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Biomedical subjects

K Gale

Publications and source records attributed to K Gale.

At least 37 records · Page 2Linked to original sources
PubMed1997

A crucial role of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptors in piriform and perirhinal cortex for the initiation and propagation of limbic motor seizures.

The role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in the initiation and propagation of limbic motor seizures in rats was examined by the intracerebral and systemic administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (f) quinoxaline (NBQX), a selective antagonist of the AMPA subtype of glutamate receptor. Limbic motor seizures were evoked focally by the application of the gamma-aminobutyric acid receptor antagonist, bicuculline, into area tempestas, an epileptogenic site in the deep anterior piriform cortex. Before eliciting seizures, NBQX was applied focally into either 1) area tempestas or 2) perirhinal or posterior piriform cortex ipsilateral to the area tempestas from which seizures were evoked. In addition, pretreatment with i.p. NBQX was evaluated for anticonvulsant actions against area tempestas-evoked clonic or systemically evoked tonic seizures. In all conditions, a dose-dependent decrease in the severity of seizures was obtained with NBQX. With focal intracerebral administration, a dose of 500 pmol of NBQX consistently protected against limbic motor seizures, with partial protection achieved with 100 pmol. After i.p. administration, 2.5 and 5.0 mg/kg significantly protected the rats from both limbic motor seizures and tonic extensor seizures. No overt disturbance of spontaneous behavior was associated with the anticonvulsant doses of NBQX. Moreover, both forebrain substrates of limbic motor seizures and hindbrain substrates of tonic extensor seizures were highly susceptible to disruption by NBQX. The results indicate that AMPA subtype of glutamate receptors are crucial mediators of seizure propagation via perirhinal and piriform cortics.

Animals↗
PubMed1997

Factor VIII Ise (R2159C) in a patient with mild hemophilia A, an abnormal factor VIII with retention of function but modification of C2 epitopes.

We found a patient with mild hemophilia A who had no detectable factor VIII antigen (FVIII:Ag), as shown by two-site ELISA using inhibitor alloantibodies (TK). We then analyzed A2, A2/B, and C2 antigen of the patient's DDAVP-induced FVIII using several anti-FVIII monoclonal antibodies. Factor VIII activity (FVIII:C) was increased from 12 to 42 U/dl by the administration of DDAVP. The DDAVP-induced increases in the A2 and A2/B antigens were 40 and 36 U/dl, respectively. However, the increase in the C2 antigen was only 7.5 U/dl. SSCP analysis and subsequent sequencing demonstrated an Arg to Cys transition at codon 2159. The anti-FVIII:C titer of monoclonal antibody, NMC-VIII/5 which recognized the C2 domain, against normal plasma was 450 Bethesda U/mg of IgG. However, the titer against DDAVP-treated patient's plasma was only 15 Bethesda U/mg. We also tested DDAVP-induced increase in the FVIII:Ag in another mild hemophilia A patient with the same mutation at Arg2159. Increase in his C2 antigen levels was only 19% of those in the A2 and A2/B antigen. We designate this abnormal FVIII as FVIII Ise. Our results show that a missense mutation at Arg2159 to Cys modifies the antigenicity of the C2 domain.

Adolescent↗
PubMed1996

The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin.

Fluoxetine, a serotonin (5-HT) reuptake inhibitor, has been documented to exert a protective action against convulsive seizures in animal models, when administered either systemically, or focally into substantia nigra. It is likely that the mechanism of anticonvulsant action of fluoxetine is due to an enhancement of endogenous 5-HT transmission. To evaluate this possibility in the context of the anticonvulsant action of intranigral fluoxetine, we examined the influence of 5-HT-mediated transmission in substantia nigra on seizure susceptibility in a rat model of focally evoked complex partial seizures. In addition to fluoxetine (3.5 nmol), we found that the directly acting 5-HT receptor agonists, 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (10 nmol), 1-(3-chlorophenyl)piperazine (m-CPP) (7.4 nmol), gepirone (70 nmol) and 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) (10 nmol), when microinjected bilaterally into substantia nigra, protected rats from limbic motor seizures evoked focally from area tempestas, an epileptogenic site in the deep rostral piriform cortex. This indicates that multiple 5-HT receptor subtypes in substantia nigra may contribute to seizure regulation. Consistent with this, the 5-HT antagonist, metergoline, partially reversed the anticonvulsant action of intranigral fluoxetine. Depletion of endogenous 5-HT, by pretreatment with parachlorophenylalanine (PCPA), completely prevented the anticonvulsant action of intranigral fluoxetine, without modifying the anticonvulsant effect of intranigral TFMPP. These findings support the proposal that the anticonvulsant action of fluoxetine in substantia nigra is due to an enhancement of the synaptic action of endogenous 5-HT in substantia nigra which in turn is mediated via multiple 5-HT receptors. Endogenous 5-HT transmission in substantia nigra is therefore capable of limiting the development and propagation of seizure activity generated in limbic circuits.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

The stem cell antigen CD34 functions as a regulator of hemopoietic cell adhesion.

