The Effects of Melatonin on Brain Injury in Acute Organophosphate Toxicity

Abstract

Organophosphates (OP) are potent toxic substances used in agriculture as insecticide and pesticides, and in warfare. Over 200,000 cases of accidental toxic exposure to OPs are reported annually (Jyaratnam, 1999). OPs inhibit acetylcholine esterase (ACE), an enzyme which breaks down acetylcholine in cholinergic synapses in the peripheral nervous system (PNS) and central nervous system (CNS). Thus OP intoxication is characterized by findings related to hyperstimulation of cholinergic synapses in the PNS and CNS. Hyper-stimulation of cholinergic synapses in CNS may result in rapid blackout attacks and inhibition of respiratory center in medulla oblongata (Marrs, 2007). In animal studies of OPs used as chemical warfare agents, status epilepticus occurs rapidly due to severe brain damage, which is demonstrated on both electrophysiologic and histopathologic studies (McDonough et al, 1998). Pharmacological treatment of OP intoxication includes anticholinergic agents like atropine sulfate to block postsynaptic cholinergic receptors, oximes to reactivate inhibited enzymes, and antiepileptics to control seizure activity (Marrs, 2007). In previous studies, oxidative stress caused by OPs was demonstrated in humans and rats. Lipid peroxidation in rat brain and human erythrocytes caused by OPs was confirmed as well (Abdollahi et al, 2004). Melatonin removes the potent hydroxyl radical secreted from pineal gland. Blood can easily pass the brain barrier and provides oxidative protection in the brain. At the same time, it also removes other reactive molecules such as hydrogen peroxide, singlet oxygen, peroxynitrite, and nitric oxide. Melatonin decreases oxidative stress by increasing the production of antioxidant enzymes like melatonin superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), the most important protective substance in the brain (Hsu et al, 2002). The aim of this study was to investigate the effects of melatonin on lipid peroxidation in erythrocytes and brain tissue in the setting of acute OP intoxication in rats and compare its effects with those of routine treatment (pralidoxime and atropine).