Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures.
Apolipoprotein E (apoE) is a 34-kD protein with multiple biological properties. Recent clinical and preclinical observations implicate a role for apoE in modifying the response of the brain to focal and global ischemia. One mechanism by which apoE might exert these effects is by reducing glutamate-induced excitotoxic neuronal injury associated with ischemic insults. We demonstrate that human recombinant apoE confers a mild neuroprotective effect in primary neuronal-glial cultures exposed to 100 microM N-methyl-D-aspartate. Furthermore, a peptide derived from the receptor-binding region of apoE (residues 133-149) maintained a significant helical population as assessed by circular dichroism, and completely suppressed the neuronal cell death and calcium influx associated with N-methyl-D-aspartate exposure. Neuroprotection was greatest when the peptide was added concurrently with N-methyl-D-aspartate; however, a significant protection was observed when peptide was preincubated and washed off prior to N-methyl-D-aspartate exposure. These results suggest that one mechanism by which apoE may modify the CNS response to ischemia is by partially blocking glutamate excitotoxicity. Moreover, small peptide fragments derived from the receptor-binding region of apoE have enhanced bioactivity compared with the intact holoprotein, and may represent a novel therapeutic strategy for the treatment of brain ischemia.
Aono
M
M
Multidisciplinary Neuroprotection Laboratories, Duke University School of Medicine, Durham, NC 27710, USA.
Bennett
E R
ER
Kim
K S
KS
Lynch
J R
JR
Myers
J
J
Pearlstein
R D
RD
Warner
D S
DS
Laskowitz
D T
DT
D000595:Amino Acid Sequence; D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy; D002478:Cells, Cultured; D018920:Coculture Techniques; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D016202:N-Methylaspartate / Q000633:toxicity*; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001057:Apolipoproteins E; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D016202:N-Methylaspartate