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D F Weaver

Publications and source records attributed to D F Weaver.

At least 37 records · Page 2Linked to original sources
PubMed1994

NMDA-mediated metabolic activation of the cerebellar cortex in behaving rats by the neuropeptide endothelin-1.

Generalized barrel-rolling convulsions and focal hypermetabolic responses in the cerebellar cortex of conscious rats to lateral ventricular injection of the neuropeptide, endothelin-1 (ET; 9 pmol), were diminished or eliminated by i.c.v. pretreatment with the glutamatergic NMDA receptor antagonist, MK-801 (44 nmol). Using the quantitative autoradiographic [14C]deoxyglucose technique, we assessed rates of glucose metabolism in individual structures anatomically connecting forebrain nuclei within a polysynaptic network linked to the cerebellar cortex. Cerebellar cortical afferent sources from specific subnuclei of the inferior olivary complex, cuneate nucleus, and medial vestibular nucleus, all of which were hypermetabolic following injection of ET alone, were also inhibited by MK-801. The findings indicate that a convulsive i.c.v. dose of ET elicits an NMDA-related stimulatory effect, whose origin is probably at the periventricular caudate nucleus, that activates rates of glucose metabolism in several afferent sources and subregions of the cerebellar cortex involved in the regulation of equilibrium, posture, and the visuovestibular system.

Animals↗
PubMed1994

Neurotoxicity in conscious rats following intraventricular SNAP, a nitric oxide donor.

A solution containing S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO.-releasing compound, was microinjected in doses of 0.25-2 mumol into a lateral ventricle of conscious rats. SNAP produced dose-dependent convulsions similar to those associated with limbic stimulation, such as tonic extension of the hindlimbs and tail, and dystonia of the forepaws. At 2 mumol, SNAP evoked hyperventilation (arterial hypocapnia), arterial hyperglycemia and caused necrotic lesions of periventricular gray (e.g. lateral septal nucleus) and white matter structures. In the caudate nucleus and lateral septal nucleus ipsilateral to injection, SNAP elicited a bipolar metabolic pattern of low glucose metabolism proximal to the ventricle with higher values occurring more distally. In control studies, we proved that the residue of SNAP decomposition, N-acetylpenicillamine disulfide injected intraventricularly (2 mumol), was without physiological, behavioral, or histological effects. Ventricular pretreatment with methylene blue (2 nmol), a putative inhibitor of guanylate cyclase and superoxide generator, suppressed several of the behavioral manifestations of 1 mumol SNAP, such as the forepaw dystonia, squinting, and facial clonus, but was ineffective on the physiological and histological variables affected by the 2 mumol SNAP dose. Another NO. donor, sodium nitroprusside (2 mumol), produced fewer behavioral and cytotoxic effects over a 55-min observation period, but caused more intense and widely distributed metabolic stimulation, especially in commissural and projection white matter tracts. The results are the basis for a conscious rat model using intraventricular injection of nitrocompounds to examine the physiological, behavioral, metabolic and cytotoxic properties of NO. in the brain.

Acid-Base Equilibrium↗
PubMed1994

FR139317, a specific ETA-receptor antagonist, inhibits cerebral activation by intraventricular endothelin-1 in conscious rats.

A comprehensive series of time-related behavioral, physiological and cerebral metabolic studies was conducted using conscious Sprague-Dawley rats to discern the anti-endothelin (ET) properties of the specific ETA receptor antagonist, FR139317. Endothelin-1 (9 pmol given by injection into one lateral ventricle, i.c.v.) produced convulsions, acute arterial hypertension, arterial hyperglycemia, and hyperventilation. Brain structures close to the i.c.v. site of injection, such as the caudate nucleus, lateral septal nucleus, corpus callosum and hippocampal CA3 medial lamellae, as well as 14 other individual structures, displayed moderate-to-intense levels of metabolic activation after endothelin. Data were assessed quantitatively by means of the autoradiographic [14C]deoxyglucose technique combined with image analysis. Neural circuits in the efferent projection paths of the stimulated forebrain structures, such as the midbrain oculomotor complex, amygdaloid nuclei, substantia nigra pars reticulata and caudal subicular subregions of the hippocampal formation, were stimulated focally by endothelin. Specific medullary nuclei and cerebellar cortical subregions displayed high rates of glucose metabolism following endothelin injection at the time of maximum behavioral and physiological stimulation. I.c.v. treatment with > or = 14 nmol FR139317 before endothelin significantly inhibited the effects produced by the peptide. At the highest dose of FR139317 (28 nmol), there was only mild behavioral stimulation following endothelin injection, and hypermetabolic responses in the brain were abolished except in two specific areas of the cerebellar cortex (approx 40% increases in metabolic activity in the copula pyramis and paramedian lobule). The results indicate that the cerebral stimulatory effects of i.c.v. endothelin are mediated by the A type of endothelin receptor. By itself, i.c.v. FR139317 had no effects on the parameters assessed. Further evaluation of FR139317 is warranted as a possible therapeutic agent for neuropathologies suspected of deriving from central neural or vascular stimulation by endothelin, such as aneurysmal vasospasm, ischemia, excitotoxicity, and peptide-mediated epilepsies.

