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Biomedical subjects

J W Olney

Publications and source records attributed to J W Olney.

At least 91 records · Page 5Linked to original sources
PubMed1993

Neonatal exposure to D,L-2-amino-3-phosphonopropionate (D,L-AP3) produces lesions in the eye and optic nerve of adult rats.

Metabotropic glutamate receptors are a recently described receptor class with emerging importance in synaptic plasticity and brain development. Activation of metabotropic glutamate receptors results in several cellular secondary messenger events that are especially important during postnatal development. This study characterized the effects of D,L-2-amino-3-phosphonopropionate (D,L-AP3), an aspartic acid analog with agonist and antagonist activity at the metabotropic receptor, on the postnatal development of the rat eye and optic nerve. Sprague-Dawley rat pups were treated daily (i.p.) with saline or 500 mg/kg D,L-AP3 on postnatal days (PND) 4-10 or 10-14. After making clinical and ophthalmoscopic examinations, rats were necropsied between 65 and 70 days of age and light microscopic evaluations were made of eyes and optic nerves. Between postnatal days 10-20, all treated rats exhibited motor tremors, circling, and head tilt. Ophthalmoscopic lesions were more severe in rats treated on days 4-10 than days 10-14 and included decreased retinal vasculature, cataracts, and retinal dysplasia, hypoplasia, and detachment. All rats treated on days 4-10 had severe optic nerve atrophy/hypoplasia grossly and severe retinal atrophy, retinal detachment, and cataracts histologically. Seven of eight rats treated on days 10-14 had qualitatively similar but less severe lesions. Overall, rats treated with D,L-AP3 on PND 4-10 had earlier and more severe retinal and optic nerve lesions when compared to rats treated on PND 10-14. These data characterize the morphologic effects in adult rats exposed to D,L-AP3 as neonates and suggest a possible role for the metabotropic receptor in the postnatal development of retina and optic nerve.

Aging↗
PubMed1993

Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex.

MK(+)801 (dizocilpine maleate) is a noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor, the major glutamate receptor at excitatory synapses in the central nervous system. Since NMDA antagonists are neuroprotective, there is interest in their development for treatment of cerebral ischemia. Unfortunately, many of these compounds also induce vacuole formation in neurons of the rat retrosplenial cortex (Olney et al., Science 244: 1360-1362, 1989). Although vacuolization was initially reported to be reversible with MK(+)801, preliminary data later suggested that higher doses might produce neuronal necrosis. To explore this issue, young male Sprague-Dawley rats were given a single subcutaneous dose of vehicle or 1, 5, or 10 mg/kg MK(+)801. At 4 h and 1, 2, 3, 4, 7, and 14 days postdose (DPD), the retrosplenial cortex was examined by light and electron microscopy. At 4 h, vacuoles occurred in neurons of retrosplenial cortical layers 3 and 4 in all rats given MK(+)801. Mitochondria and endoplasmic reticulum contributed to vacuole formation. At 1 DPD, vacuoles or necrotic neurons were rarely observed. At all subsequent time points, necrotic neurons were readily evident in rats given 5 or 10 mg/kg MK(+)801, but only rarely evident in rats given 1 mg/kg. Necrotic neurons were associated with reactive microglial cells that contained electron-dense debris ultrastructurally. If similar dose-dependent neuronal necrosis proves to be a feature of other NMDA antagonists, such effects might raise concerns for the development and use of these compounds in human cerebrovascular diseases.

Animals↗
PubMed1993

Excitotoxic neuronal damage and neuropsychiatric disorders.

Excitatory amino acids (EAA) serve important physiological functions in the vertebrate CNS, including participation in fast excitatory synaptic transmission, modulation of synaptic plasticity and regulation of neuronal morphology during development. However, paradoxically they also harbor neurotoxic (excitotoxic) potential, which, if unleashed, can cause widespread degeneration of CNS neurons. Accumulating evidence suggests a role for excitotoxins in a variety of human neuropsychiatric disorders. This paper reviews the classes of EAA receptors in the CNS, the mechanisms underlying EAA-mediated neuronal damage and the role of EAA in specific human disorders.

Amino Acids↗
PubMed1993

A benzodiazepine recognition site associated with the non-NMDA glutamate receptor.

