title: HTDP-2, a new synthetic compound, inhibits glutamate release through reduction of voltage-dependent Ca²⁺ influx in rat cerebral cortex nerve terminals.
abstract: OBJECTIVE
  The present study was aimed at investigating the effect of trans-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.
  
  
  METHODS
  The release of glutamate was evoked by the K⁺ 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 Ca²⁺ indicator, Fura-2-acetoxymethyl ester, to monitor cytosolic Ca²⁺ concentrations ([Ca²⁺](c)).
  
  
  RESULTS
  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 Ca²⁺ ions, and by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to the glutamate transporter inhibitor DL-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 [Ca²⁺](c). Furthermore, the inhibitory effect of HTDP-2 on the evoked glutamate release was abolished by the N-, and P/Q-type Ca²⁺ channel blocker ω-conotoxin MVIIC, but not by the ryanodine receptor blocker dantrolene, or the mitochondrial Na⁺/Ca²⁺ exchanger blocker CGP37157.
  
  
  CONCLUSIONS
  Based on these results, we suggest that, in rat cerebrocortical nerve terminals, HTDP-2 decreases voltage-dependent Ca²⁺ channel activity and, in so doing, inhibits the evoked glutamate release.
authors: Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao, Taiwan, ROC.
authors: Tzu-Yu
authors: TY
authors: Lin
authors: Cheng-Wei
authors: CW
authors: Lu
authors: Shu-Kuei
authors: SK
authors: Huang
authors: Shang-Shing Peter
authors: SS
authors: Chou
authors: Yuh-Chi
authors: YC
authors: Kuo
authors: Shiu-Huey
authors: SH
authors: Chou
authors: Woan-Fang
authors: WF
authors: Tzeng
authors: Chieh-Yih
authors: CY
authors: Leu
authors: Rwei-Fen S
authors: RF
authors: Huang
authors: Yih-Fong
authors: YF
authors: Liew
authors: Su-Jane
authors: SJ
authors: Wang
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000502:physiology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology*; D002540:Cerebral Cortex / Q000502:physiology*; D002998:Clonazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D003600:Cytosol / Q000502:physiology; D003620:Dantrolene / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D018698:Glutamic Acid / Q000032:analysis / Q000502:physiology* / Q000633:toxicity; D008297:Male; D008564:Membrane Potentials; D009411:Nerve Endings / Q000502:physiology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D013574:Synaptosomes / Q000502:physiology; D013841:Thiazepines / Q000494:pharmacology; D014105:Tosyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C570837:6-(4-chlorobutyl)-5-hydroxy-4-(phenylthio)-1-tosyl-5,6-dihydropyridine-2(1H)-one; D027322:Amino Acid Transport System X-AG; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D011728:Pyridones; D049994:Sodium Potassium Chloride Symporter Inhibitors; D013841:Thiazepines; D014105:Tosyl Compounds; D018698:Glutamic Acid; D002998:Clonazepam; C079032:CGP 37157; D015761:4-Aminopyridine; D003620:Dantrolene; D002118:Calcium