Animals↗
PubMed1993

A computational model of the HBK2 potassium channel ion pore.

A computational model of the putative ion pore region of the HBK2 potassium channel was developed. Utilizing experimentally derived constraints, conformations corresponding to both the open and closed states of the ion pore were determined. Also, a conformational basis for the different sensitivites of the internal and external tetraethylammonium binding sites has been proposed. The model presented here suggests a role for other regions of the HBK2 protein in determining the ion pore conformation.

Amino Acid Sequence↗
PubMed1993

Calcium-mediated metabolic stimulation of neuroendocrine structures by intraventricular endothelin-1 in conscious rats.

We examined the hypothesis that the vascular- and brain-derived peptide, endothelin-1 (ET), would affect cerebral neuroendocrine structures when administered via the peripheral circulation or via a lateral cerebral ventricle (i.c.v.). ET was infused intravenously (14 nmol/min) or injected i.c.v. (9 pmol) in conscious rats in which local cerebral glucose metabolism was assessed by the quantitative autoradiographic [14C]deoxyglucose technique. Whereas intravenously infused ET was previously demonstrated to selectively stimulate metabolic activity in the pituitary intermediate and anterior lobes of conscious rats, it was without effect in 20 individual structures or subnuclei involved in neuroendocrine functions, including several circumventricular organs. Intraventricular ET, however, caused hypermetabolic responses in 9 neuroendocrine structures, including the pineal gland, subfornical organ, median eminence, the hypothalamic paraventricular and supraoptic nuclei, and other hypothalamic and preoptic structures. The metabolic stimulation resulting from central ET was abolished or attenuated regionally by i.c.v. pretreatment with the calcium L-channel inhibitor, nimodipine. The findings indicate that i.c.v. ET elicits a calcium-mediated hypermetabolic effect on several neuroendocrine structures in the forebrain involved in the regulation of fluid homeostasis, the cardiovascular system, and body temperature.

Animals↗
PubMed1993

Potent metabolic stimulation of septal gray and cerebral white matter in vivo by intraventricular endothelin and nitric oxide.

Endothelin-1 (ET) and sodium nitroprusside (SNP, which liberates nitric oxide, NO) were given alone or together into a lateral cerebral ventricle (icv) of anesthetized rats to assess their potential interaction on cerebral rates of glucose metabolism (autoradiographic [14C]deoxyglucose technique). ET (9 pmol) produced hypermetabolic effects ipsilaterally in the septal nuclei and periventricular white matter. NO lesioned the septum, which displayed neuronal damage and diminished metabolic activity, and evoked potent increases in glucose metabolism bilaterally in commissural and projection white matter tracts. Together, ET and NO had synergistic hypermetabolic effects in the hippocampal fimbria, but were antagonistic on the metabolic rate of the lateral septal nucleus and choroid plexus. The results reveal an extraordinary sensitivity in the metabolic rate of septal gray matter to ET and of white matter fibers to NO in vivo. Icv administration offers a useful approach for examination of the metabolic and toxicological properties of the novel neurotransmitter substances ET and NO on septal neurons, myelinated fibers, and choroidal epithelia.

Animals↗
PubMed1993

Metabolic and neuroanatomical correlates of barrel-rolling and oculoclonic convulsions induced by intraventricular endothelin-1: a novel peptidergic signaling mechanism in visuovestibular and oculomotor regulation?