GYKI 52466 is a benzodiazepine molecule that has muscle relaxant and anticonvulsant properties not attributable to a gamma-aminobutyric acid receptor-mediated mechanism. Here it is shown that GYKI 52466 exerts no blocking action at N-methyl-D-aspartate (NMDA) glutamate receptors, but acts noncompetitively to block ion currents and associated excitotoxicity, including ischemic neuronal degeneration, mediated through non-NMDA glutamate receptors. The inhibition of non-NMDA responses by GYKI 52466 is antagonized by cyclothiazide, hydrochlorothiazide, and diazoxide, benzothiadiazide drugs that inhibit non-NMDA receptor desensitization. These results suggest that non-NMDA receptor-ion channel complexes may contain a novel benzodiazepine recognition site where receptor desensitization is regulated; this postulated site represents a promising new target for rational development of drugs to treat neurological disorders.

Animals↗
PubMed1993

Role of excitotoxins in developmental neuropathology.

Many years ago, it was found that glutamate has both neuroexcitatory and neurotoxic (excitotoxic) properties and that the central nervous system is more sensitive to glutamate excitotoxicity during development than in adulthood. In recent years accumulating evidence has implicated glutamate in the pathophysiology of several neurodegenerative disorders. Although the primary emphasis of this research has been on adult-onset neurological disorders, studies focusing on the developing CNS have corroborated the extreme sensitivity of the immature CNS to the excitotoxic actions of glutamate and related excitotoxins, especially those that interact selectively with the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Recent findings pertaining to the potential role of excitotoxic mechanisms in developmental neuropathology will be reviewed with special emphasis on hypoxic-ischemic and related forms of neuropathology which appear to be mediated through NMDA receptors.

Amino Acid Metabolism, Inborn Errors↗
PubMed1993

Neuroprotectants in Honghua: glucose attenuates retinal ischemic damage.

PURPOSE: This study examined the neuroprotective properties of Honghua, an extract of safflower used as an herbal medicine in China, in several experimental models of retinal ischemia. METHODS: Honghua and other agents were tested (1) in the ex vivo chick embryo retina assay (CER) for anti-excitotoxin efficacy and against simulated ischemia (30 min glucose/oxygen deprivation); and (2) in the in vivo adult rat retina dye-photothrombosis assay. Active components of Honghua were purified by conventional chromatographic techniques. RESULTS: In the CER, Honghua protected against excitotoxicity of glutamate, N-methyl-D-aspartate, kainate, and quisqualate, and against neuronal degeneration caused by simulated ischemia. Honghua more potently protected against simulated ischemia than against the agonists. In the in vivo adult rat retina, ischemic damage was reduced greatly by intravitreal injection of Honghua. An approximately 100-fold purification of an active principle was achieved chromatographically. The purest fractions were rich in glucose, so the effects of glucose in the ischemia models were determined. Many neuroprotective effects of Honghua were mimicked by pure solutions of equivalent glucose concentration. Glucose (> 3.2 mmol/l) in the CER-ischemia assay provided protection. Glucose did not protect against the lesions induced by direct application of the excitotoxic agonists. Intravitreal injection of glucose provided highly significant neuroprotection in the adult rat retina dye-photothrombosis model. CONCLUSIONS: These results suggest that retinal excitotoxic damage in vivo can occur secondary to depletion of cellular energy reserves, and therefore may be prevented by simple procedures that maintain the availability of energy sources.

Animals↗
PubMed1991

NMDA antagonist neurotoxicity: mechanism and prevention.

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including phencyclidine (PCP) and ketamine, protect against brain damage in neurological disorders such as stroke. However, these agents have psychotomimetic properties in humans and morphologically damage neurons in the cerebral cortex of rats. It is now shown that the morphological damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act at the gamma-aminobutyric acid (GABA) receptor-channel complex and are known to suppress the psychotomimetic symptoms caused by ketamine. Thus, it may be possible to prevent the unwanted side effects of NMDA antagonists, thereby enhancing their utility as neuroprotective drugs.

Animals↗
PubMed1991

Excitotoxicity in the embryonic chick spinal cord.

