Iron-Induced Oxidative Stress is Associated with Decreased Brain L-DOPA in Sickle Cell Disease

Abstract

Pain and cognitive decline are characteristic features of patients with sickle cell disease (SCD). Pain arises from the failure of blood to flow freely through blood vessels, thus creating regions of severe ischemia, the lack of blood perfusion. Pain is both a physiological and psychological event. Reflexive pain response arises in the periphery, but pain is perceived in the brain. Thus changes in the brain can modify the experience of pain. The cognitive impairments are also associated with ischemia, increased prevalence of stroke, and the degree of anemia in the patient – the direct result of hemolysis (bursting) of red blood cells in the blood vessels. This hemolysis releases toxic iron containing molecules which then freely circulate in the blood. Iron is potent oxidative stressor and generates the longest lasting radical, the potent OH radical (OH∙). In fact, OH∙ is perhaps the only radical capable of permanently modifying the amino acid tyrosine via shuffling of the side chain. Thus, proteins incorporating the modified amino acid may exhibit a change in function or altered interaction with binding partners. Importantly, tyrosine is the precursor to a host of neurotransmitters, including dopamine via the action of tyrosine hydroxylase (TH). Oxidized forms of tyrosine are no longer substrates for tyrosine hydroxylase, thus generation of dopamine is compromised. In this work, we discovered and quantified the presence of iron in the brains of mice with SCD and those without. We found significantly more iron deposited in the frontal lobe of the brain in the mice with SCD. Interrogation of L-DOPA, the precursor of dopamine, was also reduced. The amount of iron deposited was inversely proportional to the amount of L-DOPA detected in these SCD mice. Thus, these data suggest an overall decrease of dopamine in the brain. Emotion regulation, motor coordination, mood, cognition, learning and memory could all be affected. Furthermore, given the role of dopamine in addiction and reinforcement, our data suggest that patients with SCD are at a lower risk of addiction to pain medication – a primary consideration in the treatment of pain in this illness.