Although the CD34 antigen is widely used in the identification and purification of hemopoietic stem and progenitor cells, its function within hemopoiesis is unknown. We have investigated this issue by ectopically expressing human (hu) CD34 on the surface of murine hemopoietic cells. Forced expression of hu-CD34 in the thymocytes of transgenic mice did not appear to affect the development, maturation, or distribution of murine T cells but did significantly increase their ability to adhere to bone marrow stromal layers of human but not mouse origin. Ectopic expression of hu-CD34 on murine 416B cells, a multipotential progenitor that expresses murine CD34, yielded similar results. In both cases hu-CD34-dependent adhesion was enhanced by molecular engagement of the hu-CD34 protein using anti-CD34 antibodies. These results provide evidence that CD34 promotes the adhesive interactions of hemopoietic cells with the stromal microenvironment of the bone marrow thereby implicating CD34 in regulation and compartmentalization of stem cells. We propose that CD34 regulates these processes in part via an indirect mechanism, signaling changes in cellular adhesion in response to molecular recognition of an as yet unidentified stromal CD34 counterreceptor or ligand.

Animals↗
PubMed1995

Activation of tyrosine hydroxylase by haloperidol in fetal nigral transplants.

Release of dopamine (DA) from the terminals of solid fetal mesencephalic grafts has been shown to be modulated by DA receptor activity. In order to determine whether DA synthesis in the terminals of these grafts is regulated by the host, we examined the activity of tyrosine hydroxylase (TH), the rate limiting enzyme in the synthesis of dopamine, after blockade of DA receptors with haloperidol (HAL). Solid fetal mesencephalic tissue was grafted over the dorsal surface of the striatum, ipsilateral to a 6-hydroxydopamine lesion in the medial forebrain bundle. Systemic administration of HAL caused an activation of TH in the transplant terminals, reflected by an increased affinity of TH for the pteridine cofactor. Our results indicate that a transneuronal feedback mechanism similar to that operating in the intact nigrostriatal system is regulating DA synthesis and utilization in the terminals of the transplant.

Animals↗
PubMed1995

Biochemical folate, B12, and iron status of a group of pregnant adolescents accessed through the public health system in southern Ontario.

PURPOSE: This study was designed to estimate the prevalence of biochemical iron, folate, and vitamin B12 depletion among a group of Canadian pregnant adolescents accessed through the Public Health system. Further, the impact of prenatal supplement use, chronologic age, gynecologic age, living arrangement, main source of income, postpartum custody plan, time of entry into prenatal care, and cigarette smoking on laboratory indices of the three nutrients were determined. METHODS: Fifty-eight adolescents (14.5-19.0 years) were interviewed and blood samples were collected at 36 +/- 2 wk gestation. RESULTS: Thirteen (22%) of the pregnant adolescents had anemia (hemoglobin < 110 g/L) and forty-five (78%) had depleted iron stores (plasma ferritin < 26.6 pmol/L or 12.0 micrograms/L). Twenty-five subjects had plasma B12 values in the sub-optimal range (< 148 pmol/L). Five of the 16 adolescents who infrequently or never consumed a folate-containing supplement had suboptimal erythrocyte folate values. Twenty-four percent of the subjects had hypersegmented neutrophils and of these, all and 71% of subjects had plasma ferritin and B12 concentrations in the suboptimal range, respectively. Self-reported folic acid and B12 supplement intakes were correlated with the corresponding blood values for these nutrients. In contrast, supplement iron use was only weakly, or not at all associated with biochemical indices of iron status. CONCLUSIONS: Data from the present study indicate that plasma B12 and ferritin levels are low in a group of pregnant adolescents. These low values appear to be associated with a high prevalence of hypersegmented neutrophils. Prenatal supplement use appears to reduce the risk of low folate and B12 blood values but not biochemical iron status.

Adolescent↗
PubMed1994

Posterior piriform and perirhinal cortex relay seizures evoked from the area tempestas: role of excitatory and inhibitory amino acid receptors.

The functional relationship between the area tempestas (AT), an epileptogenic site within the deep prepiriform cortex, and the regions in the posterior piriform cortex which are innervated by AT, were studied in the rat. The GABAA receptor agonist, muscimol (390 pmol) was microinjected unilaterally into the posterior piriform cortex and adjacent regions in the same hemisphere from which seizures were evoked by focal application of bicuculline into AT. Pretreatment with muscimol into either the ventral posterior piriform cortex or perirhinal cortex, protected against the bilateral clonic seizures evoked from the ipsilateral AT. No seizure protection was obtained when muscimol was placed into adjacent areas of amygdala, entorhinal cortex, neocortex and ventral hippocampus. Seizure protection was also obtained when kynurenic acid, but not 2-amino-7-phosphonoheptanoic acid, was microinjected into the ventral posterior piriform cortex, suggesting that glutamate transmission mediated via non-N-methyl-D-aspartate (non-NMDA) receptors is required for the relay of seizure discharge through this region. Our data indicate that a specific region of the temporal cortex, the posterior piriform and perirhinal area, functions as a critical link in the propagation of limbic seizures evoked from AT.

2-Amino-5-phosphonovalerate↗
PubMed1994

Focal intracerebral elevation of L-lactate is anticonvulsant.

Sodium lactate (pH 7.0) infused over the area tempestas, an epileptogenic site in the prepiriform cortex, protected rats from limbic motor seizures induced by infusion of a GABA receptor antagonist in area tempestas. The anticonvulsant action, which was anatomically site-specific and reversible, persisted for 90 min. Infusions of sodium acetate (pH 5.5 or 7.0) over area tempestas were not anticonvulsant. Our findings suggest that lactate can modulate neural activity and that increased cerebral lactate as occurs with epileptic seizures, may limit the duration and spread of seizure activity.

Animals↗
PubMed1994

Unilateral destruction of dopamine pathways increases ipsilateral striatal serotonin turnover in rats.

In order to evaluate the influence of dopaminergic transmission on regional brain utilization of serotonin (5HT), the effects of the destruction of the ascending dopamine (DA) pathways on regional brain 5HT metabolism in the rat were examined. Complete unilateral lesions of the nigrostriatal DA pathways (> 90% DA loss) were made by infusing the neurotoxin 6-hydroxy-dopamine into either the left medial forebrain bundle (MFB) or the left substantia nigra (SN). At 6 weeks after the lesions, levels of 5HT and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined bilaterally in the striatum, frontal cortex, and hypothalamus. In the striatum of the lesioned hemisphere, the 5HT level decreased by more than 50%, while the ratio of 5HIAA:5HT (an index of 5HT turnover) increased by more than 90%. In the same rats, cortical and hypothalamic 5HT, 5HIAA, and 5HT turnover were not changed as a result of the MFB or SN lesions. These results suggest that the loss of DA innervation in the striatum triggers an increase in 5HT turnover and a net depletion of 5HT in the striatum. To verify that the loss of DA was responsible for the observed striatal 5HT changes, we examined the effect of intracerebral implantation of DA-containing pellets into one group of MFB-lesioned rats. The lesioned rats with placebo pellets did not differ from lesioned rats without pellets, whereas the implantation of DA pellets reversed the lesion-induced changes in the 5HT levels and 5HIAA:5HT ratios.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Regional and temporal pattern of expression of nerve growth factor and basic fibroblast growth factor mRNA in rat brain following electroconvulsive shock.

We have previously reported that focally evoked limbic motor seizures rapidly increase levels of mRNA encoding nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) in specific limbic system areas of the adult rat brain. The present studies examined the effect of both minimal and maximal electroconvulsive shock, applied via corneal electrodes, on NGF and bFGF mRNA levels in several limbic (entorhinal cortex, hippocampus, olfactory bulb) and extralimbic (striatum and cerebellum) brain regions. By 5 h following limbic motor seizures induced by low-intensity (minimal) electroshock (LES) (0.2 s, 50-70 mA; three times over a 1-h period), bFGF mRNA was significantly increased in entorhinal cortex and hippocampus, but not in the other regions examined. In contrast, tonic extensor seizures evoked by maximal electroshock (MES) (0.2 s, 150 mA; three times over a 1-h period) were associated with a significant increase in bFGF mRNA in all limbic and extralimbic regions examined. In the same animals, increases in NGF mRNA were limited to entorhinal cortex and hippocampus. Adrenal steroids were not required for the seizure-induced increase in NGF or bFGF mRNAs, based on the finding that adrenalectomized rats exhibited electroshock-induced increases in both NGF and bFGF mRNAs equivalent to the increase observed in sham-operated rats. It is suggested that the increase in mRNA levels for the neurotrophic factors occurs selectively in those regions which are especially activated by the specific seizure model, and represents an adaptive response to repeated noninjurious neuronal stimulation.

