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PubMed1995

Aluminum impairs hippocampal long-term potentiation in rats in vitro and in vivo.

Although aluminum (Al) contributes to a variety of cognitive dysfunctions and mental diseases, the underlying mechanisms of Al interactions with the nervous system are still unknown. We have studied the action of Al on synaptic transmission and long-term potentiation (LTP) by performing electrophysiological recordings both in vivo, using freely moving animals, and in vitro, using hippocampal slices. In vivo recordings of the population spikes (PSs) of dentate gyrus granule cells in response to medial perforant path stimulation were performed on both acutely and chronically (Al each day for 5 days) intraventricularly injected animals. Acute Al-infusion (calculated brain concentrations of 0.27, 0.68, and 2.7 micrograms/ml) had no influence on baseline values. Al at 0.27 microgram/ml did not alter the induction and maintenance of LTP, but 0.68 and especially 2.7 micrograms/ml Al lead to a reduction in LTP, and the potentiation declined to baseline within 2 h. In chronic animals their neuronal responsiveness was reduced and in 30% of the rats the PS was completely lost. High-frequency tetanization failed to induce LTP. In slices, field potentials were evoked stimulating Schaffer collaterals and recording pyramidal cells of the CA1 region. Bath application of 0.68 microgram/ml Al increased the baseline amplitude of the PS slightly, whereas 2.7 micrograms/ml decreased the amplitude and concentrations > 5.4 micrograms/ml blocked the PS completely. Induction of LTP in the presence of 0.68 microgram/ml Al led to a smaller increase of the PS amplitude compared to controls, but the duration of LTP was not affected. In the presence of 2.7 micrograms/ml Al LTP was further reduced and declined to baseline levels within 60 min. Given that LTP is a form of synaptic plasticity underlying some forms of learning, our data suggest that both preparations are suitable models for investigating actions of Al-induced neurotoxicity.

Aluminum↗
PubMed1999

Reformation of the nigrostriatal pathway by fetal dopaminergic micrografts into the substantia nigra is critically dependent on the age of the host.

The aim of this study was to determine whether the growth of axons along the nigrostriatal pathway from fetal dopamine cells, transplanted into the substantia nigra of young postnatal 6-OHDA-lesioned rats, is dependent on the age of the host brain. Neonatal rats were lesioned bilaterally by intraventricular injection of 6-OHDA at postnatal day 1 (P1) and received grafts of E14 ventral mesencephalon at day 3 (group P3), day 10 (group P10), or day 20 (group P20) into the right substantia nigra. One lesioned group was left untransplanted. Six months after surgery the animals were subjected to analysis of drug-induced rotation following injection of amphetamine, apomorphine, a D1 agonist (SKF38393), or a D2 agonist (Quinpirole). Animals transplanted intranigrally at day 3 and day 10 showed a strong amphetamine-induced rotational bias toward the side contralateral to the transplant. Animals transplanted into substantia nigra at P20, like the lesioned control animals, showed no rotational bias. Apomorphine and selective D1 and D2 agonists induced ipsilateral turning behavior in the P3 and P10 group, but not in the P20 or the lesion control groups. Immunofluorescence histochemistry in combination with retrograde axonal tracing, using FluoroGold injection into the ipsilateral caudate-putamen showed colocalization of tyrosine hydroxylase and FluoroGold in large numbers of transplanted neurons in the animals transplanted at postnatal day 3 and postnatal day 10, which was not observed in the group P20. The lesion control group showed a 90% complete lesion of the TH-positive cells in the substantia nigra while largely sparing the neurons in the ventral tegmental area. The results indicate that intranigral grafts can be placed accurately and survive well within the substantia nigra region at various time points during postnatal development. Furthermore, embryonic dopamine neurons have the ability to extend axons along the nigrostriatal pathway and reconnect with the dopamine-depleted striatum when transplanted at postnatal day 3 and postnatal day 10, but not at postnatal day 20.

Age Factors↗
PubMed2000

Basic fibroblast growth factor (bFGF) enhances functional recovery following severe spinal cord injury to the rat.

