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At least 451 records · Page 25Linked to original sources

PubMed1999

Decorin attenuates gliotic scar formation in the rat cerebral hemisphere.

The transforming growth factor-betas (TGF-betas) are potent fibrogenic factors implicated in numerous CNS pathologies in which fibrosis and neural dysfunction are causally associated. In this study, we aimed to demonstrate significant inhibition of fibrogenesis, glial scarring, and inflammation in penetrating incisional wounds of the rat brain using the proteoglycan decorin, which effectively inhibits TGF-beta activity. Adult rats were assigned to two treatment groups each receiving 14 daily intraventricular injections of 10 microliter total volume of: (i) saline plus 0.3% autologous rat serum = 30 microgram protein); or (ii) saline plus 30 microgram recombinant human decorin. On day 0 of the experiment, a stereotactically defined unilateral incisional lesion was placed through the cerebral cortex into the lateral ventricle and, after 14 days, brains were processed for immunohistochemical analysis of the lesion site. Specific antibodies were used to visualize the deposition within the wound of matrix molecules and the extent and nature of reactive astrocytosis and inflammation. Quantitative and qualitative image analysis of the fibrous scar was performed in sections from a defined anatomical plane through the wound to detect the antifibrotic effects of decorin treatment. Treatment of wounds with decorin led to a marked attenuation of all aspects of CNS scarring including matrix deposition, formation of an accessory glial limiting membrane, and inflammation. Our findings suggest that decorin is potentially applicable to a number of human CNS fibrotic diseases to arrest the deposition of excessive extracellular matrix components and maintain and/or restore functional integrity.

Animals↗

PubMed2000

Internalization of intracerebrally administered porcine galanin (1-29) by a discrete nerve cell population in the hippocampus of the rat.

In spite of numerous studies utilizing intraventricular administration of porcine galanin (1-29), little is known about the spread and cellular distribution of exogenous galanin following intraventricular administration. In this study a discrete nerve cell body population with their dendrites became strongly galanin immunoreactive (IR) in the dorsal hippocampus following intraventricular porcine galanin (1.5 nmol/rat). Time course experiments showed that after time intervals of 10 and 20 min, but not at 60 min, scattered small- to medium-sized galanin-IR nerve cell bodies and their dendrites were present in all layers of the dorsal and ventral hippocampus. In double-immunolabeling experiments most of these nerve cells were identified as putative GABA interneurons costoring NPY-IR or somatostatin-IR in some cases. Twenty minutes after intraventricular injection of artificial cerebrospinal fluid (aCSF), only endogenous punctate and coarse galanin-IR terminals were found, but no galanin-IR cell bodies. Intrahippocampal injection of fluorophore-labeled galanin resulted in the appearance of fluorescent nerve cell bodies with the same morphology and localization as in the above experiments. Coadministration of the putative galanin antagonist M35 (0.5 nmol) and galanin (1.5 nmol) resulted in a reduced number of galanin-IR nerve cell bodies in the hippocampus of half of the rats. These findings support the existence of a population of putative hippocampal GABA interneurons with the ability to internalize and concentrate galanin and/or its fragments present in the extracellular fluid, possibly mediated by galanin receptors.

Animals↗

PubMed2000

Serotonin release from mesencephalic raphe neurons grafted to the 5,7-dihydroxytryptamine-lesioned rat hippocampus: effects of behavioral activation and stress.

