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Results for “Infusions, Intraventricular”

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PubMed1994

Brain-derived neurotrophic factor protects against ischemic cell damage in rat hippocampus.

The neuroprotective action of brain-derived neurotrophic factor (BDNF) was evaluated in a rat model of transient forebrain ischemia. A continuous intraventricular infusion of BDNF for 7 days starting immediately before the onset of ischemia significantly increased the number of pyramidal cells in the vulnerable CA1 sector of the hippocampus. In situ hybridization experiments suggest the neuroprotection to be mediated via trkB-receptors in the hippocampus. The data indicate a therapeutic potential for the treatment of cerebral ischemia.

Animals↗

PubMed2000

HLA-mismatched CD34-selected stem cell transplant complicated by HHV-6 reactivation in the central nervous system.

We report here a patient who suffered from PCR- confirmed human herpesvirus type 6 (HHV-6) meningoencephalitis after allogeneic purified CD34+ cell transplantation from his HLA-mismatched sibling donor, even though he had been on intense prophylaxis with i.v. ganciclovir (GCV), acyclovir (ACV) and gamma-globulin containing a specific antibody against HHV-6. Serological evaluation disclosed that both the donor and recipient had IgG antibody against HHV-6 before transplantation. His blood WBC count started to transiently increase on day 10, and all blood components had decreased by day 20. He then developed a severe headache and high blood pressure, and sporadic abnormal neurological findings including nystagmus and delirium. An analysis of cerebrospinal fluid (CSF) revealed 8 cells/microl, a glucose level of 130 mg/dl and a protein level of 201 mg/dl (normal, 50 mg/dl) on day 26. At the time, HHV-6 was detected only in CSF by a PCR-based method and he was diagnosed as having meningoencephalitis due to the local reactivation of HHV-6. Although he failed to respond to high-dose therapy with ACV (60 mg/kg/day) and gamma-globulin, the DNA of this virus disappeared from the CNS upon treatment with GCV (30 mg/kg/day) combined with the intraventricular infusion of alpha-interferon. His clinical course was further complicated with meningoencephalitis due to staphylococcus epidermidis, and he died of tentorial herniation on day 79 without the recovery of blood components. This experience may indicate that intense prophylaxis to prevent reactivation of HHV-6 in the CNS is essential for the management of such profoundly immunosuppressed patients.

Acyclovir↗

PubMed2006

The mitochondrial K(ATP) channel opener BMS-191095 reduces neuronal damage after transient focal cerebral ischemia in rats.

Activation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels protects the brain against ischemic or chemical challenge. Unfortunately, the prototype mitoK(ATP) channel opener, diazoxide, has mitoK(ATP) channel-independent actions. We examined the effects of BMS-191095, a novel selective mitoK(ATP) channel opener, on transient ischemia induced by middle cerebral artery occlusion (MCAO) in rats. Male Wister rats were subjected to 90 mins of MCAO. BMS-191095 (25 microg; estimated brain concentration of 40 micromol/L) or vehicle was infused intraventricularly before the onset of ischemia. In addition, the effects of BMS-191095 on plasma and mitochondrial membrane potentials and reactive oxygen species (ROS) production in cultured neurons were examined. Finally, we determined the effects of BMS-191095 on cerebral blood flow (CBF) and potassium currents in cerebrovascular myocytes. Treatment with BMS-191095 24 h before the onset of ischemia reduced total infarct volume by 32% and cortical infarct volume by 38%. However, BMS-191095 administered 30 or 60 mins before MCAO had no effect. The protective effects of BMS-191095 were prevented by co-treatment with 5-hydroxydecanoate (5-HD), a mitoK(ATP) channel antagonist. In cultured neurons, BMS-191095 (40 micromol/L) depolarized the mitochondria without affecting ROS levels, and this effect was inhibited by 5-HD. BMS-191095, similar to the vehicle, caused an unexplained but modest reduction in the CBF. Importantly, BMS-191095 did not affect either the potassium currents in cerebrovascular myocytes or the plasma membrane potential of neurons. Thus, BMS-191095 afforded protection against cerebral ischemia by delayed preconditioning via selective opening of mitoK(ATP) channels and without ROS generation.