Recent evidence implicates excitatory amino acids (EAAs), acting as excitotoxic agents, in the pathogenesis of neurological disorders involving the spinal cord. In this study, we used the chick embryo spinal cord as an in vitro model for studying the sensitivity of spinal neurons to the excitotoxic effects of EAA agonists. Compounds tested include the prototypic receptor-specific agonists, N-methyl-D-aspartate (NMDA), quisqualic acid (Quis), and kainic acid (KA), and the plant-derived excitotoxic food poisons, beta-N-oxalylamino-L-alanine, beta-N-methylamino-L-alanine, and domoic acid. Each agonist induced concentration-dependent acute degeneration of neurons distributed throughout the spinal cord. These cytopathological changes consisted of acute edematous degeneration of dendrosomal structures in the dorsal horn and intermediate zone, and dark cell changes with intracytoplasmic vacuolization of motor neurons; this damage is identical to that induced by excitotoxin agonists in other regions of the central nervous system. The NMDA receptor-specific antagonist MK-801 completely blocked toxicity of NMDA, and the nonNMDA antagonist CNQX preferentially blocked the toxicity of Quis- and KA-type agonists in the spinal cord. Our findings suggest that (1) the majority of spinal neurons have all three subtypes of EAA receptors, making them acutely vulnerable to excitotoxin exposure; and (2) EAA antagonists are effective in preventing excitotoxin-induced damage of the spinal cord.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1991

Age-related sensitivity to kainate neurotoxicity.

Domoate, a glutamate analog, is believed to be responsible for a seafood poisoning incident that caused acute neurological disturbances and chronic memory impairment in some victims, with the incidence of mortality and neuropsychological morbidity being highest among the aged. Domoate expresses neurotoxic (excitotoxic) activity in vitro by an action at the kainate subtype of glutamate receptor, and when administered to adult rats, it mimics kainate in causing status epilepticus and a severe seizure-brain damage syndrome. Because domoate is exceedingly expensive, we explored the feasibility of using kainate to study the age-linked features of domoate neurotoxicity. We administered kainate subcutaneously in various doses to young (5-6 months), middle-aged (12-13 months), and old (22-25 months) rats and found the middle-aged and old rats significantly more sensitive than young rats to the neurotoxic actions of kainate. Low doses of kainate, which were nontoxic to young rats, frequently triggered status epilepticus, associated brain damage, and precipitous death in old rats. Middle-aged rats were more sensitive than young rats, but less sensitive than old rats to kainate neurotoxicity. These results suggest that the kainate-treated rat may be a useful model for studying mechanisms underlying age-related aspects of the human domoate neurotoxic syndrome.

Age Factors↗
PubMed1991

Blockade of both NMDA and non-NMDA receptors is required for optimal protection against ischemic neuronal degeneration in the in vivo adult mammalian retina.

Under ischemic conditions, the excitatory amino acids (EAA), glutamate and aspartate, accumulate in the extracellular compartment of brain and, by excessive stimulation of EAA receptors, trigger excitotoxic degeneration of CNS neurons. Since glutamate and aspartate exert excitotoxic activity through both of the generally recognized classes of EAA receptors [N-methyl-D-aspartate (NMDA) and non-NMDA], it follows that both receptor classes may play a role in ischemic neuronal degeneration. Although several laboratories have reported that NMDA receptor antagonists confer protection in vivo against ischemic neuronal degeneration, very little is known about the ability of non-NMDA antagonists to confer such protection, a major reason being that non-NMDA antagonists that penetrate blood-brain barriers have not been available. In the present study, we examined the ability of NMDA or non-NMDA antagonists, either individually or in combination, to prevent neuronal degeneration in vivo in the adult rat retina rendered ischemic by dye/photothrombotic occlusion of retinal blood vessels. In this model, delivery of drugs to the ischemic tissue is assured by intravitreal administration. Intravitreal administration of the NMDA antagonist, MK-801, reduced the severity of ischemic damage approximately 50% (a ceiling effect that could not be increased by administering higher doses). The predominantly non-NMDA antagonist, CNQX, when administered in the highest dose permitted by its solubility limitations, provided equivocal (statistically nonsignificant) protection, but the two drugs combined provided greater than 80% protection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

L-cysteine, a bicarbonate-sensitive endogenous excitotoxin.

