Cyclosporin-A Inhibits Constitutive Nitric Oxide Synthase Activity and Neuronal and Endothelial Nitric Oxide Synthase Expressions after Spinal Cord Injury in Rats

Abstract

Nitric oxide (NO) plays a role in the pathophysiology of spinal cord injury (SCI). NO is produced by three types of nitric oxide synthase (NOS) enzymes: The constitutive Ca2+/calmodulin-dependent neuronal NOS (nNOS) and endothelial NOS (eNOS) isoforms, and the inducible calcium-independent isoform (iNOS). During the early stages of SCI, nNOS and eNOS produce significant amounts of NO, therefore, the regulation of their activity and expression may participate in the damage after SCI. In the present study, we used Cyclosporin-A (CsA) to further substantiate the role of Ca-dependent NOS in neural responses associated to SCI. Female Wistar rats were subjected to SCI by contusion, and killed 4 h after lesion. Results showed an increase in the activity of constitutive NOS (cNOS) after lesion, inhibited by CsA (2.5 mg/kg i.p.). Western blot assays showed an increased expression of both nNOS and eNOS after trauma, also antagonized by CsA administration.

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin

“…heart block; sodium current; sudden death; inducible nitric oxide synthase; transgenic overexpression of calcineurin TRANSGENIC OVEREXPRESSION of constitutively active calcineurin (CN/Tg) in cardiac myocytes results in profound concentric hypertrophy followed by ventricular dilatation, interstitial fibrosis, heart failure, and eventually sudden cardiac death (13,26,32,33,40). The sudden deaths relate to ion channelopathies, which are downstream consequences of abnormalities of calcium homeostasis (17) and an inflammatory process (6, 10, 27, 36).Previous studies indicate that inducible nitric oxide (NO) synthase (iNOS) is a downstream target of calcineurin (12,19,36,44,45). The regulation of the iNOS gene promoter by calcineurin has been reported (36).…”

“…Previous studies indicate that inducible nitric oxide (NO) synthase (iNOS) is a downstream target of calcineurin (12,19,36,44,45). The regulation of the iNOS gene promoter by calcineurin has been reported (36).…”

Lack of neuroprotection with pharmacological pretreatment in a paradigm for anticipated spinal cord lesions

“…[9][10][11] For example, it is possible that cyclosporine-A could worsen post-traumatic ischemia by blocking the early spontaneous production of the potent vasodilator nitric oxide from an endothelial source. 20 In spite of the excitement generated by recent reports showing that a variety of drugs behave as neuroprotectant agents by diminishing secondary damage and improving functional outcome in animal models of traumatic SCI, their usefulness to prevent extensive tissue damage when given prior to or simultaneously with SCI is questionable. The future of pharmacological manipulation to reduce risk of iatrogenic cord lesions during elective spine surgery in humans lies in the better understanding of the cellular and molecular changes associated with SCI.…”

Expression of CAPON after Spinal Cord Injury in Rats

“…High concentrated NO is toxic for cells; therefore, NO concentration is strictly and finely regulated (Miscusi2002). NOS I which is also known as neuronal NOS is located within neurons (Bredt et al 1991) that is upregulated (Lin 2002) and reactivated after spinal cord injury (Diaz-Ruiz et al -Ruiz et al 2005). Long-term treatment with L-NNA, a competitive inhibitor of neuronal NOS with equal potency to inhibit endothelial NOS, attenuated SCI-induced NOS upregulation, BSCB breakdown, edema formation, and cell injury, and an made an improvement in motor function (Sharma et al 2005).…”