We have recently demonstrated that following a moderate contusion spinal cord injury (SCI) to rats, subsequent administration of basic fibroblast growth factor (bFGF) significantly enhances functional recovery and tissue sparing. To further characterize the effects of bFGF, we evaluated its efficacy after a more severe contusion injury at T(10) using the NYU impactor. Immediately after SCI, osmotic minipumps were implanted into the lateral ventricle and lumbar thecal sac to deliver bFGF at 3 or 6 microg per day versus control vehicle for 1 week. Animals were behaviorally tested for 6 weeks before histological assessment of tissue sparing through the injured segment and glial reactivity distal to the lesion. Compared to moderate SCI, all rats had more prolonged and sustained functional deficits 6 weeks after severe contusion. Subjects treated with bFGF had pronounced recovery of hindlimb movements from 2 to 6 weeks compared to controls, manifested in significantly higher behavioral scores. Only marginal tissue sparing was seen rostral to the injury in bFGF-treated spinal cords versus controls. Optical density measurements of astrocyte and microglial cell immunoreactivity in bFGF-treated spinal cords showed that after 6 weeks they approximated controls, although astrocyte immunoreactivity remained higher in controls rostrally. In summary, intrathecal infusion of bFGF following severe SCI significantly restores gross hindlimb motor function that is not correlated with significant tissue sparing. In light of previous evidence that pharmacological intervention with bFGF after moderate SCI enhances tissue preservation, the current findings indicate that yet undefined mechanisms contribute to the enhanced functional recovery following bFGF treatment.

Analysis of Variance↗
PubMed2001

Turnover of rat brain perivascular cells.

Brain perivascular spaces harbor a population of cells which exhibit high phagocytic capacity. Therefore, these cells can be labeled by intraventricular injection of tracers. Such perivascular cells at the interface between blood and brain are believed to belong to the monocyte/macrophage lineage and to be involved in antigen presentation. Currently, it is unclear whether these cells undergo a continuous turnover by entering and leaving the bloodstream. Using bone-marrow-chimeric animals, migration of donor macrophages into brain perivascular spaces has been reported. On the other hand, following intracerebral injection of india ink into nontransplanted animals, ink-labeled perivascular cells were still found 2 years after injection, suggesting a high stability of this cell pool. Thus, the turnover of perivascular cells observed in chimeras might be a result of bone marrow transplantation rather than a physiological occurrence. To address this issue, we monitored de novo invasion of macrophages into perivascular spaces of apparently healthy adult rats by applying techniques other than bone marrow transplantation, (i) consecutive injections of different tracers and (ii) ex vivo isolation of macrophages from the blood, cell labeling, and reinjection into the same animal to avoid MHC mismatch. Both approaches revealed vivid de novo invasion of macrophages into perivascular spaces, but not into brain parenchyma, rendering untenable the concept of perivascular cells forming a stable population of macrophages in the brain. Thus, brain perivascular spaces are under permanent immune surveillance of blood borne macrophages in normal adult rats.

Animals↗
PubMed2000

Peripheral pulses of oxytocin increase partner preferences in female, but not male, prairie voles.

Centrally administered oxytocin (OT) facilitates social behaviors including the partner preferences that characterize the monogamous social system of prairie voles. In contrast peripherally administered OT generally has been ineffective in influencing central processes including behavior. OT from the posterior pituitary gland is released in pulses into the peripheral circulation. We hypothesized that peripherally administered OT, if delivered in repeated injections mimicking these pulses, would influence behavior. Male and female prairie voles received three subcutaneous injections of OT, a single injection of OT, or isotonic saline. Animals then were placed with an adult member of the opposite sex, designated as a "partner," for a 1-h period of cohabitation, and subsequently tested for preference for the familiar partner versus a comparable stranger. Females treated with pulses of peripheral OT (1, 5, or 20 microg) displayed a significant preference for the partner compared to control females, while females receiving a lower dose of OT (0.1 microg) or a single injection (20 microg) did not. There was also a significant within-group effect as pulsed OT-treated females spent more time with the partner when compared to the stranger, while control females spent equal amounts of time with the partner and stranger. Peripheral pulses of OT were no longer effective in inducing partner preferences when females were pretreated with a selective OT receptor antagonist, administered either peripherally or centrally. In contrast to females, peripheral treatment with OT did not facilitate the formation of partner preferences in males.

