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PubMed2006

Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders.

Clinical observations suggest that certain gut and dietary factors may transiently worsen symptoms in autism spectrum disorders (ASD), epilepsy and some inheritable metabolic disorders. Propionic acid (PPA) is a short chain fatty acid and an important intermediate of cellular metabolism. PPA is also a by-product of a subpopulation of human gut enterobacteria and is a common food preservative. We examined the behavioural, electrophysiological, neuropathological, and biochemical effects of treatment with PPA and related compounds in adult rats. Intraventricular infusions of PPA produced reversible repetitive dystonic behaviours, hyperactivity, turning behaviour, retropulsion, caudate spiking, and the progressive development of limbic kindled seizures, suggesting that this compound has central effects. Biochemical analyses of brain homogenates from PPA treated rats showed an increase in oxidative stress markers (e.g., lipid peroxidation and protein carbonylation) and glutathione S-transferase activity coupled with a decrease in glutathione and glutathione peroxidase activity. Neurohistological examinations of hippocampus and adjacent white matter (external capsule) of PPA treated rats revealed increased reactive astrogliosis (GFAP immunoreactivity) and activated microglia (CD68 immunoreactivity) suggestive of a neuroinflammatory process. This was coupled with a lack of cytotoxicity (cell counts, cleaved caspase 3' immunoreactivity), and an increase in phosphorylated CREB immunoreactivity. We propose that some types of autism may be partial forms of genetically inherited or acquired disorders involving altered PPA metabolism. Thus, intraventricular administration of PPA in rats may provide a means to model some aspects of human ASD in rats.

Animals↗

PubMed2004

Quinoline derivatives are therapeutic candidates for transmissible spongiform encephalopathies.

We previously reported that quinacrine inhibited the formation of an abnormal prion protein (PrPres), a key molecule in the pathogenesis of transmissible spongiform encephalopathy, or prion disease, in scrapie-infected neuroblastoma cells. To elucidate the structural aspects of its inhibiting action, various chemicals with a quinoline ring were screened in the present study. Assays of the scrapie-infected neuroblastoma cells revealed that chemicals with a side chain containing a quinuclidine ring at the 4 position of a quinoline ring (represented by quinine) inhibited the PrPres formation at a 50% inhibitory dose ranging from 10(-1) to 10(1) micro M. On the other hand, chemicals with a side chain at the 2 position of a quinoline ring (represented by 2,2'-biquinoline) more effectively inhibited the PrPres formation at a 50% inhibitory dose ranging from 10(-3) to 10(-1) micro M. A metabolic labeling study revealed that the action of quinine or biquinoline was not due to any alteration in the biosynthesis or turnover of normal prion protein, whereas surface plasmon resonance analysis showed a strong binding affinity of biquinoline with a recombinant prion protein. In vivo studies revealed that 4-week intraventricular infusion of quinine or biquinoline was effective in prolonging the incubation period in experimental mouse models of intracerebral infection. The findings suggest that quinoline derivatives with a nitrogen-containing side chain have the potential of both inhibiting PrPres formation in vitro and prolonging the incubation period of infected animals. These chemicals are new candidates for therapeutic drugs for use in the treatment of transmissible spongiform encephalopathies.

Animals↗

PubMed1992

NGF restores decrease in catalase activity and increases superoxide dismutase and glutathione peroxidase activity in the brain of aged rats.