The neuroactive peptide endothelin-1 has receptors distributed abundantly among subdivisions and nuclei of the visuovestibular and oculomotor systems. In previous work, we and others described the convulsive manifestations resulting from central injection of this neuropeptide, including nystagmus, oculoclonus, exophthalmos, tonic hindlimb extension, and a generalized repetitive motor disturbance called barrel-rolling. We applied the quantitative, autoradiographic [14C]deoxyglucose method to examine the hypothesis that visuovestibular and oculomotor structures would become metabolically stimulated when endothelin was introduced into the brain via the ventricular system in conscious rats. Since previous work had demonstrated that hypermetabolic responses to endothelin in other neural systems were inhibited by an antagonist of neuronal calcium L-type channels, nimodipine, we further tested whether the increased function of vestibulooculomotor nuclei whose metabolic activity was sensitive to endothelin could be altered following nimodipine pretreatment via the ventricle. A single unilateral injection of endothelin (9 pmol in 3 microliters saline) into a lateral ventricle provoked significantly increased rates of glucose metabolism in 22 of 39 individual anatomical structures of the visuovestibular and oculomotor systems. Among those affected were the superficial stratum of the caudal superior colliculus (+25%), the optic tract bilaterally (+35 to 43%), the oculomotor cranial nerve nuclei (III, IV, VI; range of +21 to 47%), and the medial terminal nucleus of the accessory optic tract which harbors dense fields of endothelin binding sites (bilateral increase of +70 to 96%). Several other nuclei involved in the proprioceptive and visuovestibular disturbance caused by endothelin displayed increased metabolic activity, including the cuneate, gracile, sensory trigeminal, and prepositus hypoglossal nuclei, the vestibular subnuclear system, and the cerebellar flocculus. Identification of hypermetabolic responsivity to endothelin in these structures provides further information on the anatomical substrates mediating the behavioral phenomenology of endothelin-induced motor convulsions which involve the paroxysmal participation of the extraocular muscles and motor control systems producing barrel-rolling convulsions. Nimodipine pretreatment inhibited both the convulsive activity and the cerebral hypermetabolic responses to intraventricular endothelin. The results indicate that the neural systems sensitive to intraventricular endothelin become functionally active via a calcium-mediated process that may involve the neuropeptide as an intrinsic signaling molecule.

Animals↗
PubMed1993

Mechanisms of post-traumatic seizures: a quantum pharmacological analysis of the molecular properties of an epileptogenic focus following iron-induced membrane peroxidation.

Late post-traumatic epilepsy following severe head trauma has been well documented. While there is increasing evidence suggesting that iron-induced lipid peroxidation of neural membranes may accompany cerebral haemorrhage, the pathogenic processes of post-traumatic epileptogenesis remain unknown. Furthermore, the effective prophylactic use of standard anticonvulsant drugs is unsubstantiated. The rational design of therapeutic agents specific for the prevention and treatment of post-traumatic epilepsy hinges on understanding the molecular membrane events at the epileptogenic focus. This study employs the techniques of theoretical quantum pharmacology to provide a structural analysis of neural phospholipid membranes, investigating changes in membrane integrity at the epileptogenic focus as the molecular basis for seizure activity. Molecular mechanics calculations and molecular dynamics simulations were used to model the biochemical events of the epileptogenic focus. We predict that applications of quantum pharmacological techniques to model biochemical events may provide an understanding of proconvulsive pathogenic mechanisms in post-traumatic epilepsy.

Aspartic Acid↗
PubMed1993

A new experimental model of epilepsy based on the intraventricular injection of endothelin.

Injection of endothelin-1 (ET-1, 9 pmol) into a lateral cerebral ventricle (LCV) of rats produces barrel-rolling and other convulsive signs that resemble those of generalized seizures in some types of epilepsy. Using the quantitative autoradiographic [14C]deoxyglucose technique, we documented that the neuroanatomical metabolic correlates of the ET-1-induced convulsions in rats are high rates of glucose utilization by structures near the site of LCV injection and throughout a diverse circuit of anatomically related brain regions. We speculate that this circuitry connects the caudate nucleus (putative site of initial stimulation in the forebrain) to the paramedian lobule and vermis of the caudal cerebellar cortex in the hindbrain. We evaluated the behavioral, physiological, and hypermetabolic responses to central ET-1 in the presence of three agents with anticonvulsant properties, providing clues about the cellular mechanisms of this convulsive and hypermetabolic state. Intraventricular MK-801 [a noncompetitive antagonist of glutamic acid N-methyl-D-aspartate (NMDA) receptors], nimodipine (an antagonist of dihydropyridine-sensitive, voltage-gated calcium L-channels), or methylene blue (an inhibitor of guanylate cyclase, the enzyme on which nitric oxide acts) each produced significant attenuation of the behavioral and cerebral metabolic activation. The results introduce several quantitative parameters for an experimental model of employing intraventricular ET-1 in rats to study mechanisms of peptidergic convulsive disorders and the efficacies of promising anticonvulsant compounds in the treatment of epilepsy.

