Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons

Abstract

Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+.

Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

“…On the other hand, reduced sickness behavior might be due to defective HOCl production and the absence of MPO-derived chlorinated lipids. Whether or not these lipids could induce comparable behavioral deficits as reported for chlorinated dopamine [53] is currently unknown. However, intrastriatal administration of chlorodopamine resulted in loss of dopaminergic neurons and decreased locomotor activity in mice in a manner similar as observed for the Parkinsonian toxin MPP + [53].…”

“…Whether or not these lipids could induce comparable behavioral deficits as reported for chlorinated dopamine [53] is currently unknown. However, intrastriatal administration of chlorodopamine resulted in loss of dopaminergic neurons and decreased locomotor activity in mice in a manner similar as observed for the Parkinsonian toxin MPP + [53]. Selective serotonin reuptake inhibitors ameliorated LPS-induced sickness behavior in wt mice [25], a potential result of HOCl scavenging by serotonin which is a high-affinity substrate for MPO-mediated oxidation [25].…”

The Role of Myeloperoxidase in Biomolecule Modification, Chronic Inflammation, and Disease

“…These cells also release proinflammatory cytokines, including TNFa and IL-1b on HOCl exposure, thereby exacerbating neuroinflammation (137). In addition, HOCl may contribute indirectly to the development of PD by chlorinating the amine and catechol groups of dopamine to form chlorodopamines, which can selectively kill dopaminergic neurons by inhibiting mitochondrial respiration (112).…”

Epalrestat improves motor symptoms by reducing oxidative stress and inflammation in the reserpine induced mouse model of Parkinson’s disease

“…The neutrophil is one of the critical immune cells involved in many inflammatory cascades linked to neurodegenerative diseases, including PD . It is capable of producing reactive oxygen species such as hypochlorous acid (HOCl), which converts dopamine into chlorodopamine, a toxicant to dopaminergic neuron . In our study, we noticed a significant increase in the infiltration of neutrophil cells in the brain of PD model mice, which was reversed by Epalrestat treatment.…”