Bioisosteric replacement of the alpha-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-1,2-dione containing NMDA antagonists.

In this report, a novel bioisostere of the alpha-amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of compounds which are NMDA antagonists. These compounds, which are achiral and easily prepared, demonstrated good affinity at the NMDA receptor by their ability to displace [3H]CPP binding in vitro. In particular, the phosphonic acid 24 provided protection against NMDA-induced lethality in mice equivalent to 2-amino-7-phosphonoheptanoic acid (5). This was considered an encouraging result in lieu of the fact that 24, like 5, lacks the conformational rigidity of the more potent NMDA antagonists. In addition, analogs that incorporate the 1,2,4-oxadiazolidine-3,5-dione heterocycle of quisqualic acid and the unsaturation of kainic acid were prepared to explore selectivity at the non-NMDA receptor subtypes.

Polyol pathway activity in nervous tissues of diabetic and galactose-fed rats: effect of dietary galactose withdrawal or tolrestat intervention therapy.

Enhanced polyol pathway activity resulting in an accumulation of sorbitol and a depletion of myoinositol in nervous tissues has been proposed to be important in development of diabetic neuropathies. This investigation demonstrated that in two models of diabetic complications, streptozocin (STZ)-induced diabetic rats and galactose-fed rats, 5 weeks of disease led to an accumulation of sorbitol or galactitol, respectively, in three cranial nerves (the optic (II), trigeminal (V), and vagus (X) nerves), as well as the sciatic nerve, cerebral cortex, and retina. In both models, the cranial nerves and cerebral cortex contained lower levels of accumulated polyol than the sciatic nerve. In addition, myoinositol depletion was observed in the sciatic nerve only. In a second galactose-fed rat study, returning 5-week galactose-fed rats to a normal diet for 6 weeks led to complete elimination of galactitol from the optic nerve, sciatic nerve, and retina and normalization of the sciatic nerve myoinositol concentration. Similarly, continuing the galactose diet for 6 more weeks (ie, a total of 11 weeks) as well as administration of the aldose reductase inhibitor (ARI) tolrestat (20 and 40 mg/kg/day), caused the sciatic nerve to contain a normal myoinositol concentration and a galactitol concentration that was 95% below the level observed in galactose-fed controls. In the optic nerve and retina, tolrestat was less effective, resulting in 69-78% lower galactitol levels. In conclusion, these findings indicate that sorbitol and galactitol accumulate in cranial nerves, brain, and retina without a concomitant decrease in myoinositol. Either withdrawal of the galactose diet or intervention with tolrestat normalized polyol levels in the sciatic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Cranial nerve dysfunction in conscious galactosemic rats as measured by the auditory-evoked brainstem response.

The purpose of this study was to extend our previous work with the auditory-evoked brainstem response and determine whether galactosemia would produce a functional neuropathy similar to that previously seen in streptozocin-induced diabetic rats. Sprague-Dawley male rats implanted with cortical electrodes received either normal chow (n = 17) or a 50% galactose diet (n = 17) for 5 weeks. Peak II latency of the auditory-evoked brainstem response, interpreted as a functional measure of the auditory nerve (VIII cranial) in rats, was significantly prolonged in galactose-fed rats relative to controls (P less than 0.05). These results demonstrate a functional deficit in the auditory nerves of galactosemic rats. The deficit in the auditory-evoked brainstem response of galactosemic rats is similar to our previous finding in streptozocin-induced diabetic rats.

Tolrestat, an aldose reductase inhibitor, prevents nerve dysfunction in conscious diabetic rats.