Animals↗
PubMed1993

Theoretical conformational analyses of endothelin-1 in vacuum, aqueous, and lipid environments.

Endothelin-1 (ET-1) is a flexible molecule capable of existing in multiple shapes (conformations) depending on the surrounding molecular solvation. The conformational diversity of ET-1 was studied in three solvation spheres (gas phase, aqueous, and membrane lipid) with the new evolving biotechnology of computational biomolecular simulation. Simulations were performed using a combination of molecular mechanics, molecular dynamics, and semiempirical quantum mechanics calculations in a RISC architecture large-scale computing environment. Marked differences between the gas phase "folded" conformation and the membrane lipid "extended" conformation were identified.

Chemical Phenomena↗
PubMed1992

Cerebral hypermetabolism produced by intraventricular endothelin-1 in rats: inhibition by nimodipine.

Injection of endothelin-1 (9 pmol) into the lateral cerebral ventricle of rats produced barrel-rotations, convulsions, tonic hindlimb extensions, facial clonus, and kinetic ataxia for up to 45 min. Quantitative metabolic autoradiographs produced from the [14C]deoxyglucose method and analyzed over 60 individual brain structures or subregions revealed intense hypermetabolism in periventricular tissues close to the injection site and in many of their efferent projection sites. Histological examination of these areas proved that this dose of endothelin was without toxic or ischemic effects on neurons or glial cells. Structures metabolically affected ipsilateral to injection were caudate nucleus (+164%), lateral septal nucleus (+270%), and two white matter tracts--corpus callosum (+236%) and hippocampal fimbria (+318%). Distant stimulated structures included cerebellar cortical layers, but not cerebellar nuclei or white matter. Increased rates of glucose metabolism among many other nuclei, particularly distinct subunits of the hippocampal formation and structures in contact with the ventricular system, signify that endothelin induced widespread metabolic stimulation over much of the neuraxis. Furthermore, although the 9 pmol concentration of endothelin produced convulsive movements and diverse metabolic stimulation, it did not evoke detectable electroencephalographic seizure activity assessed by intra- or extracerebral electroencephalography. Both the convulsions and hypermetabolic activation were inhibited by intraventricular pretreatment with the dihydropyridine calcium-channel antagonist, nimodipine. The results identify endothelin-1 as a calcium-mediated 'convulsive' peptide with selective stimulatory effects on cerebral glucose metabolism.

Animals↗
PubMed1992

Intraventricular endothelin-1 uncouples the blood flow: metabolism relationship in periventricular structures of the rat brain: involvement of L-type calcium channels.

Endothelin-1 (ET) produces contraction of cerebral resistance vessels in vitro and in situ, but also is neuroactive causing increases in tissue energy metabolism as measured by [14C]deoxyglucose autoradiography in the intact rat brain. ET may, therefore, disengage the normally tight linkage between cerebral blood flow and tissue metabolism. Using anatomically rigorous autoradiographic and imaging techniques to measure focal blood flow in anesthetized, ventilated rats, we found that intraventricular injection of 9 pmol of ET reduced rates of perfusion by an average of 29% (compared to a saline-injected condition) in 6 individual periventricular structures bordering the injected lateral ventricle. A significant vasoconstrictor effect (41% decrease in blood flow) also occurred in the ipsilateral choroid plexus after ET injection, despite its increased rate of glucose metabolism. We employed a hydrogen clearance method to monitor rates of blood flow serially within the periventricular margin of the caudate nucleus after intraventricular injection of the dihydropyridine calcium-channel antagonist, nimodipine (72 nmol), or 9 pmol ET, alone and in sequence. Nimodipine increased caudate blood flow (by 47%) and prevented the vasoconstriction produced by ET. The results indicate that ET causes vasoconstriction in penventricular brain structures and choroid plexus even in the presence of substantial increases in glucose metabolism. The simultaneous stimulation by intraventricular ET of tissue hypermetabolic and vascular constrictor mechanisms, leading to a net reduction of periventricular blood flow, is mediated, at least in part, by dihydropyridine-sensitive calcium L-channels.

Anesthesia↗
PubMed1992

Applications of molecular physics 'biotechnology' to the rational design of an improved phenytoin analogue.

