Human serum albumin and its N-terminal tetrapeptide (DAHK) block oxidant-induced neuronal death.
OBJECTIVE
Studies using animal models of stroke have shown that human serum albumin (HSA) significantly ameliorates cerebral ischemic injury after both transient and permanent ischemia, even when administered after the onset of ischemia or reperfusion. The mechanism of this effect remains uncertain, and prior studies suggest both indirect hemodynamic and direct cytoprotective effects. HSA is a potent antioxidant, in part because of its strong copper-binding capacity. Here we examined the effect of HSA on oxidant-induced neuronal death in a cortical cell culture system.


METHODS
Murine cortical cultures were exposed to oxidative stress generated by hydrogen peroxide and by a mixture of copper plus ascorbic acid. We examined the ability of HSA and a tetrapeptide occupying its N-terminus (DAHK) to prevent neuronal death after these challenges.


RESULTS
H(2)O(2) and CuCl(2)/ascorbic acid were used at concentrations that, in the absence of HSA, killed >90% of the neurons. HSA provided complete protection at a concentration of 37.5 micromol/L and 50% protection at 3.75 micromol/L. The copper-binding tetrapeptide DAHK had nearly identical potency and efficacy. HSA and DAHK were also equally effective in preventing neuronal death induced by CuCl(2)/ascorbic acid.


CONCLUSIONS
HSA has potent antioxidant properties, probably due to binding of copper and other transition metals. HSA extravasation into ischemic brain may provide neuroprotection by limiting metal-catalyzed oxidant stress. The tetrapeptide DAHK may be an effective, small-molecular-weight alternative to HSA as a therapeutic agent for stroke.
Gum
Elizabeth T
ET
Department of Neurology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, 94121, USA.
Swanson
Raymond A
RA
Alano
Conrad
C
Liu
Jialing
J
Hong
Shwuhuey
S
Weinstein
Philip R
PR
Panter
S Scott
SS
D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003300:Copper / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D012709:Serum Albumin / Q000494:pharmacology*
D018690:Excitatory Amino Acid Agonists; D009842:Oligopeptides; D016877:Oxidants; D012709:Serum Albumin; C431583:aspartyl-alanyl-histidyl-lysine; D016202:N-Methylaspartate; D003300:Copper; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid