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Modulation of kainate--activated currents by diazoxide and cyclothiazide analogues (IDRA) in cerebellar granule neurons.

Abstract：

:1. Patch-clamp technique was used in primary cultures of cerebellar granule neurons to study the modulation of the cyclothiazide analogue (IDRA21) and of the diazoxide derivative (IDRA 5) on KA-evoked currents. 2. The dose-response of kainic acid (KA) reveals an EC50=90 microM and an Hill coefficient of 1.3. IDRA 21 and cyclothiazide potentiate KA-evoked current in a dose dependent way, being cyclothiazide more potent but less efficacious than IDRA 21. Conversely IDRA 5 acts as a negative modulator of KA evoked -current. 3. Application of IDRA 21 and cyclothiazide results in a current potentiation of 125+/-18% and 80+/-12% respectively, while IDRA 5 decreases KA-current (-21+/-5%). Coapplication of cyclothiazide and IDRA 21 produces a potentiation of 110+/-17%, suggesting a competition of the two drugs for the same site. 4. In the same experimental model we studied the ability of IDRA compounds of promoting toxicity through AMPA-receptor activation. Under basal conditions AMPA treatment (50 microM for 1 hour) results in a negligible excitotoxicity. 5. In contrast similar treatment with AMPA + IDRA 21 (1 mM) or + IDRA 5 (1 mM) or + cyclothiazide (100 microM) induces citotoxicity. The neurotoxic damage induced by IDRA 21 and cyclothiazide is blocked by GYKI 53655 (50 microM) and by NBQX (10 microM). Interestingly GYKI and NBQX are ineffective in reducing IDRA 5 toxicity.

journal_name

Prog Neuropsychopharmacol Biol Psychiatry

journal_title

Progress in neuro-psychopharmacology & biological psychiatry

authors

Puia G,Losi G,Razzini G,Braghiroli D,Di Bella M,Baraldi M

doi

10.1016/s0278-5846(00)00120-2

subject

Has Abstract

pub_date

2000-08-01 00:00:00

pages

1007-15

issue

6

eissn

0278-5846

issn

1878-4216

pii

S0278584600001202

journal_volume

24

pub_type

杂志文章

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