Neuroprotection of ulinastatin on transient cerebral ischemia via antioxidative mechanisms

Ulinastatin [also called urinary trypsin inhibitor (UTI)] has beneficial effects on cerebral ischemic injury evoked by cardiac arrest (CA). However, the underlying mechanisms are unknown. The purpose of this report was to determine the involvement of antioxidative signal pathway of the hippocampus in effects of UTI in the process of neurological functions after transient cerebral ischemia. CA was induced by asphyxia followed by cardiopulmonary resuscitation in rats. Western blot analysis and ELISA were used to examine expression of Nrf2-antioxidant response element (ARE) and superoxide dismutases (SOD), and the levels of products of oxidative stress. In addition, the modified neurological severity score (mNSS) and spatial working memory performance were employed to assess neurological deficiencies in CA rats. Our results show that CA impaired Nrf2-ARE and SOD in the hippocampus CA1 region and amplified products of oxidative stress, namely 8-isoprostaglandin F2α (8-iso PGF2α) and 8-hydroxy-2’-deoxyguanosine (8-OHdG). Systemic administration of UTI largely restored Nrf2-ARE and SOD, and this also attenuated amplification of 8-iso PGF2α and 8-OHdG induced by cerebral ischemia and thereby alleviated neurological deficits with increasing survival of CA rats. Our data suggest that UTI improves Nrf2-ARE signals and inhibits products of oxidative stress in the hippocampus, which is linked to improvement of neurological deficiencies in transient cerebral ischemia. UTI plays a beneficial role in modulating cerebral ischemic injury via antioxidative mechanisms.