Novel kainate derivatives: potent depolarizing actions on spinal motoneurones and dorsal root fibres in newborn rats

Abstract

1Neuropharmacological actions of several kainate derivatives (kainoids) were examined for electrophysiological effects in the isolated spinal cord and the dorsal root fibre of the newborn rat. 2 Some kainoids caused depolarization of the motoneurone much more effectively than kainic acid or domoic acid and others were weaker. The rank order of the depolarizing activities of the kainoids tested here is as follows: 442-methoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (MFPA) > acromelic acid A > domoic acid _ 4-(2-hydroxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (HFPA) _ acromelic acid B > kainic acid. 3 In the isolated dorsal root fibre, domoic acid caused the most significant depolarization. There were distinct differences with regard to the rank order of the depolarizing activity between the motoneurone and the dorsal root fibre. The rank order in the dorsal root fibre is domoic acid > acromelic acid B > 5-bromowillardiine _ MFPA > acromelic acid A > HFPA > kainic acid. 4 Significant desensitization of kainate receptors was observed in the isolated dorsal root fibre during prolonged application of L-glutamate, kainate and its derivatives. Cross desensitization was also observed among these excitatory amino acids. Receptors desensitized by kainate did not respond to MFPA, HFPA and acromelic acids, suggesting that these kainate derivatives activated common kainate receptors in the dorsal root fibre.5 In both motoneurones and dorsal root fibres, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) effectively depressed the depolarization induced by kainoids, and neither 3-[(±)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP) nor picrotoxin blocked or affected the depolarization, but there were some differences in pharmacological potencies of glutamate antagonists between both preparations. 6 MFPA, HFPA and acromelic acids should provide valuable pharmacological tools for analysis of physiological functions of excitatory amino acids, in particular, as specific agonists for some subtypes of kainate receptors.

A comparison of the actions of agonists and antagonists at non‐NMDA receptors of C fibres and motoneurones of the immature rat spinal cord in vitro

“…The present values correspond closely to previous molar potency ratios estimated at immature dorsal roots (Agrawal & Evans, 1986;Ishida & Shinozaki, 1991). The latter studies were on preparations untreated with concanavalin A.…”

“…Presumably in concanavalin A-treated nerves, both forms of the receptor are expressed in the depolarizing response. The present pA2 of 5.84 for the antagonism of kainateinduced depolarization of C fibres by CNQX is similar to values obtained previously at motoneurones (5.8 from Long et al (1990) and 5.7 calculated from the data of Ishida & Shinozaki (1991)). In the present study NBQX gave pA2 values not significantly different from those above for antagonism of kainate-induced depolarization at motoneurones and C fibres.…”

“…The use of domoate and AMPA as agonists revealed a degree of selectivity of NBQX (approximately thirty fold) which was not apparent with kainate and quisqualate (Long et al, 1990;Watkins et al, 1990). A similar but smaller difference has been observed with CNQX (Watkins et al, 1990;Ishida & Shinozaki, 1991) and it suggests that domoate and AMPA are more selective agonists for sub-types of non-NMDA receptors than either kainate or quisqualate and that NBQX discriminates better between these receptors than does CNQX (Sheardown et al, 1990). In particular the 'kainate' receptor appears to be characterized by high agonist sensitivity to domoate (Agrawal & Evans, 1986) and the weak activity of AMPA at C fibres is likely to be due to a relatively low affinity and/or efficacy of this agonist for kainate receptors in this tissue.…”

Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid

“…Since ACRO-A was less potent in the depolarizing activity of rat dorsal root fiber than ACRO-B (Ishida & Shinozaki, 1991) and the effective dose of ACRO-A for induction of allodynia was extremely low (Figure 2b), we examined whether AMPA/ kainate receptor antagonists could attenuate the ACROinduced allodynia. The nonselective AMPA/kainate receptor antagonist NBQX did not inhibit allodynia induced by either ACRO-A or ACRO-B (Figure 3a and b).…”

Η Χρήση Του IGF-I Σε Κυτταρικές Θεραπείες Για Την Αντιμετώπιση Νευροεκφυλιστικών Νόσων

“…ε άθθεξ ιεθέηεξ ημ ζαμηεκζηυ μλφ (ibotenic acid), ιζα άθθδ έκςζδ ιε ζζπονή δζεβενηζηή δνάζδ, πμο απμιμκχκεηαζ απυ ημ ιακζηάνζ Amanita muscarηa, έπεζ απμδεζπεεί υηζ πνμηαθεί πανυιμζεξ αθθμζχζεζξ πμο δεκ επδνεάγμοκ ημοξ κεονάλμκεξ αθθά δεκ έπεζ ζπεδυκ ηαευθμο επζθδπημβυκμ δναζηδνζυηδηα ηαζ δεκ πνμηαθεί αθθμζχζεζξ ζε απμιαηνοζιέκεξ εβηεθαθζηέξ πενζμπέξ (Köhler et al, 1979;Köhler and Schwarcz, 1983;Schwartz et al, 1979). Έπμοκ ανεεεί ηαζ άθθεξ εκχζεζξ, υπςξ ημ δμιμσηυ μλφ (domoic acid) ηαζ ημ αηνμιεθζηυ μλφ (acromelic acid) Α ηαζ Β, μζ μπμίεξ έπμοκ πανυιμζα δμιή ιε ημ ηασκζηυ μλφ (Δζηυκα 10) ηαζ ιπμνμφκ κα δνάζμοκ ιέζς ηςκ οπμδμπέςκ ημο ηασκζημφ μλέμξ ςξ δζεβενηζημί πανάβμκηεξ, μζ μπμίμζ ιάθζζηα ιπμνμφκ κα είκαζ πζμ ζζπονμί απυ ημ ηασκζηυ μλφ (Ishida and Shinozaki, 1991;Perl et al, 1990;Stewart et al, 1990;Shinozaki, 1988;Shinozaki and Shibuya, 1974;Smith et al, 1991). (Lan et al, 2000).…”