Animals↗

PubMed2006

Stroke-induced subventricular zone proliferation is promoted by tumor necrosis factor-alpha-converting enzyme protease activity.

Cerebral stroke induces proliferation of subventricular zone (SVZ) neural progenitor cells in adult rodent brain. Tumor necrosis factor-alpha-converting enzyme (TACE) proteolysis sheds the nonamyloidogenic soluble ectodomain of the amyloid precursor protein (APP) and is a convertase for tumor necrosis factor-alpha (TNFalpha). The resulting soluble peptides of APP and TNFalpha are mitogenic for neural progenitor cells of the SVZ. Therefore, we hypothesized a role for TACE proteolysis in stroke-induced neurogenesis. Using laser-capture microdissection, we found TACE transcription was increased in SVZ cells of ischemic brain. Immunohistochemistry revealed TACE protein was upregulated in SVZ neuroblasts. Intraventricular infusion of tumor necrosis factor-alpha protease inhibitor-2 (TAPI-2) decreased bromodeoxyuridine incorporation in SVZ cells of rats subjected to middle cerebral artery occlusion. Furthermore, primary culture SVZ neurospheres from ischemic brain overexpress TACE and its substrates APP and TNF-alpha. These cells proliferated more rapidly, possessed increased TACE protease-dependent alpha-secretase activity, and released more soluble APP and TNFalpha compared with nonischemic control. In addition, TAPI-2 reduced SVZ neuroblast migration out of SVZ explants in vitro. These findings indicate TACE proteolysis as a promoter of stroke-induced SVZ progenitor cell neurogenesis, and suggest this protease activity may represent an attractive therapeutic target for stroke recovery.

ADAM Proteins↗

PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗

PubMed2000

Neuropsin regulates an early phase of schaffer-collateral long-term potentiation in the murine hippocampus.

We found that neuropsin, an extracellular matrix serine protease, has a regulatory effect on Schaffer-collateral long-term potentiation (LTP) in the mouse hippocampus. Bath application of 1-170 nM recombinant neuropsin modulated early phase LTP in the Schaffer-collateral pathway with a 'bell-shape' dose-response curve. The maximum enhancing activity (134% of control LTP) was found at approximately 2.5 nM. Bath application of a neutralizing antibody against neuropsin in the hippocampal slice resulted in a marked inhibition of the tetanus-induced early phase of LTP. The in vivo continuous intraventricular infusion of an antisense oligonucleotide against neuropsin significantly reduced the amplitude of the tetanus-induced early phase of LTP in vitro. Neuropsin did not directly change the N-methyl D-aspartate (NMDA) current. Thus, neuropsin appears to act as a regulatory molecule in the early phase of LTP via its proteolytic function on extracellular matrix rather than affecting NMDA receptor-mediated calcium increase.

Animals↗

PubMed2003

Enhanced hippocampal noradrenaline and serotonin release in galanin-overexpressing mice after repeated forced swimming test.

Basal and forced swimming (FS) stress-induced release of noradrenaline (NA) and serotonin (5-HT) were determined by in vivo microdialysis in the ventral hippocampus of mice overexpressing galanin under the platelet-derived growth factor B promoter (GalOE/P) or under the dopamine beta-hydroxylase promoter (GalOE/D) (only NA). WT mice served as controls. Intraventricular infusion of galanin significantly reduced basal extracellular NA in WT mice and in GalOE/P mice (albeit less so). Microdialysis sampling during a 10-min FS showed that NA and 5-HT release were elevated to 213% and 156%, respectively, in the GalOE/P group, whereas in the WT group the increases were only 127% and 119%, respectively. The second (repeated) 10-min FS (RFS) caused a marked enhancement of NA and 5-HT release in the GalOE/P mice to 344% and 275%, respectively. However, the RFS caused only a 192% increase of extracellular NA levels in the GalOE/D mice. Pretreatment with the putative peptidergic galanin receptor antagonist M35 almost completely blocked the elevation of NA and 5-HT levels in the GalOE/P after RFS. These results suggest that the NA and 5-HT hippocampal afferents in GalOE/P mice are hypersensitive to both conditioned and unconditioned stressful stimuli, such as FS, and that this effect is mediated by galanin receptors. The present findings support a role of galanin in the regulation of release of NA and 5-HT, two neurotransmitters involved in mood control.

Animals↗

PubMed2006

A carbohydrate-binding protein, Galectin-1, promotes proliferation of adult neural stem cells.

In the subventricular zone of the adult mammalian forebrain, neural stem cells (NSCs) reside and proliferate to generate young neurons. We screened factors that promoted the proliferation of NSCs in vitro by a recently developed proteomics technique, the ProteinChip system. In this screen, we identified a soluble carbohydrate-binding protein, Galectin-1, as a candidate. We show herein that Galectin-1 is expressed in a subset of slowly dividing subventricular zone astrocytes, which includes the NSCs. Based on results from intraventricular infusion experiments and phenotypic analyses of knockout mice, we demonstrate that Galectin-1 is an endogenous factor that promotes the proliferation of NSCs in the adult brain.

Animals↗

PubMed2003

Nitric oxide negatively regulates mammalian adult neurogenesis.

Neural progenitor cells are widespread throughout the adult central nervous system but only give rise to neurons in specific loci. Negative regulators of neurogenesis have therefore been postulated, but none have yet been identified as subserving a significant role in the adult brain. Here we report that nitric oxide (NO) acts as an important negative regulator of cell proliferation in the adult mammalian brain. We used two independent approaches to examine the function of NO in adult neurogenesis. In a pharmacological approach, we suppressed NO production in the rat brain by intraventricular infusion of an NO synthase inhibitor. In a genetic approach, we generated a null mutant neuronal NO synthase knockout mouse line by targeting the exon encoding active center of the enzyme. In both models, the number of new cells generated in neurogenic areas of the adult brain, the olfactory subependyma and the dentate gyrus, was strongly augmented, which indicates that division of neural stem cells in the adult brain is controlled by NO and suggests a strategy for enhancing neurogenesis in the adult central nervous system.

Animals↗

PubMed1978

Sleep-promoting factor S: purification and properties.

Sleep-promoting factor was purified from acid/acetone extracts of whole brains of rabbits and from brainstems of slaughterhouse cattle. Intraventricular infusion of extracts purified by means of ion exchange and gel filtration induced excess slow-wave sleep in rabbits for 5-10 hr. The procedure is simple and provides material suitable for physiological studies. Further treatment by partition chromatography and electrophoresis yielded an active product that was purified at least 1 million-fold. This product was inactivated by incubation with mixed carboxypeptidases A and B. Amino acid analysis of acid hydrolysates indicated that the effective dose was less than 150 pmol per rabbit and the original concentration in brain tissue was of the order of 30 pmol/g of brain.

Animals↗

PubMed1995

A nerve growth factor peptide retards seizure development and inhibits neuronal sprouting in a rat model of epilepsy.

Kindling, an animal model of epilepsy wherein seizures are induced by subcortical electrical stimulation, results in the upregulation of neurotrophin mRNA and protein in the adult rat forebrain and causes mossy fiber sprouting in the hippocampus. Intraventricular infusion of a synthetic peptide mimic of a nerve growth factor domain that interferes with the binding of neurotrophins to their receptors resulted in significant retardation of kindling and inhibition of mossy fiber sprouting. These findings suggest a critical role for neurotrophins in both kindling and kindling-induced synaptic reorganization.

Animals↗

PubMed2004

The effects of decompression and exogenous NGF on compressed cerebral cortex.

