirakawa, Tetsuya; Rokutan, Kazuhito; Nikawa, Takeshi; Kishi, Kazushi

doi:10.1053/gast.1996.v111.pm8690199

“…Thus it seems unlikely that systemic caspase inhibitors or JNK inhibitors will be developed into safe and viable cotherapies aimed at inhibiting aminoglycoside-induced ototoxicity. However, it is possible to safely induce Hsp70 in the whole organism, either by experimental manipulation (heat stress) (Dechesne et al 1992;Yoshida et al 1999;Sugahara et al 2003) or by administration of a therapeutic agent (Hirakawa et al 1996;Ooie et al 2001;Oda et al 2002;Mikuriya et al 2005;Sone et al 2005). In order to begin to develop Hsp70 as an otoprotective therapy against aminoglycoside-induced hearing loss, a safe method of Hsp70 induction is required.…”

Section: Discussionmentioning

confidence: 99%

Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death

Taleb

¹

,

Brandon

²

,

Lee

³

et al. 2009

Cell Stress and Chaperones

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Sensory hair cells of the inner ear are sensitive to death from aging, noise trauma, and ototoxic drugs. Ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to aminoglycosides results in hair cell death that is mediated by specific apoptotic proteins, including c-Jun N-terminal kinase (JNK) and caspases. Induction of heat shock proteins (Hsps) can inhibit JNK-and caspase-dependent apoptosis in a variety of systems. We have previously shown that heat shock results in robust upregulation of Hsps in the hair cells of the adult mouse utricle in vitro. In addition, heat shock results in significant inhibition of both cisplatin-and aminoglycoside-induced hair cell death. In this system, Hsp70 is the most strongly induced Hsp, which is upregulated over 250-fold at the level of mRNA 2 h after heat shock. Hsp70 overexpression inhibits aminoglycoside-induced hair cell death in vitro. In this study, we utilized Hsp70-overexpressing mice to determine whether Hsp70 is protective in vivo. Both Hsp70-overexpressing mice and their wildtype littermates were treated with systemic kanamycin (700 mg/kg body weight) twice daily for 14 days. While kanamycin treatment resulted in significant hearing loss and hair cell death in wild-type mice, Hsp70-overexpressing mice were significantly protected against aminoglycosideinduced hearing loss and hair cell death. These data indicate that Hsp70 is protective against aminoglycoside-induced ototoxicity in vivo.

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“…For example, guinea-pig gastric mucosal cells in which HSPs were induced by heat-shock treatment showed considerable resistance against injury induced by 7.5% ethanol [33]. In addition, oral administration of geranylgeranylacetone (GGA), an anti-ulcer drug, rapidly induced HSP60, heatshock cognate protein 70, HSC70, and HSP90 in rat gastric mucosal cells, and these induced HSPs contributed to the suppression of ulcer formation induced by water-immersion restraint stress [34]. Taken together, our findings suggest that induction of HSPs by ginseng treatment may positively contribute to gastric mucosal defense and participate in cytoprotection.…”

Section: Discussionmentioning

confidence: 99%

Ginseng, the Root of Panax ginseng C.A. Meyer, Protects Ethanol-Induced Gastric Damages in Rat through the Induction of Cytoprotective Heat-Shock Protein 27

Yeo

¹

,

Kim

²

,

Cho

³

et al. 2007

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Ginseng, the root of Panax ginseng C.A. Meyer, has been reported to exert preventive effects on gastropathy via anti-oxidative and anti-inflammatory actions. In this study, we investigated the protective effects of ginseng against ethanol-induced gastric damages in rat. To examine the preventive effect of ginseng, rats received two different ginseng extracts, A and B, 1 h prior to the administration of ethanol. Pretreatment of rats with ginseng extract A and B attenuated the ethanol-induced gastric lesions by 111 AE 48 and 142 AE 47 mm 2 compared to control group (164 AE 54 mm 2 ). Significant induction of cytoprotective heat-shock proteins HSP27 and HSP70 was found in the ginseng-administrated rats, suggesting that the restoration of the proteins might contribute to prevention of ethanol-induced gastric injuries. It is, therefore, suggested that ginseng has a protective effect against ethanol-induced gastric damages by induction of heat-shock proteins 70 and 27.

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“…GGA is an isoprenoid that is used clinically for the treatment of gastritis and gastric ulcers (Murakami et al 1981(Murakami et al , 1982a. GGA induces Hsp70 in a variety of tissues, including the gastric mucosa, heart, liver, brain, and cochlea (Hirakawa et al 1996;Ooie et al 2001;Oda et al 2002;Mikuriya et al 2005;Sone et al 2005). In designing a therapy aimed at the prevention of druginduced hearing loss and/or balance disorders, Hsp70 induction by GGA or other pharmaceutical inducers may represent a rational alternative to induction by local and whole-body heat stress.…”

Section: Figmentioning

confidence: 99%

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

Taleb

¹

,

Brandon

²

,

Lee

³

et al. 2008

JARO

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Sensory hair cells of the inner ear are sensitive to death from aging, noise trauma, and ototoxic drugs. Ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to aminoglycosides results in hair cell death that is mediated by specific apoptotic proteins, including cJun N-terminal kinase (JNK) and caspases. Induction of heat shock proteins (Hsps) is a highly conserved stress response that can inhibit JNK-and caspasedependent apoptosis in a variety of systems. We have previously shown that heat shock results in a robust upregulation of Hsps in the hair cells of the adult mouse utricle in vitro. In addition, heat shock results in significant inhibition of both cisplatin-and aminoglycoside-induced hair cell death. In our system, Hsp70 is the most strongly induced Hsp, which is upregulated over 250-fold at the level of mRNA 2 h after heat shock. Therefore, we have begun to examine the role of Hsp70 in mediating the protective effect of heat shock. To determine whether Hsp70 is necessary for the protective effect of heat shock against aminoglycoside-induced hair cell death, we utilized utricles from Hsp70.1/3 −/− mice. While heat shock inhibited gentamicin-induced hair cell death in wild-type utricles, utricles from Hsp70.1/3 −/− mice were not protected. In addition, we have examined the role of the major heat shock transcription factor, Hsf1, in mediating the protective effect of heat shock. Utricles from Hsf1 −/− mice and wild-type littermates were exposed to heat shock followed by gentamicin. The protective effect of heat shock on aminoglycoside-induced hair cell death was only observed in wildtype mice and not in Hsf1 −/− mice. To determine whether Hsp70 is sufficient to protect hair cells, we have utilized transgenic mice that constitutively overexpress Hsp70. Utricles from Hsp70-overexpressing mice and wild-type littermates were cultured in the presence of varying neomycin concentrations for 24 h. The Hsp70-overexpressing utricles were significantly protected against neomycin-induced hair cell death at moderate to high doses of neomycin. This protective effect was achieved without a heat shock. Taken together, these data indicate that Hsp70 and Hsf1 are each necessary for the protective effect of heat shock against aminoglycoside-induced death. Furthermore, overexpression of Hsp70 alone significantly inhibits aminoglycoside-induced hair cell death.

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Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa

Cited by 312 publications

References 3 publications

Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death

Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death

Ginseng, the Root of Panax ginseng C.A. Meyer, Protects Ethanol-Induced Gastric Damages in Rat through the Induction of Cytoprotective Heat-Shock Protein 27

Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock

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