Transplants of fetal midbrain raphe neurons into the adult brain have been shown to promote recovery of complex behavioral deficits in several experimental models, but the mechanisms underlying these effects are only partially understood. In the present study, we have used a well-characterized model system to ascertain whether midbrain raphe graft can display behaviorally relevant changes in transmitter release and/or metabolism. Fetal mesencephalic raphe neurons were grafted unilaterally into the hippocampus previously deprived of its innate serotonergic innervation by intraventricular injections of 5,7-dihydroxytryptamine. The contralateral hippocampus remained as a nongrafted, lesioned control. Microdialysis probes were implanted in the hippocampus 5-7 months postgrafting. Under baseline conditions, extracellular levels of serotonin were similar to normal in the grafted hippocampi, but undetectable on the contralateral, nongrafted side. Levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were markedly higher than normal in the grafted hippocampi, but dramatically reduced on the contralateral nongrafted side. Handling stimulation (gentle stroking of a rat's fur and tail for 15 min) induced a 64% increase in serotonin output in the intact rats and a small but significant 12% increase in the grafted animals. Non-noxious tail-pinch (15 min) enhanced serotonin release by 86% in the intact rats and 28% in the grafted ones. Extracellular 5-HIAA levels remained unchanged during both handling and tail-pinch in both the intact and the grafted rats. Forced immobilization of the rats for 15 min induced a transient 124% increase in extracellular serotonin levels in the intact rats and a significant 19% increase in the grafted animals, whereas swimming in temperate water (25-30 degrees C; 15 min) induced no detectable changes in serotonin output in any of the groups. 5-HIAA levels remained unchanged during forced immobilization, but were significantly reduced during the swimming session in both the intact (-38%) and grafted (-15%) animals. The present results indicate that median raphe grafts can become functionally integrated in the denervated host hippocampus and respond by altered indole output when the animal is exposed to different types of environmental challenges.

5,7-Dihydroxytryptamine↗

PubMed2001

Selective antibody-induced cholinergic cell and synapse loss produce sustained hippocampal and cortical hypometabolism with correlated cognitive deficits.

The physiological interrelationships between cognitive impairments, neurotransmitter loss, amyloid processing and energy metabolism changes in AD, cholinergic dementia and Down's syndrome are largely unknown to date. This report contains novel studies into the association between cognitive function and cerebral metabolism after long-term selective CNS cholinergic neuronal and synaptic loss in a rodent model. We measured local cerebral rates of glucose utilization ((14)C-2-deoxyglucose) throughout the brains of awake rats 4.5 months after bilateral intraventricular injections of a cholinotoxic antibody directed against the low-affinity NGF receptor (p75 NGF) associated with cholinergic neurons (192 IgG-saporin). Permanent cholinergic synapse loss was demonstrated by [(3)H]-vesamicol in vitro autoradiography defining presynaptic vesicular acetylcholine (ACh) transport sites. While other metabolic studies have defined acute and transient glucose use changes after relatively nonspecific lesions of anatomical regions containing cholinergic neurons, our results show sustained reductions in glucose utilization in brain regions impacted by cholinergic synapse loss, including frontal cortical and hippocampal regions, relative to glucose use levels in control rats. In the same animals, impaired cognitive spatial performance in a Morris water maze was correlated with reduced glucose use rates in the cortex and hippocampus at this time point, which is consistent with increased postmortem cortical and hippocampal amyloid precursor protein (APP) levels (45, 46). These results are consistent with the view of cholinergic influence over metabolism, APP processing, and cognition in the cortex and hippocampus.

Alzheimer Disease↗

PubMed1983

Pyrenebutyl-methylphosphonofluoridate: a fluorescent anti-cholinesterase in vivo.

In vivo properties of pyrenebutyl-methylphosphonofluoridate (PBMPF) have been studied. The LD50 (i.v.) for mice was 15 mg/kg and toxic symptoms were typical of cholinesterase (ChE) inhibition but central signs were absent. After intraventricular injection of PBPMPF in unanaesthetized rabbits, continued walking in bizarre circular fashion together with peripheral vascular dilation and tachypnoea were observed. Recovery occurred 3 h post-injection. Fluorescent particles of unabsorbed material juxtaposed on lining ependyma were observed up to 14 days of administration. In addition, a large number of hippocampal cells showed vivid fluorescence, particularly in the cytoplasm, which was attributed to ChE inhibition. It is concluded that PBMPF seems promising as an organophosphate marker of nerve cells.

Animals↗

PubMed1986

Electron-microscopic cytochemistry of the catecholaminergic innervation of TRH neurons in the rat hypothalamus.

The catecholaminergic innervation of thyrotropin-releasing hormone (TRH) neurons was examined by use of a combined method of 5-hydroxydopamine (5-OHDA) uptake or autoradiography after intraventricular injection of 3H-noradrenaline (3H-NA) and immunocytochemistry for TRH in the same tissue sections at the electron-microscopic level. TRH-like immunoreactive nerve cell bodies were distributed abundantly in the parvocellular part of the paraventricular nucleus (PVN), in the suprachiasmatic preoptic nucleus and in the dorsomedial nucleus of the rat hypothalamus. In the PVN, a large number of immunonegative axon terminals were found to make synaptic contact with TRH-like immunoreactive cell bodies and fibers. In the combined autoradiography or 5-OHDA labeling with immunocytochemistry, axon terminals labeled with 3H-NA or 5-OHDA were found to form synaptic contacts with the TRH immunoreactive nerve cell bodies and fibers. These findings suggest that catecholamine-containing neurons, probably noradrenergic, may innervate TRH neurons to regulate TRH secretion via synapses with other unknown neurons in the rat PVN.

Animals↗

PubMed1987

Effects of arecoline and pilocarpine on learning ability in marmosets pretreated with hemicholinium-3.

Common marmosets (Callithrix jacchus) were trained to perform serial reversal position discrimination tasks in a Wisconsin General Test Apparatus. Intraventricular injection of hemicholinium-3 4 h before testing resulted in a profound impairment of position discrimination learning which could be overcome by the intramuscular administration of low doses of the muscarinic agonists, arecoline or pilocarpine.

Animals↗

PubMed1975

Recovery of brain noradrenaline after 5,7-dihydroxytryptamine-induced axonal lesions in the rat.

Time-dependent changes in regional CNS noradrenaline (NA) concentration, 3H-NA uptake and fluorescence morphology of CNS NA neurons were analysed in the adult rat up to 6 months after intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), and compared with the time-course of changes in brain and spinal cord indolamine neurons. Following a substantial depletion of both amines in all CNS regions (telodiencephalon, brainstem and spinal cord) at 10 days after 150 mug 5,7-DHT, brain NA--but not 5-HT--levels recovered to near-normal values in brainstem and forebrain (35% below the age-matched controls) within 4 months. This was accompanied by a total restoration of the initially decreased capacity of the brain tissue to accumulate 3H-NA in vitro. Within 10 days after 5,7-DHT, there was a disappearance of NA terminals from many telencephalic, diencephalic and lower brain stem nuclei, from the cerebral and cerebellar cortices, and the grey matter of the spinal cord, concomitant with the appearance of numerous distorted, highly fluorescent swellings along the non-terminal axons of the major noradrenergic projection pathways. The recovery of the NA levels was paralleled by a re-appearance of fluorescent fibres, signifying an intense sprouting and regrowth of the drug-lesioned axons, which eventually re-innervated some of the previously denervated telodiencephalic regions. Except for a permanent loss of some surface-near perikarya in group A1 (the main source of the bulbospinal projections) there was no evidence of a retrograde degeneration of noradrenergic cell bodies in the rat CNS. The results are compatible with the idea that 5,7-DHT mainly causes a lesion of NA axons at a distance from the cell bodies, and this is followed by sprouting and regrowth of axons from the lisioned neurites, and formation of new terminal-like fibres in some previously denervated telodiencephalic regions. These findings indicate that chemical axotomy of central NA neurons induced by 5,7-DHT is--in contrast to that induced by 6-hydroxydopamine--followed by extensive axonal regeneration.

5,6-Dihydroxytryptamine↗

PubMed1985

Membrane specializations and their relation to HRP transport in the medial habenular nucleus of the rat.

In the medial habenular nucleus of the rat, ependymal and endothelial membrane specializations were studied with TEM and freeze-fracturing. They comprise ependymal adherent junctions - not manifest in freeze-fracture replicas-, gap junctions, and membrane-associated orthogonal particle complexes ("assemblies") - not identifiable in thin-sectioned material. Ependymal tight junctions being absent, no brain-liquor barrier exists. The capillary endothelium is provided with tight junctions only. Intraventricularly injected HRP was transported in large amounts through the ependyma, mainly through the intercellular spaces and additionally by way of massive pinocytosis through the cytoplasm of particular ependymal cells only, and finally through the parenchymal intercellular compartments towards habenular capillaries. Following intravenous injection of HRP, considerable transport of the enzyme took place by means of transendothelial pinocytosis, followed by some pinocytotic transport through diverse parenchymal elements and markedly profuse incorporation and lysis within pericytes. The habenular blood-brain barrier appeared to be considerably leaky with respect to HRP.

Animals↗

PubMed1980

Metrizamide enhanced CT in hydrosyringomyelia.

The exact evaluation of a hydrosyringomyelic cyst by metrizamide enhanced CT is reported. After intraventricular injection of metrizamide and overflow of contrast medium in the central canal of the spinal cord, CT scan revealed the exact shape and extension of the cyst from C0 to T7.

Adult↗

PubMed1978

Changes in the behavioral response to a novel environment following lesioning of the central dopaminergic system in rat pups.

During the third week of life, a hyperactive period for laboratory rat, the occurrence of 8 behavioral categories was recorded in individual littermates transferred to a novel environment. Neonatal destruction of the catecholaminergic system by intraventricular injection of 6-OH-DA resulted in increased motor activity during the third week of life. Selective lesioning of the dopaminergic system by the combined treatment of 6-OH-DA + desmethylimipramine also induced a significant increase in some active behavioral categories. It appeared that in contrasts to the gross behavioral sequence, as seen in controls, which compromised locomotion and rearing leads to grooming leads to sitting and lying down, the lesioned animals showed a prolonged phse of restless locomotion. These data are interpreted as a disability to habituate adequately to a novel environment after neonatal lesioning of the dopaminergic system.

Aging↗

PubMed1976

Development of tolerance to the antinociceptive effect of mescaline intraventricularly administered to rabbits.

Some effects of intraventricular injection of mescaline are examined in conscious rabbits. By means of electrical stimulation of the tooth pulp it is shown that an acute treatment with 70, 100, 150 mug/kg of mescaline elicits analgesia, the intensity of which is dose-dependent: with daily administration of 100 mug/kg for 5 days a complete tolerance develops to the antinociceptive effect. A tolerance also develops to the behavioral effects of mescaline after repeated administrations, with the exception of the stuporous state, a symptom which, on the contrary, is accentuated as the treatment proceeds. An EEG arousal is induced in the rabbit by acutely administered mescaline; the chronic treatment (100 mug/kg) makes the return of voltage to original levels progressively slower. Finally, the confrontation of certain of the mescaline-induced effects with those of morphine suggests some biochemical and neural patterns common to the 2 drugs.

Analgesia↗

PubMed1984

Cholinergic learning deficits in the marmoset produced by scopolamine and ICV hemicholinium.

Common marmosets (Callithrix jacchus) were trained to perform daily position discrimination learning tasks in a Wisconsin General Test Apparatus. Acetylcholine receptor blockade with scopolamine was found to impair position learning. Testing on the day after scopolamine treatment suggested that a task learnt under scopolamine was not encoded into long term memory. Acetylcholine depletion achieved by the intraventricular injection of hemicholinium 4 h before testing resulted in a profound impairment of position discrimination learning. It is suggested that central acetylcholine depletion in primates may provide a useful model of senile dementia.

Animals↗

PubMed1975

Behavioural supersensitivity to apomorphine following cerebral dopaminergic denervation by 6-hydroxydopamine.

Intraventricular injections of 6-hydroxydopamine that induce a marked and long lasting depletion of cerebral dopamine as well as noradrenaline, greatly enhanced the stimulation of locomotor activity of mice produced by the injection of apomorphine. Dose-response relationships indicated that the maximal response to apomorphine was greatly increased but that there was no apparent change in the ED50 from the response in vehicle-treated mice. 6-Hydroxydopamine treated mice were also considerably less susceptible to the cataleptic activity of pimozide and it is suggested that cerebral dopaminergic denervation may result in an increased number of available post-synaptic dopamine receptors.

Apomorphine↗

PubMed1980

Effect of 5,7-dihydroxytryptamine on the development of tolerance to ethanol.

5,7-Dihydroxytryptamine (5,7-DHT) or the vehicle was administered once into both lateral ventricles of the rat. Desmethylimipramine (DMI) was administered IP prior to the intraventricular injection of 5,7-DHT to prevent the destruction of norepinephrine (NE) terminals. Following recovery from surgery, ethanol (5 g/kg, PO) or isocaloric sucrose was given daily for 25 days. Tests at 5-day intervals showed that chronic ethanol treatment produced tolerance to the motor impairment on the moving belt test and to hypothermic effects of ethanol. The 5,7-DHT treatment did not alter either the motor impairment or hypothermia produced by the initial dose of ethanol. However, 5,7-DHT treatment produced a 75% depletion of brain serotonin (5-HT) without altering NE concentration and retarded the development of tolerance to ethanol in both measurements. This study with a specific central depletor of 5-HT, without alteration in NE concentration, extends and supports our hypothesis that brain 5-HT modulates the development of tolerance to ethanol.

5,7-Dihydroxytryptamine↗

PubMed1980

Intraventricular 6-hydroxydopamine in the newborn rat and locomotor responses to drugs in infancy: no support for the dopamine depletion model of minimal brain dysfunction.

Bilateral intraventricular injections of 6-hydroxydopamine (6-OHDA) after desmethylimipramine (DMI) in rats 1 and 2 days of age, severely depleted brain dopamine (DA) particularly in the neostriatum, where levels in adulthood were about 7% of control. Compared to vehicle-injected controls these rats were hyperactive only at 15 and 20 days of age, and in adulthood were impaired in a two-way avoidance. Rats with similar 6-OHDA treatment but without DMI pretreatment showed severe depletion of brain norepinephrine (NE) as well as DA, and were behaviorally similar to the DA-depleted only rats. This behavioral syndrome is similar to that reported after intracisternal injection of 6-OHDA in 5-day-old rats, which has been argued as a model for minimal brain dysfunction (MBD). Contrary to expectation from this model, however, challenge doses of either d-amphetamine or methylphenidate did not reduce, but instead increased activity of these rats. The 6-OHDA treatments also did not alter the enhancement of locomotor activity by scopolamine, which was present at 30 days but not at 15 days.

Aging↗

PubMed1982

Prostaglandin inhibition of amphetamine-induced circling in mice.

The effect of prostaglandins (PG) on amphetamine(AMPH)-induced circling was examined in mice unilaterally lesioned with 6-hydroxy-dopamine. At doses of 0.03-1.0 nmol/g, intraventricularly injected PGD2, PGE2, and PGF2 alpha all inhibited AMP-induced circling, while thromboxane-B2 (TxB2) was inactive at 1.0 nmol/g. The inhibition of circling was not due to alterations in body temperature as measured by rectal temperature changes. When injected intrastriatally, the same major PG inhibited AMP-induced circling at the lower doses of 0.01-0.1 nmol/g, while the PGE2 metabolite 13, 14-dihydro-15-keto-PGE2 was inactive at 0.1 nmol/g. PG administered alone did not procude circling. For both routes of administration, the order of potency was PGE2 greater than PGD2 greater than PGF2 alpha. These results suggest that PG can alter motor function governed by central dopaminergic pathways.

Amphetamine↗

PubMed1976

Inhibition of the reuptake of serotonin by tryptoline.

Tryptoline, a metabolite of tryptamine, competitively inhibits serotonin accumulation in nuclei-free homogenate of rat "forebrains". After intraventricular injection the drug elicits an increase of serotonin levels in the same part of the brain whereas the monoamine oxidase activity is not altered.

Animals↗