The effects of ageing on the activity of copper-zinc superoxide dismutase (SOD), selenium-dependent and independent glutathione peroxidase (GSH-Px) and catalase in several areas of the brain in 3-, 12-, and 24-month-old rats were studied. In addition, the effects of a subacute intracerebroventricular treatment of NGF (1 microgram daily for 28 consecutive days) on SOD, GSH-Px, and catalase activity in the same areas of the brain were assessed. The effects of ageing on the activities of antioxidant enzymes varied considerably in the different brain areas studied. Copper-zinc SOD was alone in being unaffected by ageing. Intraventricular infusion of NGF significantly increased SOD activity in the prefrontal cortex, hypothalamus, caudate nucleus, and mesencephalon of 24-month-old rats. Selenium-dependent GSH-Px activity did not significantly change in 12-month-old rats but it increased in the lower brain stem of 24-month-old animals. In comparison to vehicle-treated rats, NGF significantly increased selenium-dependent GSH-Px activity in all brain areas studied in 12- and 24-month-old rats. Catalase activity decreased significantly in the majority of the brain areas studied in 12- and 24-month-old rats. NGF completely restored the fall in catalase activity in 12- and 24-month-old animals to levels similar to those occurring in young rats. In conclusion, the present experiments show, for the first time, that long-term intraventricular administration of NGF significantly increases in old animals the activity of key enzymes involved in the metabolic degradation of superoxide radicals and hydrogen peroxide.

Aging↗

PubMed1994

Intraventricular administration of insulin and IGF-1 in transient forebrain ischemia.

A beneficial effect of insulin in reducing cerebral ischemic damage has been recently demonstrated, and a direct central mechanism of insulin action in cerebral ischemia has been proposed. To test the hypothesis that one of the neuroprotective mechanisms of insulin action involves a direct interaction with CNS tissue via a growth factor effect, a continuous intraventricular infusion of two doses of insulin and of insulin-like growth factor 1 (IGF-1) was given to fed Wistar rats subjected to 10 min, 15 s of transient forebrain ischemia. Quantitative neuropathology after 1-week survival showed that low-dose insulin (7 IU/rat/day; n = 10) reduced selective necrosis in the striatum (p = 0.015) and one level of the hippocampus (p = 0.023) as compared with animals infused with phosphate-buffered saline (200 microliters/rat/day; n = 8). IGF-1 (50 micrograms/rat/day; n = 8) significantly ameliorated hippocampal damage in four of the six hippocampal levels (p < 0.05). High-dose insulin infusion (23 IU/rat/day; n = 8) produced a robust reduction in cortical (p = 0.0108), striatal (p = 0.003), and hippocampal (p < 0.05) necrosis at all coronal levels. However, this high-dose insulin reduced the blood sugar significantly (p < 0.01), from 11.8 to 7.8 mM, probably by virtue of centrally administered insulin reaching the periphery. We conclude that insulin and IGF-1 offer a moderate, centrally mediated, neuroprotective effect, likely mediated at least in part via a growth factor mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Ascorbate antagonizes the behavioral effects of amphetamine by a central mechanism.

The behavioral response to amphetamine was monitored in rats that received simultaneous intraventricular infusions of saline or ascorbate. Both groups of animals displayed comparable responses, although ascorbate significantly delayed the onset of amphetamine-induced locomotion and rearing. In rats pretreated with a threshold dose of haloperidol (0.025 mg/kg), virtually all aspects of the amphetamine response were attenuated, and this effect was enhanced by ascorbate. In haloperidol-pretreated rats, ascorbate significantly lowered sniffing and forepaw shuffling throughout the amphetamine response. These results suggest that ascorbate antagonizes dopaminergic transmission by a central mechanism.

Amphetamine↗

PubMed1976

Effect of intraventricular administration of isoprenaline on urinary function in the goat.

Intraventricular infusion of small doses of isoprenaline (ISO) in conscious non-hydrated goats produced a significant diuretic response, as well as a decrease in the excretion rate of Na+, K+ and Cl- in the urine; these effects were dose-dependent. An increase in free water clearance was observed as well. Pretreatment with propranolol, injected into the 3rd ventricle, completely abolished the ISO-induced diuretic effects, whereas phentolamine was ineffective. The data suggest that hypothalamic beta-adrenoreceptors are concerned with an inhibition of vasopressin release, inducing a diuretic response.

Animals↗

PubMedDate not supplied

Opposite effects of intraventricular serotonin and bufotenin on rat startle responses.