This study exploits molecular physics, in conjunction with a large scale computing environment, as a tool for understanding the clinical phenomenology of phenytoin (PHT) toxicology at a molecular level and for employing this understanding in an attempt to design improved drugs. The application of molecular physics techniques, such as quantum mechanics and molecular force field calculations, to the process of rational anticonvulsant drug design remains virtually unexplored. A 3-step strategy for applying these techniques to the design of an improved PHT molecule is presented. Step 1 employs quantitative structure-activity relationship calculations on 80 PHT analogues to ascertain the portion of the PHT molecule necessary for bioactivity (i.e. the 'bioactive face' of PHT); the N3-C4(O)-C5-R fragment of PHT was identified as the bioactive face. Step 2 employs molecular modelling studies to determine the portion of the PHT molecule necessary for the teratogenic, mutagenic and connective tissue toxicities of PHT (i.e. the 'biotoxic face'); the C2(O)-N3 fragment of PHT was identified as the biotoxic face. Step 3 experiments design an 'improved' PHT analogue, which maintains the bioactive face while eliminating the integrity of the biotoxic face; 2-deoxy-5,5-diphenylhydantoin was designed and synthesized as the improved PHT analogue. This compound had biological activity equivalent to PHT, but was unable to bind to nucleic acids or to chelate metals involved in connective tissue metabolism.

Biotechnology↗
PubMed1992

Aspartame exacerbates EEG spike-wave discharge in children with generalized absence epilepsy: a double-blind controlled study.

There are anecdotal reports of increased seizures in humans after ingestion of aspartame. We studied 10 children with newly diagnosed but untreated generalized absence seizures. Ambulatory cassette recording of EEG allowed quantification of numbers and length of spike-wave discharges in a double-blind study on two consecutive days. On one day the children received 40 mg/kg aspartame and on the other day, a sucrose-sweetened drink. Baseline EEG was the same before aspartame and sucrose. Following aspartame compared with sucrose, the number of spike-wave discharges per hour and mean length of spike-wave discharges increased but not to a statistically significant degree. However, the total duration of spike-wave discharge per hour was significantly increased after aspartame (p = 0.028), with a 40% +/- 17% (SEM) increase in the number of seconds per hour of EEG recording that the children spent in spike-wave discharge. Aspartame appears to exacerbate the amount of EEG spike wave in children with absence seizures. Further studies are needed to establish if this effect occurs at lower doses and in other seizure types.

Adolescent↗
PubMed1990

A pattern recognition study of acyclic ureide anticonvulsants.

A pattern recognition structure-activity study employing topological, geometric and physicochemical descriptors was performed on 27 acyclic ureide anticonvulsants. Twelve numerical descriptors were used as variables in a discriminant function analysis which categorized the ureide analogues with respect to their bioactivity. The results from the discriminant function analysis were interpreted to support a model for antiepileptic activity.

Anticonvulsants↗
PubMed1988

Eosinophil-induced neurotoxicity: axonal neuropathy, cerebral infarction, and dementia.

Although beneficial in allergic and parasitic disease, eosinophils exert nonspecific toxic effects upon host tissues, especially the central and peripheral nervous systems. Eosinophil-induced neurotoxicity is characterized by axonal neuropathy, cerebral infarction, and dementia. Eosinophil-derived cytotoxic proteins are fundamental to the pathogenesis of this disorder.

Adult↗
PubMed1988

Massive carbamazepine overdose: clinical and pharmacologic observations in five episodes.

We report five episodes of carbamazepine (CBZ) intoxication in four patients. Clinically, there were four distinct stages: I--coma, seizures (CBZ levels more than 25 micrograms/ml [105 mumol/l]); II--combativeness, hallucinations, choreiform movements (15 to 25 micrograms/ml [65 to 105 mumol/l]); III--drowsiness, ataxia (11 to 15 micrograms/ml [45 to 65 mumol/l]); and IV--potentially catastrophic relapse (less than 11 micrograms/ml [45 mumol/l]). Pharmacokinetic studies revealed a prolongation of the CBZ half-life, elevation of the CBZ-epoxide/CBZ ratio, and emergence of CBZ-epoxide as a significant toxic metabolite. A treatment approach is proposed including repeated gastric lavage, detection of an insoluble tablet coagulum, electrolyte monitoring, avoidance of cathartics, and treatment of seizures with diazepam and phenytoin.

Adolescent↗