Using a rat epidural bead implantation model, we found that compression alone could reduce the overall and individual layer thicknesses of cerebral cortex with no apparent cell death. The dendritic lengths and spine densities of layer II/III and V pyramidal neurons started to decrease within 3 days of compression. Decompression for 14 days resulted in near complete to partial recovery of the cortical thickness and of the dendritic lengths of layer II/III and V pyramidal neurons, depending on the duration of the preceding compression. The recoverability was better following short (3-day) than long (1- or 3-month) periods of compression. The loss of dendritic spines nevertheless persisted. An intraventricular infusion of NGF was performed after decompressing the lesions following 3 days of cortical compression, and this increased the recovery of the spines but not the dendritic length of the cortical pyramidal neurons, nor did it alter the recovery of the cortical thickness. NGF also promoted the increase of the dendritic spines, but not the dendritic length of the cortical pyramidal neurons of normal animals. In short, the data show that a few days of compression alone can cause permanent cortical damage. Exogenous NGF, if applied topically, may restore the dendritic spine density of cortical neurons subjected to compression.

Animals↗

PubMed1995

Nerve growth factor treatment restores [3H]QNB binding site density in adult rat subjected to cortical infarction.

The effects of unilateral cortical devascularization and nerve growth factor treatment on muscarinic cholinoceptors labelled with [3H]QNB were investigated in rat cerebral cortex. The lesion induced a significant ipsilateral decrease in the density (Bmax) but not in the affinity (kD) of [3H]QNB binding sites. Intraventricular infusion of 2.5 S mouse nerve growth factor (NGF) increased the density of binding sites such that Bmax values of lesioned animals treated with NGF were not different from control subjects.

Animals↗

PubMed1994

Comparative effects of fluoxetine, amitriptyline and serotonin on functional motor recovery after sensorimotor cortex injury.

A recent investigation of the effects of the antidepressants desipramine and trazodone on behavioral recovery in brain-injured animals suggested that antidepressants, which act to increase noradrenergic activity in the brain, may facilitate the rate of recovery, whereas those that act to increase serotonergic (5-HT) activity may hinder recovery and reinstate deficits in recovered animals. The present study was designed to evaluate these findings further by assessing the effect of a single intraperitoneal injection of fluoxetine (a relatively pure 5-HT reuptake blocker), amitriptyline (a mixed 5-HT and noradrenergic reuptake blocker with alpha 1-adrenergic receptor blocking activity) or a single intraventricular infusion of 5-HT on recovery of beam-walking ability in animals with a unilateral sensorimotor cortex injury. None of the drugs significantly affected the rate of recovery. Although fluoxetine was ineffective in reinstating the motor deficit in recovered animals, amitriptyline reinstated the deficit in a dose-dependent fashion. Infusion of 5-HT resulted in an extremely transient reinstatement of the deficit, which was largely attributable to its short-term sedative properties. These results suggest that 5-HT may be less involved in functional recovery than previously thought. They also add further support to previous findings that indicate that drugs which act to antagonize alpha 1-adrenergic activity (e.g., phenoxybenzamine) may interfere with motor recovery after sensorimotor cortex injury. An appreciation of the potential impact of certain antidepressants on functional recovery in brain-injured patients appears warranted.

Amitriptyline↗

PubMed1990

Indium-111 DTPA flow study to evaluate surgically implanted drug pump delivery system.

The authors describe a radionuclide technique for evaluating intrathecal and intraventricular infusions by surgically implanted drug pump delivery systems. Sixteen patients underwent flow studies, performed by injecting 500 mu Ci of indium-111 DTPA into the pumps. Early and delayed images were obtained. These studies enabled distinction among functioning pumps, nonfunctioning pumps, and obstructed or occluded catheters. We conclude that indium-111 DTPA flow studies provide an excellent way to assess these drug pump delivery systems.

Equipment Failure↗

PubMed1995

NGF deprivation of adult rat brain results in cholinergic hypofunction and selective impairments in spatial learning.