Rat startle responses to air puffs were monitored in a stabilimeter during the intraventricular infusion of various doses of 5-hydroxytrptamine (5-HT) or the putative hallucinogenic congener of 5-HT, 5-hydroxy-N, N-dimethyltrytamine (5-HDMT) or saline. Qualitativity opposite effects were observed, with 5-HT producing a dose-dependent decrease in responsivity and 5-HDMT increasing the magnitude of startle responses. No specific effects of either compound could be demonstrated on the presumably separable processes of sensitization and habituation. The results are discussed in the context of a central serotonergic system which facilitates behavioral inhibition and which is antagonized by indoleamine hallucinogens.

Animals↗

PubMed1981

Effects of sleep-promoting factor from human urine on sleep cycle of cats.

Slow-wave sleep (SWS) and rapid-eye-movement sleep (REM) were recorded in cats for 32 h a) under control conditions, b) following intraventricular infusions of artificial cerebrospinal fluid (CSF), and c) following infusions of sleep-promoting factor S prepared from human urine (SPU). During the first 12 h after receiving artificial CSF, the cats slept 4.9 +/- 0.2 h in slow-wave sleep (SWS) and 1.4 +/- 0.1 h in REM. Similar values were obtained from the same cats under control conditions. After infusions of SPU, the duration of SWS in the same cats increased to an average of 6.9 +/- 0.5 h with no significant change in REM averaged over 12 h; a transient decrease of REM in the first 4 h was fully compensated in subsequent hours. The increased SWS induced by the sleep-promoting factor from human urine subsided after 12 h, and there was no compensatory increase in wakefulness during the subsequent 20 h. The normal sleep cycle was not affected. In cats, therefore, the primary effect of SPU is to increase normal SWS, with little effect on REM.

Animals↗

PubMed1997

Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington's disease.

The present study determined the effects of intraventricularly administered glial cell line-derived neurotrophic factor on the behavioral and neurochemical sequelae of unilateral excitotoxic lesions of the striatum. Distinct asymmetrical rotational behavior in response to peripheral administration of amphetamine (5 mg/kg) was noted one and two weeks following injections of quinolinic acid (200 nmol) into two sites in the left striatum. In rats given a single intraventricular injection of glial cell line-derived neurotrophic factor (10-1000 micrograms) 30 min before the toxin, amphetamine-induced rotational behavior was significantly attenuated. Analysis of Nissl-stained coronal sections showed marked neuronal loss in the striatum ipsilateral to the quinolinic acid injections, which was at least partially prevented by glial cell line-derived neurotrophic factor D1 and D2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GABAergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neurotrophic factor treatment to a similar degree, suggesting that the two subpopulations of GABAergic striatal output neurons are equally vulnerable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [3H]GABA uptake into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [3H]choline and [3H]dopamine uptake into striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide levels of similar magnitude were evident ipsilateral to the lesion; substance P, met-enkephalin and dynorphin A contents in the globus pallidus and substantia nigra were significantly reduced. Striatal somatostatin and neuropeptide Y levels were not altered. All of the neurochemical deficits induced by striatal quinolinic acid lesions were attenuated by intraventricular delivery of glial cell line-derived neurotrophic factor. Continuous intraventricular infusion of this trophic factor (10 micrograms/day) over a two-week period did not afford notable improvement compared to the single injection of 10 micrograms. In contrast, continuous infusion of brain-derived neurotrophic factor (10 micrograms/day) directly into the striatum did not affect any of the neurochemical parameters studied. However, neurotrophin-3 (10 micrograms/day) delivery into the striatum significantly increased [3H]GABA uptake, but only modestly affected [3H]choline uptake. The results indicate that glial cell line-derived neurotrophic factor counteracts neuronal damage induced by a striatal excitotoxic insult and support its potential use as a treatment for central nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease.

Animals↗

PubMed2001

The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells.

