Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase

Abstract

The anti-malaria drug chloroquine is well known as autophagy inhibitor. Chloroquine has also been used as anti-inflammatory drugs to treat inflammatory diseases. We hypothesized that chloroquine could have a dual effect in liver ischemia/reperfusion (I/R) injury: chloroquine on the one hand could protect the liver against I/R injury via inhibition of inflammatory response, but on the other hand could aggravate liver I/R injury through inhibition of autophagy. Rats (n=6 per group) were pre-treated with chloroquine (60 mg/kg, i.p.) 1 h before warm ischemia, and they were continuously subjected to a daily chloroquine injection for up to 2 days. Rats were killed 0.5, 6, 24 and 48 h after reperfusion. At the early phase (i.e., 0–6 h after reperfusion), chloroquine treatment ameliorated liver I/R injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory cytokines and fewer histopathologic changes. In contrast, chloroquine worsened liver injury at the late phase of reperfusion (i.e., 24–48 h after reperfusion). The mechanism of protective action of chloroquine appeared to involve its ability to modulate mitogen-activated protein kinase activation, reduce high-mobility group box 1 release and inflammatory cytokines production, whereas chloroquine worsened liver injury via inhibition of autophagy and induction of hepatic apoptosis at the late phase. In conclusion, chloroquine prevents ischemic liver damage at the early phase, but aggravates liver damage at the late phase in liver I/R injury. This dual role of chloroquine should be considered when using chloroquine as an inhibitor of inflammation or autophagy in I/R injury.

Effectiveness of a single versus repeated administration of trimetazidine in the protection against warm ischemia/reperfusion injury of rat liver

“…Indeed, Western blot results revealed that TMZ pretreatment significantly reduced the cleaved caspase 9, the cleaved caspase 3 levels, and cytochrome C release when compared to the I/R group. Previous studies demonstrated that TMZ could limit apoptotic death in different experimental models (15,16). These apoptotic proteins are known to have a pivotal role in I/R pathophysiology (15).…”

“…Previous studies demonstrated that TMZ could limit apoptotic death in different experimental models (15,16). These apoptotic proteins are known to have a pivotal role in I/R pathophysiology (15). In fact, TMZ might bind to the inner mitochondrial membrane and inhibit the activation of the permeability transition pore and subsequent cytochrome C release (17).…”

High Mobility Group Box 1 (HMGB1) Phenotypic Role Revealed with Stress

“…HMGB1-mediated autophagy increases chemoresistance in cancer cells such as colon cancer, pancreatic cancer, osteosarcoma, leukemia, gastric cancer, retinoblastoma and ovarian cancer (22,28,(34)(35)(36)(37)(38)(39)(40)(41). In addition, HMGB1-mediated autophagy in vitro or in vivo prevents polyglutamine aggregates in Huntington disease (42), systemic inflammation during sepsis (9,43), N-methyl-D-aspartate-induced excitotoxicity (44) and hepatic I/R injury (45,46) and sustains T-cell survival in myositis (47). Microtubule-associated protein light chain 3 (LC3) is now widely used to monitor autophagy.…”

Beneficial effect and potential molecular mechanism of chloroquine on sperm motility and fertilizing ability in yellow catfish

“…Chloroquine is an anti-malaria drug and well known as an autophagy inhibitor (Fang et al, 2013). The effects of chloroquine on sperm are time and dose-dependent, as short-term or low-dose treatment resulted in an increase in sperm motility and fertility in mammalians (Norman and Gombe, 1975;Egbunike, 1982), whereas long-term or high-dose treatment resulted in a dose dependent decrease in sperm motility and fertility (Adeeko and Dada, 1998;Okanlawon et al, 1993).…”