Carbon monoxide and outcome of stroke--a dream CORM true?.

S troke, a focal and prolonged neurologic deficit of vascular origin and sudden onset, is the second most common cause of death worldwide and the major cause of disability in adults. Despite progress in understanding its pathophysiology and in particular the secondary growth of lesions, translation of this knowledge— beyond thrombolysis for ischemic stroke—into neuroprotective drugs has largely failed (1). Essentially, a stroke can be classified as ischemic or hemorrhagic and there is evolving evidence that in particular in hemorrhagic stroke, accumulation of hemoglobin and subsequent formation of free heme and its degradation products are of utmost significance for secondary injury (2–4). In addition, heme degradation-dependent repair mechanisms influence the overall outcome. Accumulation of heme induces heme oxygenase, a stress protein catalyzing the oxidative breakdown of heme, yielding equimolar amounts of biliverdin, free iron ion, and carbon monoxide (CO [5]). More recently, metabolites of higher order such as “bilirubin oxidation end products” were also identified to be present in liquor after (subarachnoidal) hemorrhage and have been shown to promote severe vasospasm (6, 7). Although heme oxygenase activity had classically been considered as a sink to cope with excessive amounts of heme proteins accumulating on hemorrhage, heme degradation products receive increasing attention because of their profound and diverse biological implications, e.g., for vascular tone, inflammation, and programmed cell death (5, 8–10). The seminal discovery that the inorganic gas nitric oxide may act as a cellular messenger prompted a flurry of studies addressing the potential role of CO as an alternative signaling molecule mediating the well-documented protective effects of the heme oxygenase pathway. Initial positive results in a wide range of rodent models of diverse pathologies anticipated a great potential as a therapeutic gas (8, 9) but also underscored intrinsic limitations resulting from its feared toxicity. Pioneered by Roberto Motterlini, prodrugs acting as CO-releasing molecules (CORMs) evolved as a feasible alternative to inhalation of CO (11). However, their chemistry (most of them are transition metal carbonyl complexes) has proven to be delicate regarding the mode and kinetics of CO release and off-target effects. For instance, CORM-2 was observed to diminish the activity of voltage-activated K channels such as Kv2.1 responsible for modulation of neuronal spike frequency and membrane repolarization in pancreatic -cells and cardiomyocytes in a CO-independent manner (12). Thus, the challenge remains to equip this promising novel class of molecules with drug-like properties but also to define the potential scope of application. In this issue of Critical Care Medicine, Yabluchanskiy and colleagues offer additional insights into the therapeutic potential of CORM-3, a watersoluble CO-releasing molecule with documented anti-inflammatory properties, in a model of intracerebral hemorrhage resulting from collagenase injection into rat brains (13). The model is characterized by marked brain damage along with a profound local and systemic immune response. Interestingly, CORM-3 displayed Yin–Yang effects on outcome depending on timing of the intervention. Neuroprotection was observed when CORM-3 was given as a pretreatment or administered in the postacute phase on day 3 after the insult. However, given in the acute phase of injury, i.e., at 3 hrs postcollagenase injection, a substantial aggravation of the lesion ensued. Notably, these effects were not restricted to inflammatory response and size of the lesion, but were translated into functional outcome after stroke. In contrast to the critical timing of its application, no graded effect for the studied doses of CORM-3 (4 and 8 mg/kg) was observed. Although the authors assessed and discussed the impact of CORM-3 on the local and systemic inflammatory response to stroke, additional effects, e.g., on nutritive blood flow in the penumbra, are not ruled out. Similarly, although the authors attribute the observed effects to release of CO, this assumption is extrapolated from historic studies in which a decomposed CORM as a true vehicle rather than a saline injection was used as a control and potential side effects of these transition metal complexes remain a matter of concern (12). The present study nicely documents that development of novel and effective therapeutic strategies for stroke will require detailed investigation regarding their temporal profile and risk-tobenefit ratios. It also highlights that the heme oxygenase/CO pathway holds great promise as a potential therapeutic target for this devastating condition. Nevertheless, uncertainty remains regarding this new class of prodrugs as well as a potential species specificity of CO effects on the inflammatory response because a previous study using inhaled CO in humans failed to confirm the substantial blunting effect of CO on the cytokine response to endotoxin observed in rodents (14). Michael Bauer, MD Department of Anesthesiology and Critical Care Therapy and Center for Sepsis Control and Care Jena University Hospital Jena, Germany Otto W. Witte, MD Hans Berger Department of Neurology Jena University Hospital; and Center for Sepsis Control and Care Jena, Germany *See also p. 544.