zVLL-CHO at low concentrations acts as a calpain inhibitor to protect neurons against okadaic acid-induced neurodegeneration.
There is evidence that β-secretase and amyloid precursor protein β-C-terminal fragments (APP-CTF) are involved in the pathogenesis of Alzheimer's disease (AD). Previously, we have reported that N-benzyloxycarbonyl-Val-Leu-leucinal (zVLL-CHO) reduced APP β-CTF accumulation in axonal swellings of degenerating neurons. Here, in an effort to discover more effective neuroprotective agents, we examined the effects of the β-secretase inhibitors, H-KTEEISEVN-stat-VAEF-OH (VAEF) and H-EVNstatineVAEF-NH2 (GL-189) as well as zVLL-CHO on OA (okadaic acid)-induced neurodegeneration. Unexpectedly, we found that pretreatment with zVLL-CHO (1 μM) protected neurons after OA treatment, whereas both VAEF and GL-189 lacked neuroprotective effects. Interestingly, 1 μM zVLL-CHO did not inhibit β-secretase. We previously reported that calpain is activated by OA treatment and calpain inhibitors protect against OA-induced neurodegeneration. The data presented here show that pretreatment with 1 μM zVLL-CHO decreased the levels of calpain-cleaved α-spectrin with a concomitant decrease in LDH release and an increase in average dendritic branch length compared to neurons treated with OA alone. These findings suggest that zVLL-CHO protects against OA-induced neurodegeneration via calpain inactivation.
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, 388-1 PoongNap-Dong, SongPa-Gu, Seoul 138-736, Republic of Korea.
Seung-Yong
SY
Yoon
Jung-Eun
JE
Choi
Ju-Hee
JH
Ham
Han
H
Choe
Hui-Sun
HS
Lee
Dong-Hou
DH
Kim
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019319:Okadaic Acid / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013049:Spectrin / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D015853:Cysteine Proteinase Inhibitors; C495708:N-benzyloxycarbonyl-valyl-leucyl-leucinal; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D013049:Spectrin; D019319:Okadaic Acid; D007770:L-Lactate Dehydrogenase; D053829:Amyloid Precursor Protein Secretases; D002154:Calpain