Hydralazine modifies Aβ fibril formation and prevents modification by lipids in vitro.
Lipid oxidative damage and amyloid β (Aβ) misfolding contribute to Alzheimer's disease (AD) pathology. Thus, the prevention of oxidative damage and Aβ misfolding are attractive targets for drug discovery. At present, no AD drugs approved by the Food and Drug Administration (FDA) prevent or halt disease progression. Hydralazine, a smooth muscle relaxant, is a potential drug candidate for AD drug therapy as it reduces Aβ production and prevents oxidative damage via its antioxidant hydrazide group. We evaluated the efficacy of hydralazine, and related hydrazides, in reducing (1) Aβ misfolding and (2) Aβ protein modification by the reactive lipid 4-hydroxy-2-nonenal (HNE) using transmission electron microscopy and Western blotting. While hydralazine did not prevent Aβ aggregation as measured using the protease protection assay, there were more oligomeric species observed by electron microscopy. Hydralazine prevented lipid modification of Aβ, and Aβ was used as a proxy for classes of proteins which either misfold or are modified by HNE. All of the other hydrazides prevented lipid modification of Aβ and also did not prevent Aβ aggregation. Surprisingly, a few of the compounds, carbazochrome and niclosamide, appeared to augment Aβ formation. Thus, hydrazides reduced lipid oxidative damage, and hydralazine additionally reduced Aβ misfolding. While hydralazine would require specific chemical modifications for use as an AD therapeutic itself (to improve blood brain barrier permeability, reduce vasoactive side effects, and optimization for amyloid inhibition), this study suggests its potential merit for further AD drug development.
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, 142E Reynolds Medical Building, College Station, Texas 77843-1114, United States.
Mukesh
M
Maheshwari
Jessica K
JK
Roberts
Brent
B
Desutter
Karen T
KT
Duong
Joseph
J
Tingling
Janelle N
JN
Fawver
Hayley E
HE
Schall
Michael
M
Kahle
Ian V J
IV
Murray
D000447:Aldehydes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000682:Amyloid / Q000009:adverse effects / Q000378:metabolism* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008055:Lipids / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000009:adverse effects / Q000378:metabolism* / Q000648:ultrastructure; D017510:Protein Folding / Q000187:drug effects; D051381:Rats
D000447:Aldehydes; D000682:Amyloid; D016229:Amyloid beta-Peptides; D008055:Lipids; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C462359:tert-4-hydroxy-2-nonenal; D006830:Hydralazine