Ulinastatin alleviates early brain injury after traumatic brain injury by inhibiting oxidative stress and apoptosis

Abstract

Purpose: Traumatic brain injury (TBI) remains a major public health problem and cause of death. Ulinastatin (UTI), a serine protease inhibitor, has been reported to have an anti-inflammatory effect and play a role in immunoregulation and organ protection by reducing reactive oxygen species (ROS) production, oxidative stress and inflammation. However, the neuroprotective of UTI in TBI has not been confirmed. Therefore, this study aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in TBI-induced EBI in a C57BL/6 mouse model. Methods: The neurological score and brain water content were evaluated. Enzyme-linked immunosorbent assay was used to detect neuroinflammatory cytokine levels, ROS and malondialdehyde detection to evaluate oxidative stress levels, and TUNEL staining and western blotting to examine neuronal damages and their related mechanisms. Results: Treatment with UTI markedly increased the neurological score; alleviated brain oedema; decreased the inflammatory cytokine tumour necrosis factor a, interleukin-1β (IL-1β), IL-6 and nuclear factor kappa B (NF-kB) levels; inhibited oxidative stress; decreased caspase-3 and Bax protein expressions; and increased the Bcl-2 levels, indicating that UTI-mediated inhibition of neuroinflammation, oxidative stress and apoptosis ameliorated neuronal death after TBI. The neuroprotective capacity of UTI is partly dependent on the TLR4/NF-kB/p65 signalling pathway. Conclusions: Therefore, this study reveals that UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation, oxidative stress and apoptosis.

Ulinastatin Alleviates Repetitive Ketamine Exposure-Evoked Cognitive Impairment in Adolescent Mice

“…In addition, it can treat acute inflammatory disorders, sepsis, toxic shock, and hemorrhagic shock [ 6 ]. It is reported that UTI can alleviate the cerebral ischemia-reperfusion injury by regulating inflammation and oxidative stress [ 35 ]. Another study also reported that UTI could attenuate the brain edema after intracranial hemorrhage (ICH) of male Sprague-Dawley rats and that the preliminary molecular mechanism may be related to the decrease of the expression levels of proinflammatory cytokines including IL-1 β and TNF- α [ 36 ].…”

Traumatic brain injury: Mechanisms, manifestations, and visual sequelae

“…TBI disturbs the balance between pro-apoptotic BAX, which forms pores in the outer mitochondrial membrane, and anti-apoptotic B cell lymphoma 2 (BCL-2), a pro-survival protein that binds to BAX (Wennersten et al, 2003;Stoica and Faden, 2010;Deng et al, 2020). Numerous natural and artificial caspase inhibitors have been identified and developed with the intention for therapeutic use in reducing neuronal cell death post TBI (Dhani et al, 2021;Feng et al, 2022;Unnisa et al, 2022).…”

Effects of ulinastatin therapy in emergency severe multiple trauma: A single-center randomized controlled trial

“…The primary pharmacological activities of this compound were anti-inflammatory, immunoregulatory, and organ protection. [4][5][6] Drugs act as anti-inflammatory and antiapoptotic agents in the treatment of acute inflammatory disorders, such as sepsis and ischemia-reperfusion injury. [7] He et al reported that cardiological surgery patients may benefit from UTIs by inhibiting postoperative inflammatory processes and providing pulmonary protection through a meta-analysis including 15 randomized controlled trials.…”

“…[7] He et al reported that cardiological surgery patients may benefit from UTIs by inhibiting postoperative inflammatory processes and providing pulmonary protection through a meta-analysis including 15 randomized controlled trials. [8] Our recent animal studies also found that UTI can alleviate traumatic brain injury by inhibiting oxidative stress and apoptosis, [5] improve early brain injury after intracerebral hemorrhage by inhibiting oxidative stress and neuroinflammation via the ROS/MAPK/Nrf2 signaling pathway, [9] and relieve cerebral ischemia–reperfusion injury. [10] UTIs have been widely used in China for the treatment of patients with inflammatory disorders, postoperative organ protection, and shock.…”