The cytokines that signal through the common receptor subunit gp130, including ciliary neurotrophic factor (CNTF), interleukin-6, leukemia inhibitory factor (LIF) and oncostatin M, have pleiotropic functions in CNS development. Given the restricted expression domain of the CNTF receptor alpha (CNTFR) in the developing forebrain germinal zone and adult forebrain periventricular area, we have examined the putative role of CNTFR/LIFR/gp130-mediated signaling in regulating forebrain neural stem cell fate in vivo and in vitro. Analysis of LIFR-deficient mice revealed that a decreased level of LIFR expression results in a reduction in the number of adult neural stem cells. In adult LIFR heterozygote (+/-) mice, the number of neural stem cells and their progeny in the forebrain subependyma and TH-immunoreactive neurons in the olfactory bulb were significantly reduced. Intraventricular infusion of CNTF into the adult mouse forebrain, in the absence or presence of epidermal growth factor (EGF), enhanced self-renewal of neural stem cells in vivo. Analyses of EGF-responsive neural stem cells proliferating in vitro found that CNTF inhibits lineage restriction of neural stem cells to glial progenitors, which in turn results in enhanced expansion of stem cell number. These results suggest that CNTFR/LIFR/gp130-mediated signaling supports the maintenance of forebrain neural stem cells, likely by suppressing restriction to a glial progenitor cell fate.

Animals↗

PubMed2000

Brain-blood permeability: TNF-alpha promotes escape of protein tracer from CSF to blood.

The objective of this study was to determine the effect of tumor necrosis factor (TNF)-alpha on the efflux of protein from the central nervous system to blood based on assessing the clearance of radiolabeled albumin from the cerebrospinal fluid (CSF) to blood in rats. (125)I-labeled human serum albumin ((125)I-HSA) was injected into a lateral ventricle, and venous blood was sampled hourly to determine the basal CSF protein clearance into the blood. After this, rats were intraventricularly infused with 10 microliter TNF-alpha and 10 microliter (131)I-HSA (n = 6) or 10 microliter saline and 10 microliter (131)I-HSA (n = 6). Venous blood was sampled hourly for 3 h. (131)I-HSA tracer recovery increased threefold in the venous blood and was significantly higher in the spleen, muscles, and skin in animals treated with TNF-alpha. No significant changes were observed in control animals treated with saline. The data suggest that TNF-alpha promotes the clearance of protein macromolecules from the CSF to the venous blood.

Animals↗

PubMed1993

Antisense oligodeoxynucleotide reduces brain dopamine D2 receptors: behavioral correlates.

Intraventricular infusion of an antisense oligodeoxynucleotide corresponding to the rat dopamine D2 receptor mRNA reduced rat striatal D2 receptors by 485, as measured by homogenate binding assays, while D1, muscarinic, and serotonin 5-HT2 receptors were unaffected. D2 receptor autoradiography indicated a homogeneous down-regulation of about 50% throughout the striatum and over 70% in the nucleus accumbens. A random oligodeoxynucleotide failed to affect either striatal D2 or D1 receptor density. The antisense treatment inhibited the D2 receptor agonist quinpirole-induced locomotor activation, without altering grooming behavior induced by SKF38393, a D1 receptor agonist. Antisense treatment also elicited catalepsy and reduced spontaneous locomotor activity.

Animals↗

PubMed1994

Lesions of central serotonin systems affect responding on a progressive ratio schedule reinforced either by intravenous cocaine or by food.

The effect of intraventricular infusions of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), was examined in rats trained on a progressive ratio schedule for either IV cocaine or food reinforcement. Animals in the 5,7-DHT treatment group responded to significantly higher breaking points than vehicle-injected control animals, regardless of whether food or cocaine was used as the reinforcing stimulus. Analysis of the regional brain amines indicated that depletions of mesencephalic 5-HT correlated with postsurgical alterations in responding. These findings suggest that depletion of forebrain 5-HT produces a general effect on responding rather than a specific alteration in the reinforcing effects of psychomotor stimulant drugs.

5,7-Dihydroxytryptamine↗

PubMed2003

Morphology and ultrastructure of rat hippocampal formation after i.c.v. administration of N-acetyl-L-aspartyl-L-glutamate.

