Time-of-day dependence of neurological deficits induced by sodium nitroprusside in young mice

Sodium nitroprusside [Na2(Fe(CN)5NO] has been known to inorganic chemists since 1849 [1]. SNP is clinically used for lowering blood pressure in hypertension emergencies [2], for producing controlled hypotension during anaesthesia [3], and for treating acute myocardial infarction [4] and chronic heart failure [5]. However, toxic effects of this drug have been reported [6], originally ascribed to the nitroso moiety or to various decomposition products such as cyanide, thiocyanate, and nitrite. It was postulated that the iron atom of the nitroprusside complex reacts with free sulfhydryl groups (-SH) in erythrocytes and releases cyanide in vivo by nonenzymatic reaction [7]. Free cyanide can be converted to thiocyanate by the enzyme thiosulfate sulfurtransferase (rhodanese) that is present in various tissues [8-10] and particularly high in liver [11]. Moreover, the vasodilating effect of SNP is due to of its ability to release nitric oxide (NO) group to the vascular wall. Release of the NO is triggered by reduction of the (CN)5FeNO-2 anion. SNP has been suggested to cause cytotoxicity through either the release of cyanide and/or nitric oxide. The major target of NO is soluble guanylate cyclase [12], but many more molecules are modified by NO or reactive oxygen species derived from NO. Other studies reveal that the in vitro cytotoxicity of SNP may or may not be mediated by NO [13]. Indeed, some NO donor compounds (e.g. S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione) have been shown to protect neurons against oxidative injury and cell death caused by small molecular weight iron complexes such as ferrous citrate [14]. With this discrepancy, it is debatable whether the SNP's neurotoxicity is or is not due to the NO release.Biological rhythms are regular and periodic phenomena existing in all living organisms [15]. In fact, most physiological functions have a rhythm with a period of approximately 24 h [15]. Desired and nondesired (toxic) effects of several chemical and