Geranylgeranylacetone protects the human gastric mucosa from diclofenac-induced injury via induction of heat shock protein 70.
OBJECTIVE
Geranylgeranylacetone (GGA) enhances gastric mucosal protection against nonsteroidal anti-inflammatory drugs by upregulating mucosal heat shock proteins (HSP), but the effects of GGA on the human gastric mucosa have not been well examined. This study was conducted to determine whether a clinical dose of GGA protects the human gastric mucosa from diclofenac (DIC)-induced gastric mucosal injury.


METHODS
The study group comprised 40 healthy volunteers: 20 subjects were randomly assigned to take either placebo (lactose 1.5 g/day) or GGA (150 mg/day) for 2 weeks (study 1), and 20 subjects were assigned to take DIC (75 mg/day) plus placebo (lactose 1.5 g/day) or DIC (75 mg/day) plus GGA (150 mg/day) for 2 weeks (study 2). In both studies, gastroscopic biopsy specimens were obtained before and after treatment. Mucosal HSP70 expression and DNA damage were analyzed by measuring the levels of HSP70 and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG), respectively.


RESULTS
In study 1, GGA increased the mucosal HSP70 expression without increasing the 8-OHdG production. In study 2, DIC treatment increased the 8-OHdG production, whereas the combination of GGA and DIC enhanced the HSP70 expression and attenuated the increase in 8-OHdG induced by DIC.


CONCLUSIONS
The clinical dose of GGA enhanced the gastric mucosal HSP70 expression and inhibited the DIC-induced gastric mucosal damage in humans.
Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. ynk-aki@md.tsukuba.ac.jp
Akinori
A
Yanaka
Songhua
S
Zhang
Daisuke
D
Sato
Masafumi
M
Tauchi
Hideo
H
Suzuki
Takeshi
T
Shibahara
Hirofumi
H
Matsui
Akira
A
Nakahara
Ichinosuke
I
Hyodo
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D017209:Apoptosis; D001706:Biopsy; D004249:DNA Damage; D004008:Diclofenac / Q000009:adverse effects*; D004224:Diterpenes / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects*; D005773:Gastroscopy; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000517:prevention & control*; D016896:Treatment Outcome; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D004008:Diclofenac; C031049:geranylgeranylacetone