In:
Pharmacology, S. Karger AG, Vol. 88, No. 1-2 ( 2011), p. 26-32
Abstract:
〈 i 〉 Aim: 〈 /i 〉 The present study was aimed at investigating the effect of 〈 i 〉 trans 〈 /i 〉 -6-(4-chlorobutyl)-5-hydroxy-4-(phenylthio)-1-tosyl-5,6-dihydropyridine-2(1H)-one (HTDP-2), a novel synthetic compound, on the release of endogenous glutamate in rat cerebrocortical nerve terminals (synaptosomes) and exploring the possible mechanism. 〈 i 〉 Methods: 〈 /i 〉 The release of glutamate was evoked by the K 〈 sup 〉 + 〈 /sup 〉 channel blocker 4-aminopyridine (4-AP) and measured by an on-line enzyme-coupled fluorimetric assay. We also used a membrane potential-sensitive dye to assay nerve terminal excitability and depolarization, and a Ca 〈 sup 〉 2+ 〈 /sup 〉 indicator, Fura-2-acetoxymethyl ester, to monitor cytosolic Ca 〈 sup 〉 2+ 〈 /sup 〉 concentrations ([Ca 〈 sup 〉 2+ 〈 /sup 〉 ] 〈 sub 〉 c 〈 /sub 〉 ). 〈 i 〉 Results: 〈 /i 〉 HTDP-2 inhibited the release of glutamate evoked by 4-AP in a concentration-dependent manner. Inhibition of glutamate release by HTDP-2 was prevented by the chelating intraterminal Ca 〈 sup 〉 2+ 〈 /sup 〉 ions, and by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to the glutamate transporter inhibitor 〈 i 〉 D 〈 /i 〉 〈 i 〉 L 〈 /i 〉 -threo-β-benzyloxyaspartate. HTDP-2 did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization whereas it decreased the 4-AP-induced increase in [Ca 〈 sup 〉 2+ 〈 /sup 〉 ] 〈 sub 〉 c 〈 /sub 〉 . Furthermore, the inhibitory effect of HTDP-2 on the evoked glutamate release was abolished by the N-, and P/Q-type Ca 〈 sup 〉 2+ 〈 /sup 〉 channel blocker ω-conotoxin MVIIC, but not by the ryanodine receptor blocker dantrolene, or the mitochondrial Na 〈 sup 〉 + 〈 /sup 〉 /Ca 〈 sup 〉 2+ 〈 /sup 〉 exchanger blocker CGP37157. 〈 i 〉 Conclusion: 〈 /i 〉 Based on these results, we suggest that, in rat cerebrocortical nerve terminals, HTDP-2 decreases voltage-dependent Ca 〈 sup 〉 2+ 〈 /sup 〉 channel activity and, in so doing, inhibits the evoked glutamate release.
Type of Medium:
Online Resource
ISSN:
0031-7012
,
1423-0313
Language:
English
Publisher:
S. Karger AG
Publication Date:
2011
detail.hit.zdb_id:
1483550-2
SSG:
15,3
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