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Neurodegeneration in the locus coeruleus (LC) has been documented in several central nervous system (CNS) neurodegenerative diseases. In the present study, iron-induced oxidative injury in the LC was investigated in chloral-hydrate anesthetized rats. Three days after bilateral infusion of iron in the LC, both vertical and horizontal locomotor activities were decreased. Seven days after unilateral infusion of iron, lipid peroxidation was elevated in the infused LC, and the norepinephrine content was depleted in the ipsilateral hippocampus of the brain. Furthermore, the immunohistochemical study demonstrated a reduction in tyrosine hydroxylase-positive neurons in the infused LC. The involvement of programmed cell death (apoptosis) in iron-induced oxidative injury in the LC was investigated. Forty-eight hours after iron infusion, cytosolic cytochrome c was elevated in the infused LC. Moreover, terminal deoxytransferase-mediated dUTP-nick end labeling (TUNEL)-positive cells, an indicative of apoptosis, were detected in the infused LC. In an attempt to prevent oxidative injury in the LC, melatonin was systemically administered. Intraperitoneal injection of melatonin attenuated iron-induced behavioral changes in locomotor activity as well as iron-induced increases in cytosolic cytochrome c and TUNEL-positive cells. Moreover, melatonin diminished iron-induced oxidative injury. At the same time, the level of glial derived neurotrophic factor (GDNF) was elevated in the LC of melatonin-treated rats. Our data suggests that oxidative stress because of iron results in apoptosis in the infused LC and causes degeneration of the coeruleohippocampal noradrenergic system in the rat brain. Furthermore, melatonin, among other mechanisms, may exert its neuroprotection via up-regulation of GDNF levels in CNS.