Animals↗
PubMed2000

Changes in leptin levels during lactation: implications for lactational hyperphagia and anovulation.

In these studies we investigated the time course of changes in circulating leptin levels in lactating rats and the dependence of these changes on the energetic cost of lactation and evaluated the contribution of changes in leptin levels to lactational hyperphagia and infertility. In the first experiment, plasma leptin levels were measured on Days 5, 10, 15, 20, and 25 postpartum in freefeeding lactating rats and age-matched virgin females. Retroperitoneal and parametrial fat pads weights were obtained from the same females. In the second experiment the same measures, together with plasma insulin and prolactin levels, were taken on Days 15 and 20 postpartum from galactophore-cut and sham-operated females. In Experiments 3 and 4, the effects of exogenous leptin administration, either subcutaneously (sc) or intracerebroventricularly (icv), on lactational anovulation, maternal food intake, and dam and litter weights were examined. Circulating leptin levels decreased in lactating rats. Leptin levels were highly positively correlated with fat pad weight. Eliminating the energetic costs of lactation by preventing milk delivery induced dramatic increases in plasma leptin and insulin levels and also increased adiposity. Exogenous leptin administration did not affect length of lactational anovulation but reduced food intake, maternal body weight, and litter weight gain when given centrally and maternal body weight when given systemically. Together, these data show that the energetic costs of lactation are associated with a fall in circulating leptin levels but that these do not make a major contribution to the suppression of reproduction in lactating rats; however, they may be permissive to the hyperphagia of lactation.

Animals↗
PubMed1997

Reduced size of retinal ganglion cell axons and hypomyelination in mice lacking brain-derived neurotrophic factor.

While brain-derived neurotrophic factor (BDNF) delays the death of axotomized retinal ganglion cells in rodents, it is unclear if it affects any aspect of the normal development of these cells. Here we examined the optic nerve of bdnf-/- mice. Axonal numbers were normal, but their diameter, as well as the proportion of myelinated axons, was reduced at postnatal day 20 (P20). In contrast, the facial nerve was not hypomyelinated. Expression levels of mRNAs coding for the myelin proteins PLP and MBP were substantially reduced in the hippocampus and cortex at P20, but not in the sciatic nerve. Intraventricular injections of BDNF into the ventricles of wild-type mice at P10 and P12 up-regulated expression of PLP in the hippocampus at P14. These results indicate a role of BDNF, discussed as indirect, in the control of myelination in the central nervous system.

Animals↗
PubMed2002

Preferential transfection of adult mouse neural stem cells and their immediate progeny in vivo with polyethylenimine.

The subventricular zone of the adult mammalian brain harbors the neural stem cell population with potential neural regeneration and repair capacity. We describe a nonviral technique to preferentially transfect in vivo the adult neural stem cell population and its immediate progeny based on intraventricular injection of PEI/DNA complexes. The transfected population was identified by cellular and ultra-structural evidence showing their proliferating status and expression of the specific markers GFAP and nestin. Stable activation of the lacZ reporter by cre-recombinase transfection in R26R mice demonstrated survival and migration of stem cell derivatives three months after injection. Apoptosis is thought to be the most common fate of the stem cell progeny. Overexpression of Bcl-X(L) increased number and survival time of transduced progenitors and decreased the frequency of cells immunopositive for activated Caspase-3. This method thus provides selective targeting of the stem cell population and should allow an in-depth understanding of their biology.

Animals↗
PubMed1997

Zinc metabolism in the brain: relevance to human neurodegenerative disorders.

