Novel synthesis of enantiomerically pure natural inositols and their diastereoisomers.

The various inositol polyphosphates have been found to trigger many important biological processes. Although the knowledge of this phosphoinositide signaling system has been discovered in the past 10 years, many factors remain unclear. For this reason, there is an increased demand for supplies of D-myo-inositol and particularly of novel analogues to investigate these biological mechanisms in more detail. Herein, we report the efficient syntheses of all diastereoisomers of inositol starting with 6-O-acetyl-5-enopyranosides. Conversion of 6-O-acetyl-5-enopyranosides into the corresponding substituted cyclohexanones (Ferrier-II rearrangement) was found to proceed efficiently with a catalytic amount of palladium dichloride. Stereoselective reduction of beta-hydroxy ketones obtained provided the precursors to all inositol diastereoisomers in good to excellent yields and with high stereoselectivities. Good accessibility of these enantiomerically pure inositol diastereoisomers results in the efficient syntheses of D-myo-inositol 1,4,5-trisphosphate and D-myo-inositol 1,3,4,5-tetrakisphosphate.

The effects of N-methyl-D-aspartate (NMDA) and its competitive antagonist, 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP), injected into caudate-putamen on kindled amygdaloid seizures in rats.

N-methyl-D-aspartate (NMDA) is an agonist of NMDA receptors and 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) is an NMDA receptor antagonist. NMDA (1 or 2 nmol per side) or CPP (2.5 or 10 nmol per side) was injected into the bilateral caudate-putamen of amygdaloid-kindled rats. In addition, CPP (10 nmol) was ipsilaterally or contralaterally injected into the unilateral caudate-putamen. Either 20 min after NMDA or 60 min after CPP, the kindled amygdala was stimulated at the generalized seizure triggering threshold. In a few animals tested, injection of NMDA into the bilateral caudate-putamen produced transient spiking activity, with no clinical manifestations. This feature began about 5 min after the injection and lasted about 10 s. When these animals were excluded from the statistical analysis, NMDA in the caudate-putamen showed a weak and non-significant anticonvulsant action. Injection of CPP into the bilateral caudate-putamen caused no ictal change, but markedly suppressed the kindled seizures. Injection of CPP into the unilateral caudate-putamen, regardless of the site, did not cause any ictal change, or affect the stimulation of the amygdala. These findings suggest that: (1) NMDA receptors in the caudate-putamen facilitate the development of kindled amygdaloid seizures; (2) activation of NMDA receptors in the bilateral, but not in the unilateral, caudate-putamen is required for the generalization and expression of kindled amygdaloid seizures.

Anticonvulsant action of metabotropic glutamate receptor agonists in kindled amygdala of rats.

1S,3R-1-Aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) and L-2-amino-4-phosphonobutyrate (L-AP4) are selective agonists of metabotropic glutamate receptors (mGluRs). 1S,3R-ACPD (200 nmol) injected into the amygdala (AM) of non-kindled rats produced immediate and transient seizures, characterized by immobility, searching, and wet-dog shakes. However, this ictal response was not observed in AM-kindled rats. Intra-AM injection of 1S,3R-ACPD (40 or 200 nmol) or L-AP4 (200 nmol) resulted in a delayed and marked suppression of kindled seizures, 3 days after 40 nmol of 1S,3R-ACPD, 1 day after 200 nmol of 1S,3R-ACPD, and from 1 to 3 days after 200 nmol of L-AP4. These and the previous findings suggest that: (1) the excitatory action of 1S,3R-ACPD in the AM, which may be mediated by the postsynaptic mGluRs, is reduced after completion of kindling; (2) 1S,3R-ACPD and L-AP4 exert anti-convulsant action in the AM, presumably by activating the presynaptic as well as postsynaptic mGluRs.

Different effect of hippocampal granule cell destruction on amygdaloid kindling in Sprague-Dawley and Wistar rats.

The hippocampal granule cells receive major inputs via the perforant path from other limbic structures such as the amygdala (AM). In this study, we examined Sprague-Dawley (SD) and Wistar rats, the effect of bilateral destructions of the hippocampal granule cells on the process of AM kindling and kindled AM seizures after completion of kindling. The granule cells were selectively and completely destroyed bilaterally by intra-hippocampal injections of colchicine. The left AM was used as the primary kindling site and the right AM as the secondary site. In SD rats, prior destruction of the granule cells caused a marked delay in the seizure development of both the primary AM kindling and subsequent secondary AM kindling. However, once AM kindling was established in SD rats, the destruction of granule cells was totally ineffective in preventing kindled seizures. In Wistar rats, unlike SD rats, prior destruction of the granule cells failed to change the rate of kindling at the primary and secondary sites. However, Wistar rats showed a transient and marked regression of kindled seizures when the granule cells were destroyed after the completion of AM kindling. In both strains, granule cell destruction had no effect on the re-establishment of kindled seizures at the time of primary-site re-test. These findings suggest that hippocampal granule cells of SD and Wistar rats play different roles in AM kindling.