Adrenalectomy↗
PubMed1993

Blockade of GABA receptors in superior colliculus protects against focally evoked limbic motor seizures.

Blockade of GABA receptors in the rat superior colliculus (SC) has been shown to protect against maximal electroshock-induced tonic convulsions and spontaneous generalized non-convulsive seizures. In the present study, we determined that blockade of GABA receptors in SC could also protect against focally evoked limbic motor seizures. Limbic motor seizures were induced by the unilateral focal application of bicuculline methiodide into area tempestas (AT), an epileptogenic site in the deep prepiriform cortex. Control rats (receiving bilateral infusions of saline into SC) all exhibited convulsive seizures following bicuculline in AT. Rats pretreated (5 min before) with bicuculline (50 pmol) bilaterally in the deep layers of the SC, were protected against the AT-evoked convulsive seizures. Unilateral application of bicuculline in the deep SC or bilateral application in the superficial layers of the SC did not alter the convulsive response to bicuculline in AT. These results indicate that the anticonvulsant action of GABA blockade in SC is not limited to tonic convulsive seizures but extends to the clonic manifestations evoked by seizures originating in forebrain limbic circuits. Given that the deep layers of SC receive inputs from GABA neurons in substantia nigra and that suppression of the activity of nigral neurons is anticonvulsant against a variety of seizures (including those evoked from AT), it is likely that the anticonvulsant action of bicuculline in SC is due to interference with the influence of a nigrotectal GABAergic projection.

Animals↗
PubMed1993

Expression of c-fos mRNA following seizures evoked from an epileptogenic site in the deep prepiriform cortex: regional distribution in brain as shown by in situ hybridization.

Using in situ hybridization histochemistry for the detection of c-fos mRNA, we examined the pathways activated by seizures evoked by a focal application of bicuculline into a highly discrete epileptogenic site in the deep prepiriform cortex, the area tempestas (AT). Thirty minutes after the initiation of limbic motor seizures evoked by bicuculline in AT, a marked increase in c-fos mRNA was detected in the hippocampal formation, amygdala, olfactory bulb, piriform cortex, and entorhinal cortex. The increase of c-fos mRNA was strictly dependent upon the infusion of the drug in AT. Infusions of bicuculline in the same dose outside the AT did not increase c-fos mRNA levels. The extent to which the mapping pattern of c-fos mRNA expression was specific to limbic seizures was evaluated by examining another focally evoked seizure model involving the application of bicuculline bilaterally into the inferior colliculus. The absence of any detectable c-fos induction in the limbic system after explosive running-bouncing clonic seizures evoked by bicuculline injected into the inferior colliculus indicates that the pattern of activation that we found in the AT-evoked seizure model is not common to all forms of convulsive activity. Furthermore these observations suggest that the pattern of activation we have observed is seizure dependent and not stress induced. Our results indicate that c-fos mRNA expression is useful in the functional mapping of pathways involved in seizure propagation and that the anatomic pattern of activation is selectively related to the type of seizure evoked.

Animals↗
PubMed1993

Temporal and spatial patterns of expression of c-fos, zif/268, c-jun and jun-B mRNAs in rat brain following seizures evoked focally from the deep prepiriform cortex.

Using in situ hybridization, we previously investigated (17) the regional pattern of c-fos mRNA increases in the brain following convulsive seizures elicited from a highly circumscribed epileptogenic site located in the deep prepiriform cortex. In this paper, we focus on the hippocampus and examine mRNAs encoding other immediate early genes (IEGs), namely c-jun, jun-B, and zif/268, for changes following the focally evoked seizures. Although the anatomic distribution of increases in each IEG mRNA was qualitatively comparable, the temporal analysis indicated that increases in zif/268 mRNA appeared prior to the other genes studied. Each of the mRNAs reached a maximum increase by 30 min and declined to basal levels within 3 h following seizure initiation. The data indicate that these four IEGs respond in a coordinated fashion to propagated seizure activity with increases in mRNA and, furthermore, that increased expression of all four genes appears to occur in the same cell types in the hippocampus.

