ZJM‐289, a novel nitric oxide donor, alleviates the cerebral ischaemic–reperfusion injury in rats

Abstract

1. Current studies indicate that nitric oxide (NO) plays a dual role as both a protective and pathogenic factor in focal cerebral ischaemia depending on the level, location, source and environment. The present study hypothesized that the NO donor ZJM-289 could inhibit cerebral ischaemia-reperfusion (I/R) injury and investigated the mechanism of the beneficial events. 2. Adult male rats were randomly divided into four groups: (i) sham operated; (ii) I/R (ischaemia for 90 min and reperfusion for 24 h) treated with vehicle; (iii) I/R treated with 0.1 mmol/kg body weight ZJM-289; and (iv) I/R treated with 0.2 mmol/kg body weight ZJM-289. We evaluated the changes in brain infarction, brain-water content, neurological deficits and histopathology. Western blot analysis was used to study the expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) in the brain after I/R. The levels of NO and cyclic guanosine monophosphate (cGMP) were also determined. 3. ZJM-289 reduced infarct volume and brain-water content in ischemic brains and promoted functional recovery. Western blotting showed significant inhibition of nNOS in ZJM-289 treated rats compared with untreated rats. However, eNOS expression in the ischemic brain was enhanced in the ZJM-289 groups. The cGMP and NO levels increased in the ZJM-289 groups after I/R. The study showed that ZJM-289 could alleviate cerebral injury after I/R through inhibition of nNOS and stimulation of the NO/soluble guanylate cyclase/cGMP pathway. Therefore, a suitable NO donor might be an effective candidate for the treatment of acute stroke by neuroprotection.

RETRACTED: NOSH-NBP, a Novel Nitric Oxide and Hydrogen Sulfide- Releasing Hybrid, Attenuates Ischemic Stroke-Induced Neuroinflammatory Injury by Modulating Microglia Polarization

“…Absence of CSE or CAT/3-MST aggravates ischemic brain injury (Zheng et al, 2015). Many preclinical studies revealed that exogenous NO donors (e.g., SNP, sydnonomines, NONOates, and NO-NBP) and H 2 S donors (e.g., NaSH, ADTOH, and H 2 S-NBP) are beneficial in ischemic stroke (Willmot et al, 2005; Zhuang et al, 2010; Wang X. et al, 2014; Wang Y. et al, 2014). In this study, we firstly performed both in vivo and in vitro experiments to explore whether NOSH-NBP, in comparison with the single-donors, i.e., NO-NBP and H 2 S-NBP, have therapeutic effects on ischemic stroke.…”

“…Previous reports demonstrated that NO or H 2 S-donor derivatives of NBP, NO-NBP (zjm-289), and H 2 S-NBP (8e) exhibit anti-thrombosis, anti-platelet aggregation and neuroprotective properties (Zhuang et al, 2010; Wang X. et al, 2014). NBP was approved by the State Food and Drug Administration (SFDA) of China as a new anti-ischemic drug for stroke in 2002.…”

Effect of Treatment Delay, Stroke Type, and Thrombolysis on the Effect of Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome after Acute Stroke: A Systematic Review and Meta-Analysis of Individual Patient from Randomised Trials

“…Fifthly, NO donors can reduce thrombosis, as in microvessels. And last, in addition to increases in blood levels of NO, other potentially beneficial biochemical changes may occur, as seen experimentally and including increases in endothelial nitric oxide synthase (NOS) and cyclic guanosine monophosphate and reductions in neuronal NOS, nitrotyrosine, and adhesion molecules [32–35]. …”

Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

“…In short, it appears that NO activation of the GC-PKG pathway may be deleterious, particularly when it leads to induction of iNOS, and some or most of these deleterious effects may be due to NO itself or its peroxide byproducts driven by iNOS. In support of this hypothesis, the NO donor, ZJM-289, was found to alleviate cerebral ischemic-reperfusion injury through inhibition of neuronal NOS and stimulation of the soluble GC-cGMP pathway [100]. The combination therapy of NO donors and PDE5 inhibitors appears to facilitate neurogenesis, oligodendrogenesis, and angiogenesis after stroke [101].…”