After systemic administration to immature rodents, L-cysteine destroys neurons in the cerebral cortex, hippocampus, thalamus, and striatum, but the underlying mechanism has never been clarified. This neurotoxicity of L-cysteine, in vitro or in vivo, has now been shown to be mediated primarily through the N-methyl-D-aspartate subtype of glutamate receptor (with quisqualate receptor participation at higher concentrations). In addition, the excitotoxic potency of L-cysteine was substantially increased in the presence of physiological concentrations of bicarbonate ion. L-Cysteine is naturally present in the human brain and in the environment, and is much more powerful than beta-N-methylamino-L-alanine, a bicarbonate-dependent excitotoxin, which has been implicated in an adult neurodegenerative disorder endemic to Guam. Thus, the potential involvement of this common sulfur-containing amino acid in neurodegenerative processes affecting the central nervous system warrants consideration.

Animals↗
PubMed1990

Behavioral effects of MK-801 in the rat.

Several experiments were conducted to study the effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on learning and memory in the rat. Rats displayed impaired performance on several sensorimotor tests and appeared grossly intoxicated when treated IP with 0.2 mg/kg MK-801, but not when treated with lower doses (0.05 or 0.1 mg/kg). Postacquisition performance on two spatial learning tasks involving working memory protocols (reinforced alternation and radial arm maze) was impaired by MK-801 at intoxicating doses (greater than or equal to 0.2 mg/kg) but not at lower doses (0.05 or 0.1 mg/kg). Using a position habit reversal task, we found that rats could learn to reverse a position habit while under the influence of a nonintoxicating dose of MK-801 (0.1 mg/kg), but when tested on the following day performed as if they did not recall what they had learned. Thus, acute administration of a nonintoxicating dose of MK-801 disrupts the retention of new information learned under the influence of the drug but does not interfere with the performance of tasks that are well learned before the drug is administered. Whether the performance deficits on the spatial learning tasks observed only following intoxicating doses of MK-801 reflect an effect on memory is not clear.

Animals↗
PubMed1990

Domoic acid: a dementia-inducing excitotoxic food poison with kainic acid receptor specificity.

Domoic acid (Dom), a rigid analog of the excitotoxic amino acids, glutamate and kainic acid, is believed to be the mussel neurotoxin responsible for a recent food poisoning incident in Canada that killed some people and left others with memory impairment. Since the literature contains very little information pertaining to Dom excitotoxicity, we have systematically evaluated the neuroexcitatory properties of Dom in vitro (cultured hippocampal neurons) and its neurotoxic properties both in vitro (chick embryo retina) and in vivo (adult rat). In the in vitro experiments, the properties of Dom were compared with those of kainic acid, N-methyl-D-aspartate (NMDA) and quisqualate, each of which is a prototypic agonist at a different subtype of glutamate receptor. Currents induced in hippocampal neurons by Dom and kainic acid were identical and displayed a linear current/voltage relationship (in contrast to NMDA currents) and were nondesensitizing (in contrast to quisqualate currents). Dom currents were not blocked by NMDA antagonists but were blocked by CNQX, an antagonist of non-NMDA receptors. In the chick embryo retina, Dom induced a lesion pattern having the same distinctive characteristics as a kainic acid lesion which differs from that induced by either NMDA or quisqualate, and the Dom lesion was blocked by CNQX but not by NMDA antagonists. Subcutaneous administration of Dom (2.5-3 mg/kg) to adult rats resulted in an acute seizure-brain damage syndrome almost identical to that induced in rats by KA (12 mg/kg) and having important features analogous to the neurotoxic syndrome observed in the human food poison victims.

Animals↗
PubMed1990

Excitotoxicity of L-dopa and 6-OH-dopa: implications for Parkinson's and Huntington's diseases.

