Biliverdin administration ameliorates cerebral ischemia reperfusion injury in rats and is associated with proinflammatory factor downregulation

Abstract

Biliverdin (BV), one of the heme oxygenase-1 (HO-1) catalytic products, has been demonstrated to have protective effects in liver ischemia reperfusion injury (IRI). The present study aimed to explore the effects of BV on cerebral IRI, and to investigate the potential mechanisms thereof. Adult male SD rats, weighing 200–240 g, were randomly divided into sham (group S), cerebral ischemia reperfusion control (group C) and BV (group BV) groups. Rats in group C underwent transient middle cerebral artery occlusion (tMCAO) and received 2 ml normal saline; rats in group BV received BV (35 mg/kg) intraperitoneally 15 min prior to reperfusion and 4 h after reperfusion, then twice a day thereafter for 5 days. Group S served as the control. Neurological Severity Scores (NSS) were evaluated at days 1–5 following reperfusion. Staining with 2, 3, 5-triphenyltetrazolium chloride was performed to determine the cerebral infarction at 48 h post reperfusion. mRNA expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, inducible nitric oxide synthase (iNOS) and HO-1 in the ischemic cerebral cortex were detected via reverse transcription-quantitative polymerase chain reaction at 3, 6, 12 and 24 h after reperfusion. Western blotting was used to detect the protein expression levels at 3 h after reperfusion. Compared with group S, the NSS, cerebral infarct volume, and the mRNA and protein expression levels of TNF-α, IL-6, IL-1β, iNOS and HO-1 of Group C were significantly increased (P<0.05). However, BV administration significantly improved and reduced these expression levels (P<0.01). The present study indicates that BV is able to ameliorate cerebral IRI in rats and that the mechanism may be associated with the downregulation of proinflammatory factors.

Heme Oxygenase-1: Clinical Relevance in Ischemic Stroke

“…In a further study, intravenously applied PEGylated COHb in a transient focal cerebral ischemia model in rats resulted in reduced infarct volumes and better neurologic deficit scores [49]. Besides CO, biliverdin treatment has also been shown to ameliorate oxidative injury on neurons and decrease infarct size in rat MCAO models [50, 51].…”

Bioinspired biliverdin/silk fibroin hydrogel for antiglioma photothermal therapy and wound healing

“…Our previous research indicated that bilirubin possesses a power anti-inflammatory property, which showed significant cytoprotective effects against oxidative and inflammatory damage in multiple cell lines 40 , 63 - 65 . Biliverdin, as a precursor substance of bilirubin, has also been demonstrated as an important cytoprotective and anti-inflammatory molecule 34 , 35 . Then, we further used immunostaining to evaluate the level of pro-inflammatory cytokines, including IL-1 and TNF-α, which play an essential role in wound repair (Figure 8 A-B).…”

“…For instance, Xing et al reported that biliverdin nanoagent could effectively elevate tumor temperature under mild NIR irradiation, and consequently induce efficient photothermal tumor ablation 4 . In addition, biliverdin also showed a cytoprotective effect by the antioxidative and anti-inflammatory properties 32 - 34 , which would be beneficial for wound healing. Based on these facts, biliverdin holds the potential to be utilized as not only a biodegradable photothermal agent for PTT but also a bioactive drug for the following wound healing, rather than PTT waste.…”

The Role of Bilirubin and the Other “Yellow Players” in Neurodegenerative Diseases

“…The YPs: Aβ, amyloid β; BV, biliverdin; BVR, biliverdin reductase; CO, carbon monoxide; CREB, cAMP-responsive element-binding; HMOX, heme oxygenase; NFT, neurofibrillary tangles; Nrf2, nuclear factor erythroid 2–related factor 2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; ROS, reactive oxygen species; RNS, reactive nitrogen species; UCB, unconjugated bilirubin; UPR, unfolded protein response; UPS, ubiquitin-proteasome system; Tp53, human p53 tumor protein. (For details see [ 201 , 202 , 203 , 204 , 205 , 206 , 207 ]).…”