Animals↗
PubMed1992

Anticonvulsant effect of intranigral fluoxetine.

Bilateral focal injections of the serotonin uptake inhibitor, fluoxetine (1.75-7.0 nmol) into substantia nigra (SN) protected against convulsive seizures evoked by the focal injection of bicuculline methiodide into area tempestas, an epileptogenic site within the deep prepiriform cortex. Injection of fluoxetine unilaterally in SN or bilaterally into a site dorsal to SN was not anticonvulsant. Blockade of nigral gamma-aminobutyric acid (GABA) receptors with bicuculline in SN did not reverse the anticonvulsant action of intranigral fluoxetine. These data suggest that serotonergic transmission in SN exerts a seizure suppressing action which is independent of GABA transmission in SN.

Animals↗
PubMed1992

A rodent model of focally evoked self-sustaining status epilepticus.

We describe a novel model of status epilepticus produced by the focal application of bicuculline methiodide into the deep prepiriform cortex of rats pretreated with lithium chloride. Three out of eight rats pretreated with one dose of lithium (3 mmol/kg) 24 h prior to induction of seizures by focal bicuculline, and eight out of 12 rats pretreated with two doses of lithium (at 24 and 48 h) prior to seizure induction, exhibited continual uninterrupted convulsive seizure activity (status epilepticus) lasting between 10 min and > 2 h. This status epilepticus which was manifest both behaviorally and electroencephalographically, was sensitive to reversal by diazepam (5 mg/kg i.p.) given as long as 2 h after the onset of sustained status epilepticus. Pilocarpine (25 mg/kg) pretreatment also predisposed to status epilepticus in response to the focal application of bicuculline, but diazepam (5 or 10 mg/kg i.p.) was ineffective in suppressing the status epilepticus in the presence of pilocarpine.

Animals↗
PubMed1992

Basic fibroblast growth factor mRNA increases in specific brain regions following convulsive seizures.

Basic fibroblast growth factor (bFGF) is a trophic factor synthesized in the central nervous system (CNS), where it is believed to play a role in neuronal maintenance and repair. Little is known about the regulation of this growth factor in the CNS. To determine whether the expression of the bFGF gene in the brain of adult animals changes in response to alterations of neuronal activity, we examined bFGF mRNA levels in several brain regions of rats experiencing focally-evoked convulsive seizures. Seizures were induced by microinjecting bicuculline unilaterally into an epileptogenic site within the deep prepiriform cortex, area tempestas (AT). By 5 h after initiation of brief limbic motor seizures from AT, there was a four fold increase in the levels of bFGF mRNA in the entorhinal cortex, hippocampus and olfactory bulb, but not in the caudate-putamen. The maximal expression of bFGF mRNA was reached by 10 h after seizure onset. In the same animals, the mRNA encoding nerve growth factor (NGF) was increased in entorhinal cortex and hippocampus, but not in the olfactory bulb. Our results demonstrate that neuronal activity can influence bFGF expression in an anatomically selective fashion and that acute changes in bFGF can occur in the uninjured mature brain. The increase in bFGF expression in response to excessive activation of specific neuronal circuitry may represent an adaptive response to protect against potential injury in those circuits.

Animals↗
PubMed1992

Role of GABA in the genesis of chemoconvulsant seizures.

The direct or indirect interference with GABA-mediated neurotransmission results in convulsive seizure activity in humans and experimental animals. When this convulsant effect is experimentally analyzed, it turns out to be a product of discrete and restricted cerebral sites of drug action. Depending upon the brain circuitry affected, different convulsant patterns are produced. Acute interference with GABA transmission in convulsant trigger sites in the forebrain evokes convulsant seizures which can be clearly distinguished from those evoked by interference with GABA transmission in the hindbrain convulsant sites. While acute alterations of forebrain seizure susceptibility do not change hindbrain seizure susceptibility, chronic or repeated exposure to seizures may cause simultaneous "kindling" of both systems. In addition to the specific convulsant sites of action of GABA antagonists in the brain there are specific sites where GABA antagonists exert an anticonvulsant action. The ability of a chemical agent to evoke a convulsive seizure by interfering with GABA transmission depends upon the relative effect of the agent on GABA transmission in different brain areas as well as its effect on other excitatory and inhibitory neurotransmitters with which GABA interacts.

Animals↗