Neuroprotective effect of aldehyde trapping agent, hydralazine, in a Parkinson’s disease mouse model

Abstract

Elevated levels of biogenic aldehydes were reported in brains of Parkinson’s disease (PD) patients. Aldehydes are primarily detoxified by aldehyde dehydrogenases (ALDH). In PD patients, reduced ALDH1 expression and impaired complex I activity that limit the availability of the NAD⁺ co-factor may compromise aldehyde detoxification and play a role in PD pathogenesis. Previously, our lab showed that mice null for two Aldh isoforms known to be expressed in midbrain dopamine neurons, Aldh1a1 and Aldh2, exhibited age-related deficits in motor performance. The deficits were rescued by L-DOPA administration. Significant aldehyde accumulation in nigrostriatal pathway of Aldh1a1^-/-×Aldh2^-/- mice was observed, including accumulation of the lipid peroxidation product, 4-HNE, and DOPAL, the aldehyde product of dopamine metabolism. Some studies indicated that aldehyde trapping agents may be cytoprotective in conditions of increased “aldehyde load”. Therefore, we hypothesized that aldehyde trapping agents may be beneficial in PD. To test the hypothesis, we first used a PC12 cell culture model, and found that hydralazine prevented 4-HNE-induced cell death. Hydralazine (250 mg/L) was then delivered chronically in drinking water to Aldh1a1^-/-×Aldh2^-/- mice and improved motor performance. Reduced striatal DOPAL and midbrain 4-HNE level in Aldh1a1-/-×Aldh2-/- mice after long-term (9 month) hydralazine treatment supported our hypothesis that aldehyde trapping agents scavenge accumulating aldehydes and may provide a novel therapeutic approach to PD. As a currently FDA-approved antihypertensive treatment, hydralazine would be readily approved as a neuroprotective agent in PD.

Keywords: Biogenic aldehydes, neurotoxicity, aldehyde dehydrogenase (ALDH1A1, ALDH2), motor deficits, neurodegeneration