Bipyridine, an Iron Chelator, Does Not Lessen Intracerebral Iron-Induced Damage or Improve Outcome After Intracerebral Hemorrhagic Stroke in Rats

Abstract

Iron chelators, such as the intracellular ferrous chelator 2,2'-bipyridine, are a potential means of ameliorating iron-induced injury after intracerebral hemorrhage (ICH). We evaluated bipyridine against the collagenase and whole-blood ICH models and a simplified model of iron-induced damage involving a striatal injection of FeCl2 in adult rats. First, we assessed whether bipyridine (25 mg/kg beginning 12 h post-ICH and every 12 h for 3 days) would attenuate non-heme iron levels in the brain and lessen behavioral impairments (neurological deficit scale, corner turn test, and horizontal ladder) 7 days after collagenase-induced ICH. Second, we evaluated bipyridine (20 mg/kg beginning 6 h post-ICH and then every 24 h) on edema 3 days after collagenase infusion. Body temperature was continually recorded in a subset of these rats beginning 24 h prior to ICH until euthanasia. Third, bipyridine was administered (as per experiment 2) after whole-blood infusion to examine tissue loss, neuronal degeneration, and behavioral impairments at 7 days post-stroke, as well as body temperature for 3 days post-stroke. Finally, we evaluated whether bipyridine (25 mg/kg given 2 h prior to surgery and then every 12 h for 3 days) lessens tissue loss, neuronal death, and behavioral deficits after striatal FeCl2 injection. Bipyridine caused a significant hypothermic effect (maximum drop to 34.6 °C for 2-5 h after each injection) in both ICH models; however, in all experiments bipyridine-treated rats were indistinguishable from vehicle controls on all other measures (e.g., tissue loss, behavioral impairments, etc.). These results do not support the use of bipyridine against ICH.

Intracerebral Hemorrhage, Oxidative Stress, and Antioxidant Therapy

“…Therefore, those studies suggest that there are critical differences between these ICH models. Additionally, bipyridine, an iron-chelator, does not lessen intracerebral iron-induced damage or improve outcome after ICH in rats [ 170 ]. Perhaps, the current clinical work with iron-chelator will help identify the more clinically predictive model for future neuroprotection studies [ 171 ].…”

Haematoma scavenging in intracerebral haemorrhage: from mechanisms to the clinic

“…Clioquinol, a ferrous iron chelator, improved the neurological outcome and attenuated brain oedema and ROS production besides reducing iron levels . Another ferrous chelator, 2,2′‐bipyridine, is a potential means of ameliorating iron‐induced injury after ICH ; unfortunately, another results failed to support the use of bipyridine against ICH , and the function of bipyridine on ICH is uncertain so far.…”

Brain iron overload following intracranial haemorrhage

“…Furthermore, this study found that DP post-treatment ameliorated neurobehavioral deficits and brain oedema formation while not affecting mortality rates. However, more recently, Caliaperumal et al 217 performed a series of experiments assessing DP's effect following ICH and found that it failed to chelate non-haem iron levels following ICH, failed to reduce oedema in the ipsilateral cortex and failed to lessen tissue loss or decrease neurodegeneration. These somewhat contradictory findings could be partly explained by the difference in experimental setup (the first was more focused on a pretreatment vs post-treatment administration while the second was simply assessing post-treatment in a variety of circumstances), but they still warrant further investigation and clarification.…”