Despite several decades of research aimed at elucidating the mechanisms underlying neuronal degeneration in Parkinson's and Huntington's diseases, these mysteries remain unfathomed. The brain contains high concentrations of the putative transmitters, glutamate and aspartate, which have neurotoxic (excitotoxic) potential and are thought to cause neuronal degeneration in certain acute neurological disorders. However, no mechanism has been identified by which these diffusely distributed agents might cause the regionally selective patterns of neuronal degeneration characterizing Parkinson's and Huntington's diseases. Here we report that L-DOPA, the natural precursor to dopamine, is a weak excitotoxin and its ortho-hydroxylated derivative, 6-OH-DOPA, is a powerful excitotoxin. We propose that an excitotoxic process mediated by L-DOPA or an acidic derivative such as 6-OH-DOPA might be responsible for degeneration of nigral neurons in Parkinson's disease or striatal neurons in Huntington's disease.

2-Amino-5-phosphonovalerate↗
PubMed1990

Excitotoxin-mediated neuron death in youth and old age.

Here I have discussed current issues in excitotoxicology (neurotoxicity of Glu and related agents) with special emphasis on the NMDA receptor and its possible role in neuropsychiatric disorders. I have briefly described several classes of anti-excitotoxic agents which are currently under study for their ability to protect neurons against excitotoxin-mediated neuronal degeneration. There is growing interest in the possibility that such agents, especially NMDA antagonists will prove useful in the clinical management of neurodegenerative disorders; however, neither their efficacy nor safety has been adequately established at present. With the plethora of new information about the NMDA receptor--ionophore complex, one tends to forget that non-NMDA receptors can also mediate excitotoxic events. Thus, although we know less about the physiology and make up of non-NMDA receptors, it seems likely that new information, as it becomes available, will reveal new links between endogenous excitotoxins and neuropsychiatric disease processes. In particular, since NMDA receptors are relatively more sensitive in early life and non-NMDA receptors more sensitive in adulthood, it is reasonable to postulate the greatest involvement of the former in developmental psychoneuropathology and the latter in neurodegenerative diseases of the elderly.

Aging↗
PubMed1990

Antagonism of morphine analgesia by nonopioid cold-water swim analgesia: direct evidence for collateral inhibition.

The demonstrated existence of opioid and nonopioid forms of pain control has raised questions as to how they interact. Previous indirect evidence suggests that activation of one system inhibited the activation of the other. The present study assessed this directly using morphine as an opiate form of analgesia and continuous cold-water swims (CCWS, 4 degrees C, 2 min) as the nonopioid form. A significant reduction in morphine (8 mg/kg, SC) analgesia on the tail-flick test was observed if rats were acutely exposed to CCWS immediately prior to morphine administration. The inability of naloxone (10 mg/kg, SC) to reduce CCWS analgesia verified its nonopioid nature. The antagonism of morphine (3 mg/kg, SC) analgesia was greater following preexposure to 2 min of CCWS than 1 min of CCWS. CCWS was also more effective in antagonizing analgesia induced by the 3 mg/kg than the 8 mg/kg dose of morphine. The antagonism of morphine analgesia by CCWS was dependent upon the temporal patterning of stimulus presentation: exposure to CCWS 20 or 60 min prior to morphine failed to alter subsequent morphine analgesia. A significant reduction in analgesia induced by intraperitoneal administration of morphine (10 mg/kg) was also observed when CCWS was presented immediately prior to injection, suggesting that pharmacokinetic factors such as altered drug absorbance by CCWS-induced vasoconstriction do not appear to explain these effects. These data provide direct support for the existence of collateral inhibitory mechanisms activated by CCWS and morphine, and suggests that these opioid and nonopioid forms of analgesia do not function synergistically, but instead involve some form of hierarchical order.

Analgesia↗
PubMed1990

Synthesis, phencyclidine-like pharmacology, and antiischemic potential of meta-substituted 1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines.

A series of 1-[1-arylcyclohexyl]-1,2,3,6-tetrahydropyridines were prepared by the reaction between 1-(1-cyanocyclohexyl)-1,2,3,6-tetrahydropyridine (1) and an appropriately substituted Grignard reagent. The resulting compounds were tested for their phencyclidine binding site affinities. Selected compounds were then tested for their ability to produce ketamine appropriate responding in monkeys and/or to show neuroprotective effects in a baby rat hypoxia/ischemia model. While it was found that binding site affinity correlated well with discriminative stimulus effects, it was found to be a poor indicator of neuroprotective efficacy within this series.

Animals↗