The Analgesic Effect of the Mitochondria-Targeted Antioxidant SkQ1 in Pancreatic Inflammation

Abstract

Background. Chronic pancreatitis is one of the main risk factors for pancreatic cancer. In acute and chronic pancreatitis, oxidative stress is thought to play a key role. In this respect, the recently described mitochondria-targeted antioxidant SkQ1 effectively scavenges reactive oxygen species at nanomolar concentrations. Therefore, we aimed to characterize the influence of SkQ1 on tissue injury and pain in acute and chronic pancreatitis. Methods. Both acute and chronic pancreatitis were induced in C57BL/6 mice by intraperitoneal cerulein injections and treatment with SkQ1 was carried out by peroral applications. Hyperalgesia was assessed by behavioral observation and measurement of abdominal mechanical sensitivity. Blood serum and pancreatic tissue were harvested for analysis of lipase and histology. Results. SkQ1 did not influence pain, serological, or histological parameters of tissue injury in acute pancreatitis. In chronic pancreatitis, a highly significant reduction of pain-related behavior (p < 0.0001) was evident, but histological grading revealed increased tissue injury in SkQ1-treated animals (p = 0.03). Conclusion. After SkQ1 treatment, tissue injury is not ameliorated in acute pancreatitis and increased in chronic pancreatitis. However, we show an analgesic effect in chronic pancreatitis. Further studies will need to elucidate the risks and benefits of mitochondria-targeted antioxidants as an analgesic.

Figure 1

Vertical activity in acute (a) and chronic (b) pancreatitis: displayed are the rearing numbers that were counted during the observation time. While there were no differences between the groups in acute pancreatitis (a), treated mice (SkQ1+) with chronic pancreatitis showed significantly more activity than the untreated (SkQ1−) and saline controls (sham), suggesting less pain in the treated mice (b). ^∗Statistically significant results (p < 0.05).

Figure 2

Evoked pain-related behavior measured by Von Frey's hairs in acute pancreatitis: both baseline and final measurements did not show any significant differences between the groups. ^∗Statistically significant results (p < 0.05).

Figure 3

Serum lipase levels in acute (a) and chronic pancreatitis (b): while mice with acute pancreatitis showed significantly higher levels of serum lipase than the saline controls, no differences were observed with or without treatment (a). In chronic pancreatitis, mice showed lower serum lipase levels than the saline controls, reflecting advanced disease. As in acute pancreatitis, no differences were observed in treated versus untreated mice (b). ^∗Statistically significant results (p < 0.05).

Figure 4

Histological severity of acute (a) and chronic pancreatitis (b) measured by Spormann's score: in acute pancreatitis, no differences were observed in treated versus untreated mice (a). In chronic pancreatitis mice treated with SkQ1 showed a slightly higher tissue damage when compared to the untreated mice (SkQ1−) (b). ^∗Statistically significant results (p < 0.05).

Figure 5

Subparameters of histological severity in acute pancreatitis as measured by Spormann's score: neither edema (a) nor neutrophil infiltration (b) nor parenchymal necrosis (c) nor fat necrosis (d) showed statistically significant differences between the SkQ1+ and SkQ1− groups. ^∗Statistically significant results (p < 0.05).

Figure 6

Subparameters of histological severity in chronic pancreatitis as measured by Spormann's score: again, none of the subparameters (edema (a), neutrophil infiltration (b), parenchymal necrosis (c), and fat necrosis (d)) showed statistically significant differences between the SkQ1+ and SkQ1− groups. ^∗Statistically significant results (p < 0.05).

Figure 7

Representative HE staining of pancreatic tissue samples of mice with acute (a–c) and chronic pancreatitis (d–f).

Figure 8

Evoked pain-related behavior measured by Von Frey's hairs in chronic pancreatitis: while baseline measurements did not differ significantly (a), mice with pancreatitis developed significantly increased pain scores after 4 weeks when compared to the saline controls (b). After 8 weeks of pancreatitis and 8 weeks of treatment, the SkQ1-treated mice show significantly less pain-related behavior than the untreated controls (c + d). ^∗Statistically significant results (p < 0.05).