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In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum.

Abstract：

:Excitotoxic mechanisms may play a critical role in the pathophysiology of several neurological and psychiatric diseases. Excitatory amino acid receptor antagonists are therefore of great therapeutic interest, but untoward side effects often prevent their clinical use. Targeting the glycine coagonist site of the (NMDA) receptor may bypass these shortcomings. The present study was designed to evaluate the neuroprotective characteristics of l-4-chlorokynurenine (4-Cl-KYN), a synthetic compound which is enzymatically converted to the selective glycine/NMDA receptor antagonist 7-chlorokynurenate (7-Cl-KYNA). Using slow (2 h) intrastriatal infusions of the excitotoxins quinolinate (QUIN; 120 nmol) or malonate (6.8 micromol) as the experimental paradigm, the neuroprotective potency of 4-Cl-KYN was first compared with that of exogenous 7-Cl-KYNA, using glutamate decarboxylase activity as a lesion marker. One hundred and thirty-five nanomoles of the prodrug 4-Cl-KYN or 27 nmol 7-Cl-KYNA, the former used in a pre- and cotreatment regimen, were required to block QUIN or, less efficiently, malonate toxicity. In separate animals, the metabolic fate of this neuroprotective dose of 4-Cl-KYN was examined in vivo. In control striata, the treatment gave rise to 170 +/- 25 pmol 7-Cl-KYNA/mg protein, approximately six times less than an infusion of 27 nmol exogenous 7-Cl-KYNA, indicating greatly superior efficacy of the focally produced antagonist. Notably, the conversion of 4-Cl-KYN to 7-Cl-KYNA increased by 82% in the presence of QUIN. 4-Cl-KYN was also metabolized to 4-chloro-3-hydroxyanthranilate, an established, powerful inhibitor of QUIN synthesis. This unique pharmacological profile and the fact that the prodrug, unlike 7-Cl-KYNA, readily penetrates the blood-brain barrier suggest that 4-Cl-KYN may be exceptionally useful as an anti-excitotoxic agent.

journal_name

Exp Neurol

journal_title

Experimental neurology

authors

Guidetti P,Wu HQ,Schwarcz R

doi

10.1006/exnr.1999.7284

keywords:

subject

Has Abstract

pub_date

2000-05-01 00:00:00

pages

123-30

issue

eissn

0014-4886

issn

1090-2430

pii

S0014-4886(99)97284-9

journal_volume

163

pub_type

杂志文章

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In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum.