Yabluchanskiy, Y.; (2012) The effect of CORM-3 on the inflammatory nature of haemorrhagic stroke. Doctoral thesis , UCL (University College London).

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Abstract

Objective─ Intracerebral hemorrhage (ICH) is accompanied by a pronounced inflammatory response that mediates brain damage but is also essential for the tissue reparative process. Here we assessed the effect of CORM-3, a water-soluble carbon monoxide-releasing molecule possessing anti-inflammatory properties, on inflammation and brain injury after ICH. Design─ In vivo, in vitro and ex vivo laboratory study. Setting─ Research laboratory. Subjects─ Male Sprague-Dawley rats, 250-350g. Interventions and Measurements─ A model of collagenase injection (2 μl) in brain was established to induce ICH. CORM-3 (4 or 8 mg/kg) was administered i.v. at different times as follows: a) 5 min prior to collagenase, b) 3 hours after collagenase and c) 3 days after collagenase challenge. Saline was used as a negative control. Brain damage, brain water content and behavioural assessment were evaluated. The inflammatory response was determined at set intervals after ICH by counting peripheral neutrophils and lymphocytes, neutrophils and activated microglia/macrophages in the ICH area, brain water content and measuring plasma TNF-α levels. BV2 microglia and DI-TNC1 astrocytes were exposed to triton (1%) or CORM-3 (10-100 μM) and cytotoxicity (LDH assay) measured at 24 hours. Main Results─ Challenge with collagenase to induce ICH caused marked brain damage and modified the levels of inflammatory markers. Pre-treatment with CORM- 3 significantly prevented injury, modulated inflammation and reduced plasma TNF-α. CORM-3 given 3 hours after collagenase significantly increased brain injury and TNF-α production. In contrast, CORM-3 given 3 days after collagenase afforded partial protection, modulated inflammation and decreased TNF-α starting from the day of application. No dose-dependent effects were observed. Conclusions─ CORM-3 promotes neuroprotection or neurotoxicity after ICH depending on the time of administration. Beneficial effects are achieved when CORM-3 is given either before or 3 days after ICH, namely, as a prophylactic agent or during the post-acute inflammatory phase.

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