Cholinergic hypofunction has often been correlated with a variety of behavioural impairments. In the present study, adult Wistar rats were intraventricularly infused with antibodies to nerve growth factor (anti-NGF) to examine the effects on cholinergic neurons of the basal forebrain, and on behavioural performance. Immunocytochemical techniques indicated that chronically infused anti-NGF penetrates into the basal forebrain, cortex, striatum, corpus callosum and hippocampus, confirming previous findings after a single injection. Treatment with anti-NGF for 1 or 2 weeks resulted in a significant decrease of 27-33% in density of choline acetyltransferase immunostaining of the cholinergic cell bodies in the medial septum and vertical diagonal band, and a 26% reduction in choline acetyltransferase enzyme activity in the septal area. An array of spatial learning Morris water maze tasks was used to distinguish between acquisition skills and the flexible use of learned information in novel tests. Rats subjected to the spatial learning paradigm received anti-NGF infusion for 2 weeks prior to and for another 2 weeks during the behavioural testing. The anti-NGF-treated animals were found to be no different from those receiving control serum in the Morris water maze acquisition task, either in the latency to find the platform or in the time spent searching in the training quadrant when the platform was removed. However, in consecutive extinction trials, anti-NGF rats continued to search in the empty training quadrant, suggesting the occurrence of perseveration; control rats expanded their search over other areas of the pool.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Mobilization of storage pool dopamine and late ipsilateral augmentation of striatal dopamine synthesis in the trained circling rat.

Rats were infused intraventricularly with [3H]tyrosine over a 20-min period during various times while circling. 3,4-Dihydroxyphenylethylamine (dopamine) and dihydroxyphenylacetic acid (DOPAC) levels were measured using HPLC with electrochemical detection and fractions were collected for tritium monitoring. During the first 20 min of circling, the specific activity of dopamine was increased by 290% in striatum contralateral to the circling direction whereas DOPAC specific activity was increased 50% on the same side. This differential change in relative specific activity suggests that unlabeled storage pool dopamine was mobilized to DOPAC during circling. Synthesis of dopamine and DOPAC in contralateral striatum returned to baseline levels as turning slowed (50-70 min). When turning ceased, there was an increase in ipsilateral striatal dopamine synthesis during the 20-min period following circling. We hypothesize that this ipsilateral increase represents either a "stop" signal following circling or a release of inhibition of ipsilateral nigral neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Relationship of putative nicotinic cholinergic receptors in the suprachiasmatic nucleus to levels of pineal serotonin N-acetyltransferase activity in the normally cycling female, the male, and the ovariectomized rat.

We have examined the nocturnal increase in pineal serotonin N-acetyltransferase (SNAT) activity in the rat and the decrease in activity of this enzyme as a result of exposure of the rats to light during the nocturnal period. In females with normal ovulatory cycles and ovariectomized females, levels of the enzyme were similar during the dark (695 +/- 70 pmol/min/gland vs. 590 +/- 68) or after 20 min of lights on at night (107 +/- 5 vs. 105 +/- 8). Carbachol, a cholinergic agonist, was injected at 2400 hr (EST) into the lateral ventricle of orbitally enucleated rats. The agonist simulated the lights on effect in both intact and ovariectomized rats. Highly purified fractions of alpha-bungarotoxin, a nicotinic cholinergic antagonist were injected into either the third ventricle or bilaterally adjacent to the SCN in intact females, intact males, or ovariectomized rats. These injections had no effect on either the nighttime increase or the lights on inhibition of SNAT. This study makes the following observations: 1) As was previously demonstrated [Illnerova, H. Endocrinol. Exp. 9:141-148, 1975], ovariectomy affects neither the daytime (light period) nor nighttime (dark period) activity of pineal SNAT. This study extends previous work by demonstrating that ovariectomy also has no effect on the lights on at night decrease of SNAT activity. 2) This study confirms that intraventricular infusion of carbachol decreases the nocturnal pineal SNAT activity [Zatz, M., and Brownstein, M.J. Brain Res. 213:438-442, 1981]. 3) This study does not confirm the report that the nicotinic cholinergic antagonist alpha-bungarotoxin prevents the loss of nocturnal SNAT activity induced by turning lights on at night [Zatz, M., and Brownstein, M.J. Brain Res. 213:438-442, 1981].

Acetyltransferases↗