Zinc is an important trace element in biology. An important pool of zinc in the brain is the one present in synaptic vesicles in a subgroup of glutamatergic neurons. In this form it can be released by electrical stimulation and may serve to modulate responses at receptors for a number of different neurotransmitters. These include both excitatory and inhibitory receptors, particularly the NMDA and GABA(A) receptors. This pool of zinc is the only form of zinc readily stained histochemically (the chelatable zinc pool), but constitutes only about 8% of the total zinc content in the brain. The remainder of the zinc is more or less tightly bound to proteins where it acts either as a component of the catalytic site of enzymes or in a structural capacity. The metabolism of zinc in the brain is regulated by a number of transport proteins, some of which have been recently characterized by gene cloning techniques. The intracellular concentration may be mediated both by efflux from the cell by the zinc transporter ZrT1 and by complexing with apothionein to form metallothlonein. Metallothionein may serve as the source of zinc for incorporation into proteins, including a number of DNA transcription factors. However, zinc is readily released from metallothionein by disulfides, increasing concentrations of which are formed under oxidative stress. Metallothionein is a very good scavenger of free radicals, and zinc itself can also reduce oxidative stress by binding to thiol groups, decreasing their oxidation. Zinc is also a very potent inhibitor of nitric oxide synthase. Increased levels of chelatable zinc have been shown to be present in cell cultures of immune cells undergoing apoptosis. This is very reminiscent of the zinc staining of neuronal perikarya dying after an episode of ischemia or seizure activity. Thus a possible role of zinc in causing neuronal death in the brain needs to be fully investigated. intraventricular injections of calcium EDTA have already been shown to reduce neuronal death after a period of ischemia. Pharmacological doses of zinc cause neuronal death, and some estimates indicate that extracellular concentrations of zinc could reach neurotoxic levels under pathological conditions. Zinc is released in high concentrations from the hippocampus during seizures. Unfortunately, there are contrasting observations as to whether this zinc serves to potentiate or decrease seizure activity. Zinc may have an additional role in causing death in at least some neurons damaged by seizure activity and be involved in the sprouting phenomenon which may give rise to recurrent seizure propagation in the hippocampus. In Alzheimer's disease, zinc has been shown to aggregate beta-amyloid, a form which is potentially neurotoxic. The zinc-dependent transcription factors NF-kappa B and Sp1 bind to the promoter region of the amyloid precursor protein (APP) gene. Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of beta-amyloid. The changes in zinc metabolism which occur during oxidative stress may be important in neurological diseases where oxidative stress is implicated, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Zinc is a structural component of superoxide dismutase 1, mutations in which give rise to one form of familiar ALS. After HIV infection, zinc deficiency is found which may be secondary to immune-induced cytokine synthesis. Zinc is involved in the replication of the HIV virus at a number of sites. These observations should stimulate further research into the role of zinc in neuropathology.

Animals↗
PubMed1988

Discriminative stimulus effects of cholinergic agonists and the actions of their antagonists.

Both muscarinic- and nicotinic-cholinergic agonists have been used for discrimination training, but only nicotine has been studied extensively. The limited information available suggests that the discriminative stimulus effects of drugs classified as muscarinic-cholinergic agonists are blocked competitively by atropine but not by ganglion-blockers. The discriminative effects of nicotine are blocked non-competitively by ganglion-blocking drugs that penetrate into the CNS (e.g. mecamylamine), but they are not blocked by atropine. The specificity of the block is shown by the failure of mecamylamine to block several non-nicotinic drugs. The ganglion-blocking drug chlorisondamine penetrates poorly into the CNS when injected systemically; when injected intraventricularly, it is a potent and specific nicotine antagonist with a 4-week duration of effect. Haloperidol attenuates discriminative effects of nicotine but this is not a specific block; there are marked reductions in response rate, the morphine stimulus is also attenuated, and other neuroleptics have much weaker effects. The results support the view that the discriminative effect of nicotine involves predominantly cholinoceptive sites, and they suggest that it is not mediated primarily by the dopamine system. The transduction mechanisms for the nicotine stimulus may include the receptor sites that mediate many of its other CNS effects, but more information is needed about possible subtypes of nicotinic receptors before definitive conclusions are possible.

Animals↗
PubMed1985

Phase I clinical trial of intralesional or intraventricular leukocyte interferon for intracranial malignancies.

