The ferric iron chelator 2,2′-dipyridyl attenuates basilar artery vasospasm and improves neurological function after subarachnoid hemorrhage in rabbits

Abstract

We investigated the efficacy of the ferrous iron (Fe(2+)) chelator 2,2'-dipyridyl (DP) to attenuate cerebral vasospasm after subarachnoid hemorrhage (SAH). Thirty-six New Zealand white rabbits were randomly assigned to four groups: untreated control, SAH, SAH + dimethyl sulfoxide (DMSO) vehicle, and SAH + DP. SAH was induced by injection of autologous blood into the cisterna magna and then DP or vehicle was infused into the cistern magna for 5 days (20 mg/kg/day or an equal volume of DMSO). Neurological deficit score (NDS) was used to assess neurological function and cerebral angiography to measure basilar artery (BA) diameter following SAH. TUNEL staining was used to detect BA endothelial cell apoptosis, and immunohistochemistry and Western blotting to assess changes in caspase-3 protein levels 5 days post-SAH. The SAH + DP group had a significantly larger mean BA diameter and lower mean NDS post-SAH compared to the SAH + DMSO and SAH groups (p < 0.05). TUNEL-positive cell numbers and caspase-3 levels were significantly reduced in BA endothelial cells of the SAH + DP group as compared to the SAH and SAH + DMSO groups (p < 0.05). The iron chelator DP reduced vasospasm and neurological sequelae in rabbits, likely by chelating the Fe(2+) in oxyhemoglobin and reducing oxidative stress-induced endothelial cell apoptosis.

Recombinant osteopontin attenuates experimental cerebral vasospasm following subarachnoid hemorrhage in rats through an anti-apoptotic mechanism

“…The endothelial cell loss and detachment can lead to smooth muscle cell proliferation and vasoconstriction (Yan et al, 2008). Smooth muscle cell apoptosis itself may further reduce its vasodilatory effect (Yu et al, 2014).…”

Programmed Cell Deaths and Potential Crosstalk With Blood–Brain Barrier Dysfunction After Hemorrhagic Stroke

“…Fibrin cleaved from fibrinogen has been reported to play a potential role in neuroinflammation and microglial activation (Lim-Hing and Rincon, 2017). Iron, degraded from hemoglobin, is one of most important factors among various components for hemorrhagic stroke-induced BBB hyperpermeability (Hua et al, 2007;Gomes et al, 2014), which is supported by ICH/SAH studies revealing alleviated brain edema with administration of the iron chelator, deferoxamine (Lee et al, 2010;Okauchi et al, 2010;Yu et al, 2014), or a heme oxygenase (HO) inhibitor (Wagner et al, 2000;Han et al, 2018). HO plays a critical role in the degradation of heme and the release of free ferrous iron (Kamat et al, 2019).…”

“…However, according to the mechanisms of BBB dysfunction and ferroptosis discussed above, the role of ferroptosis on BBB damage warrants more attention. We have mentioned above with sufficient evidence that iron, when degraded from hemoglobin, has a critically important role in BBB hyperpermeability after hemorrhagic stroke, and decreasing iron content through various methods significantly reversed the brain edema (Wagner et al, 2000;Hua et al, 2007;Gomes et al, 2014;Yu et al, 2014). The key point of this problem lies in the poor understanding regarding the exact mechanism of iron overload-induced BBB hyperpermeability.…”

Ethyl pyruvate attenuates delayed experimental cerebral vasospasm following subarachnoid haemorrhage in rats: possible role of JNK pathway

“…There were also drugs with anti-apoptotic effects, including proanthocyanidin, N-acetylcysteine, mexiletine, immunoglobulin, telmisartan, 2,2 0 -dipyridyl, recombinant human erythropoietin, human tissue kallikrein, alpha lipoic acid and so on. 6,[42][43][44][45][46][47][48][49][50] Signalling pathways participating in the anti-apoptotic effects include the Akt pathway, JAK2/STAT3 pathway, and others. Based on the above results, we could conclude that anti-apoptotic and anti-inammatory mechanisms play an important role in the attenuation of CVS aer SAH.…”