The effect of 4 wk of streptozocin (STZ)-induced diabetes on the transmission time of the auditory-evoked brain stem response (ABR) was examined in conscious male Sprague-Dawley rats. Distal nerve transmission time of the auditory pathway (latency of peak II), which includes conduction along the 8th cranial nerve, increased in diabetic rats (n = 9) relative to nondiabetic rats (n = 17). The difference in peak II latency between diabetic and control rats was significant beginning 2 wk after the induction of diabetes (P less than .05). In contrast, 4 wk of STZ-induced diabetes had no effect on the central transmission time of the auditory pathway (interpeak latency between peaks II and IV). Oral administration of tolrestat, a structurally novel aldose reductase inhibitor (n = 8; 20 mg/kg twice daily 1 wk before and 4 wk after STZ injection), prevented the diabetes-induced increase in distal nerve transmission time. These findings indicate that experimentally induced diabetes can result in a nerve dysfunction as measured by the increased latencies of the early components of the ABR. Furthermore, because tolrestat prevents these changes in the ABR, aldose reductase and the polyol pathway are implicated in this neuropathy.

The motor program and role of sensory feedback in claw extension of the crayfish.

The motor program and role of the meropodite sensory organs (the chordotonal organs MC-1, MC-2 and the myochordotonal organ MCO) in extension of the merocarpodite (M-C) joint of the claw was examined during an antennal-evoked defense response. Recordings from the meropodite extensor muscle indicated that the tonic extensor motoneuron was primarily responsible for M-C joint extension. The phasic extensor motoneuron was co-activated with the tonic motoneuron in only 48% of the responses. Tonic motoneuron discharge was elevated in those responses in which the phasic motoneuron was active. Inactivation of individual meropodite sensory organs did not alter the tonic motoneuron response. Simultaneous inactivation of all 3 organs reduced tonic motoneuron discharge by 47%. Phasic motoneuron discharge was reduced following inactivation of the individual MC-1, MC-2 and MCO organs as well as in the sham operated group. Following inactivation of all 3 organs phasic motoneuron activity ceased. These results suggest that feedback from the M-C sensory organs during an active extension response is positive and redundant.

Baroreflex control of renal sympathetic nerve activity in hypertensive miniature swine.

The baroreceptor reflex control of renal nerve activity was examined in seven normotensive and 14 deoxycorticosterone acetate-treated anesthetized Yucatan miniature swine. Pressor responses evoked by the administration of phenylephrine were used to assess reflex control. The mean absolute threshold for inhibition of renal nerve activity was higher but not significantly different between the deoxycorticosterone acetate-treated and normotensive group. However, the mean relative threshold for inhibition of renal nerve activity was significantly greater in the deoxycorticosterone acetate-treated group (p less than 0.05). Responses from five deoxycorticosterone acetate-treated and five normotensive swine were used to examine the time course of the baroreflex inhibition of renal nerve activity. During the initial rise in pressure the percent inhibition of renal nerve activity was similar for the two groups. During the recovery phase of the response, renal nerve activity in the deoxycorticosterone acetate-treated group returned to baseline while renal nerve activity remained attenuated below baseline in the normotensive group. The gain of the reflex was significantly lower in the deoxycorticosterone acetate-treated group compared with the control group (p less than 0.05). The results of this study clearly indicate that baroreceptor reflex control of renal nerve activity is altered in anesthetized deoxycorticosterone acetate-treated hypertensive swine.

Role of the hemigiant neurons in the crayfish defense response.

The medial and lateral hemigiant neurons of the crayfish were isolated in the circumesophageal connective and electrically stimulated to examine their ability to elicit a defense response. In contrast to previous reports, neither a defense response nor any other thoracic or abdominal movements were observed following stimulation of either hemigiant. Small fibers that lie adjacent to the hemigiants in the circumesophageal connective evoked defense responses when they were electrically stimulated. Two types of defense responses could be evoked by stimulation of small fibers.

Anatomical organization of neurons descending from the supraesophageal ganglion of the lobster.

A population of somata in the supraesophageal ganglion of the lobster was filled by retrograde diffusion of cobalt through the circumesophageal connectives. These somata are located predominantly in the dorsal anterior median region of the protocerebrum. They are organized into a contralateral and two ipsilateral clusters. These 3 clusters include approximately one-half of the neurons in the dorsal anterior median region.