Alterations in striatal oxidative stress level produced by pharmacological manipulation of dopamine as shown by a novel synthetic marker molecule

Oxidative stress (OS) is thought to participate in neurodegenerative diseases such as Parkinson’s disease, but the contribution of dopamine metabolism and auto-oxidation to OS in Parkinson’s and other diseases is not clear. Oxidative stress in rat striatum was measured by microdialysis using a novel synthetic compound composed of tyrosine and linoleic acid (LT), and determination of the oxidation products LT-OOH and LT-epoxy by HPLC-MS. Since LT is non-diffusible through the microdialysis membrane, the oxidized products formed in microdialyzate reflect oxidation state in the extracellular compartment. The extracellular oxidative stress (OS ec) was compared with intracellular oxidative stress (OS ic) as measured by tissue levels of oxidized and reduced glutathione and 7-ketocholesterol. Reserpinization caused an increase in OS ic but a reduction in OS ec. Inhibition of both subtypes of monoamine oxidase (MAO-A and MAO-B) with tranylcypromine caused a reduction in both OS ic and OS ec whereas selective inhibition of MAO-A with clorgyline caused a reduction in Os ic but no change in OS ec. A high dose (10 mg/kg) of amphetamine caused an increase in OS ec whereas a smaller dose (4 mg/kg) caused a reduction in OS ec. Both doses of amphetamine reduced OS ic. The present findings are consistent with a role of monoamine oxidase as well as dopamine auto-oxidation in production of striatal OS. ► Striatal extra- and intra-cellular oxidative stress (OS ec, OS ic) was determined. ► Reserpinisation reduced microdialyzate dopamine, increased OS ic but reduced OS ec. ► Tranylcypromine reduced both OS ec and OS ic despite increasing microdialyzate dopamine, clorgyline decreased OS ic. ► Amphetamine reduced OS ic but increased OS ec in a 10 mg/kg dose. ► MAO and extracellular dopamine contribute to OS ec determined by novel technique.