Eight patients were treated with leukocyte interferon for a variety of neurological malignancies that had failed or recurred after conventional therapy. Three patients with malignant astrocytoma received intratumoral interferon in dosages up to 9 million units 3X/week, with total dosages of up to 160 million units. Interferon was administered intraventricularly in 4 patients with leptomeningeal metastases and one patient with multiple brain metastases. Dosages increased from 1 to 10 million units 3X/week, and total dosages of up to 113 million units were given intraventricularly. Acute side effects of fever, nausea, vomiting, and headache occurred almost exclusively with intraventricular injections, and these subsided after the initial injection. Fatigue, loss of appetite, weight loss, and hematologic toxicity developed a few weeks after onset of treatment, independent of the dose given. A modest tumor regression was seen on CT scans of one patient with a malignant astrocytoma, who was treated with interferon for 8 months. In all 4 patients with leptomeningeal metastases, the CSF became free of malignant cells for 6 to 10 weeks, while clinical improvement was less dramatic.

Adult↗
PubMed1991

Effects of diazepam on nociception in rats.

Acute i.p. injection of diazepam (1 mg/kg) resulted in a moderate increase in the tail-flick latency in rats. Tolerance to this diazepam effect developed after 10 days of diazepam treatment (1 mg kg-1 day-1). The benzodiazepine antagonist Ro 15-3505 only partially reversed the effect of diazepam on nociception. Naloxone (5 mg/kg i.p.) failed to affect the effect of diazepam on nociception, while the kappa antagonist MR 2266 fully antagonized the diazepam-induced increase of the tail-flick latency. Diazepam injected intracerebroventricularly (1, 5, 20 micrograms/rat) did not alter basal nociceptive threshold, however, diazepam injected intrathecally (20 micrograms/rat) prolonged the tail-flick latency. Furthermore, intracerebroventricular injection of muscimol partially antagonized the i.p. diazepam-induced increase of the tail-flick latency. These results suggest that benzodiazepine receptor sites are partially involved in the effect of diazepam on nociception and indicate that an indirect kappa-opioid-receptor-mediated mechanism may be involved. The anatomical site of diazepam action on tail-flick latency seems to be at the spinal level. Descending axons to the spinal cord from brain areas reached by intracerebroventricular injection of muscimol seem to modulate the effect of diazepam effect on nociception.

Animals↗
PubMed1996

Pharmacologic strategies for the treatment of meningeal malignancy.

There have been significant strides in the treatment and prevention of meningeal cancer, particularly meningeal leukemia, during the past thirty years. These advantages are a direct result of innovative therapeutic approaches specifically designed to overcome the limitations of systemically administered chemotherapy. Such approaches include the administration of intrathecal chemotherapy by intralumbar or intraventricular injection, the administration of very high-dose systemic chemotherapy, and the administration of cranial or craniospinal irradiation. A better understanding of the central nervous system pharmacokinetics of commonly used anticancer agents has also resulted in improvements in the treatment of meningeal cancer. In this article, the clinical pharmacology of the most commonly used intrathecal agents and pharmacologic strategies for the treatment of meningeal cancer will be discussed. In addition, an overview of new agents for intrathecal administration and other novel CNS targeted therapies will be presented.

Antineoplastic Agents↗
PubMed1988

Naloxone prevents the facilitatory effect upon retention induced by adrenaline administration in rats.

The possible involvement of endogenous opioid peptides in the development of the facilitatory effect of adrenaline on memory has been investigated. For this purpose post-training administration of adrenaline and/or naloxone was carried out in rats tested in an inhibitory avoidance paradigm and subjected or not to pre-training (extensive familiarization with the training situation prior to the acquisition trial). Adrenaline injected subcutaneously in a dose of 500 micrograms/kg facilitated retention performance in rats both subjected or not to pre-training. Naloxone administered SC (400 micrograms/rat) did not influence retention behaviour in rats subjected or not to pre-training, nor did ICV (0.80 ng/rat) administration. Interestingly, the opiate antagonist when injected SC (400 micrograms/rat) prevented the facilitatory effect exerted by adrenaline in pretrained as well as in not pre-trained rats. However, ICV administration of naloxone (0.80 microgram/rat) dit not influence the behavioral effects exerted by the bioamine. These data suggested a role of endogenous opioid peptides on the facilitatory effect of adrenaline on memory, possibly independent of novelty factors and thus of the brain beta-endorphin system. In addition, our results point to the periphery as the most likely site for such interaction.

