clazosentan and Nerve-Degeneration

Endothelin-1 (ET-1) is a 21 amino acid peptide that has been closely linked to cerebral vasospasm and more recently to oxidative stress after traumatic brain injury. In this study, we have examined the effects of the endothelin receptor subtype A antagonist, Ro 61-1790, on acute cortical neuronal injury and delayed neuronal death in the cerebellum after mild traumatic brain injury. Rats were administered Ro 61-1790 or vehicle for 24 h after injury and euthanized at 1 day, 3 days, or 7 days. Heat shock protein70 (HSP70), a marker of neuronal stress/injury, was immunolocalized in the cortex. Induction of heme oxygenase-1 (HO-1) and enhanced immunoexpression of the complement C3bi receptor, both of which are indicators of cerebellar glial reactivity, and Purkinje cell loss were evaluated in the cerebellum. There was maximal induction of HSP70 in cortical neurons at 24 h postinjury in all animals. Drug treated animals showed significantly fewer HSP70 labeled cortical neurons at this time point. There were fewer reactive glia in the cerebellum of drug treated animals as compared to vehicle controls at 3 days postinjury. However, at 7 days postinjury glial reactivity and Purkinje cell loss were similar in both groups. These findings demonstrate that Ro 61-1790, when administered for the first 24 h postinjury, limits acute neuronal injury in the cortex, transiently influences glial reactivity in the cerebellum, and does not attenuate delayed Purkinje cell death. The latter finding may reflect the duration of infusion of the drug.

Topics: Animals; Antibodies, Monoclonal; Brain Injuries; Cell Count; Cell Death; Cerebral Cortex; Dioxanes; Endothelin Receptor Antagonists; Endothelin-1; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; HSP70 Heat-Shock Proteins; Macrophage-1 Antigen; Male; Microglia; Nerve Degeneration; Purkinje Cells; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Sulfonamides; Tetrazoles