Animals↗
PubMed1990

Supersensitivity to intrathecal 5-hydroxytryptamine, but not noradrenaline, following depletion of spinal 5-hydroxytryptamine by 5,7-dihydroxytryptamine administered into various sites.

The present study was conducted (a) to determine if cross-supersensitivity at spinal noradrenergic receptors could be demonstrated in antinociceptive tests following depletion of spinal cord 5-hydroxytryptamine (5HT) by the intrathecal (i.t.) and intracerebroventricular (i.c.v.) administration of 5,7-dihydroxytryptamine (5,7DHT), and (b) to compare the pattern of supersensitivity at spinal 5HT receptors following these manipulations and 5,7DHT microinjected into the ventral raphe (VR) region and the nucleus raphe magnus (NRM). Both i.t. and i.c.v. administration of 5,7DHT produced a marked depletion of spinal cord 5HT (greater than 75%) and supersensitivity to the i.t. injection of 5HT in the tail flick and hot plate tests. No supersensitivity to the i.t. injection of noradrenaline (NA) was observed. Microinjection of 5,7DHT into the VR and NRM produced less depletion of spinal cord 5HT (40-57%), and supersensitivity to the i.t. injection of 5HT was observed only in the hot plate test following microinjection of 5,7DHT into the VR. An increased incidence of signs of the 5HT behavioural syndrome, particularly tremor and Straub tail, was observed in all 5,7DHT-pretreated groups. These results indicate that cross-supersensitivity to spinal NA receptors does not occur following depletion of spinal cord 5HT. In addition, responses mediated by 5HT receptors show a differential pattern of development of supersensitivity. Thus, the 5HT behavioural syndrome (presumably mediated by 5HT1A receptors) more readily reflects the development of supersensitivity than the tail flick test (presumably mediated by 5HT2 receptors), while the hot plate test (uncharacterized subtype) shows an intermediate development of supersensitivity.

5,7-Dihydroxytryptamine↗
PubMed1987

Distribution and fine structure of ependymal cells possessing intracellular cysts in the aqueductal wall of the rat brain.

The wall of the cerebral aqueduct was examined in 20 male rats at the light- and electron-microscopic levels. Disorder in ciliary orientation was occasionally seen in ordinary ependymal cells. Ependymal cells possessing intracellular cysts of 5 to 30 micron in diameter were observed within and beneath the aqueductal ependyma in all animals examined. Light-microscopic reconstruction from serial, 10-micron thick frontal sections revealed an extensive distribution of cystic ependymal cells (CECs), especially along the ependymal ridges in the rostral half of the aqueduct, and along the dorsal region of the aqueductal lining in the caudal half. Both cystic and surface membranes of CECs bore microvilli and cilia. Ectopic ependymal cells (EECs) characterized by densely packed microvilli, well-developed intermediate junctions and cilia, but without cysts, were situated in the subependymal region adjacent to a CEC or another EEC. The ependymal ridges were long, narrow and sporadically stratified ependymal linings extending rostrocaudally and bilaterally along the aqueductal surface. Tanycyte-like cells filled the surface region of the ridge, and CECs and EECs were frequently seen in the core. Intraventricularly injected microperoxidase was detected among densely packed microvilli but not in the cystic lumina of CECs, indicating that EECs and CECs are distinct entities.

Animals↗
PubMed1977

Effects on gonadal function by lesioning tanycytes in the median eminence of the rat and Japanese Quail.

The ependymal linings of the median eminence were destroyed by electric cautery or intraventricular injection of picric acid in the rat and Japanese quail. In these animals the ventricular lumen near the median eminence disappeared due to adhesion of lesioned walls on both sides of the third ventricle. Electric lesions of the ependymal layer containing tanycytes did not induce appreciable disturbance in the estrous cycles. Rats in which tanycytes were lesioned by picric acid displayed 4-day estrous cycles after prolonged diestrus (10-22 days). After destruction of tanycytes in the quail, a photostimulated gonadal growth was observed. It is concluded that the tanycyte transport of the ventricular fluid to capillaries of the portal vessels appears unnecessary for maintenance of adenohypophysial gonadotrophic activities.

Animals↗