N-Acetyl-L-aspartyl-L-glutamate (NAAG) is one of the most abundant neuroactive compounds in the mammalian CNS. Our recent observations have suggested that NAAG administered into rat cerebral ventricles can cause neuronal death by apparently excitotoxic mechanisms that can be antagonized by the N-methyl-D-aspartate-receptor blockers and by ligands of metabotropic glutamate receptor of Group II. Therefore, the principal aim of the present study has been to use quantitative morphology, electron microscopy and terminal deoxynucleotidyl transferase-mediated biotin dUTP nick-end labeling to study a dose- and time-dependence as well as regional distribution of neurodegeneration in hippocampi of rats after the intraventricular infusion of 0.25 micromol NAAG/ventricle and of equimolar doses of L-glutamate (L-GLU) and N-acetyl-L-aspartate (NAA), breakdown products of NAAG. The degenerative changes were observed after the infusion of 0.25 and 1.25 micromol of NAAG/ventricle, but not when a dose of 0.05 micromol of NAAG/ventricle was injected into each lateral cerebral ventricle. With a dose of 0.25 micromol of NAAG/ventricle the number of degenerated neurons reached a maximum on the fourth day after the infusion. The neuronal damage following bilateral administration of 0.25 micromol of NAAG/lateral cerebral ventricle exhibited features of a delayed neuronal degeneration, expressed mainly in the layer of dentate granule neurons. The degeneration was characterized on the basis of ultrastructural appearance and DNA-fragmentation. The morphological changes caused by L-glutamate and NAA were much smaller than those observed after the administration of NAAG and displayed a different pattern of regional distribution. The present findings suggest that NAAG can cause a loss of hippocampal neurons in vivo, apparently resulting from the neurotoxicity of NAAG itself.

Animals↗

PubMed1984

Uridine as an active component of sleep-promoting substance: its effects on nocturnal sleep in rats.

A 10-h intraventricular infusion of 10 pmol of uridine from 19.00 to 05.00 h resulted in significant increases in sleep in otherwise saline-infused male rats (n = 8) during the environmental dark period (20.00-08.00 h). Increments of slow wave sleep (SWS) and paradoxical sleep (PS) were 21.0% and 68.1%, respectively, of the baseline value. This was due to increases in the frequencies of both SWS and PS episodes but not to their durations. Similar increases occurred the first recovery night under saline infusion, but sleep amounts returned to the baseline levels the second night. Brain temperature was not affected by uridine administration. A small dose of uridine (1 pmol/10 h) exerted no effect (n = 6) while larger doses (100 and 1000 pmol/10 h, each n = 5) resulted in slight but insignificant increases in SWS and PS. The 1000-pmol uridine administration seemed to be non-physiological since it brought about irregularities in locomotor activity and sleep-waking rhythms. Thus, authentic uridine exhibited the same sleep-enhancing effects as a naturally occurring active component of sleep-promoting substance, which was recently identified with uridine.

Animals↗

PubMed1982

Electrophysiologic correlates of steroid modulation of luteinizing hormone release.

In both ovariectomized (OVX) and steroid-primed OVX freely moving rats, attempts were made to correlate the effects of intraventricular norepinephrine (NE) on multiunit activity (MUA) of different brain regions with NE-induced alterations in blood LH levels. MUA-recording electrodes were implanted in the diagonal band of Broca (DBB), medial preoptic area (MPOA), arcuate nucleus (ARC) and/or ventromedial hypothalamic nucleus (VMH). Steroid priming included 50 micrograms estradiol benzoate (EB) and 25 mg progesterone (P) 3 days prior to experiment. The unanesthetized animals were bled via indwelling atrial cannulas before and after intraventricular infusion of NE (10 micrograms in 2 microliters over 2 min). In OVX-primed rats NE lengthened the interval between episodic LH peaks and decreased mean blood LH levels. In contrast, in OVX-EBP-primed rats, NE stimulated an LH surge. Concurrent recording of MUA revealed that, in OVX-unprimed rats, NE dramatically depressed MUA in both DBB-MPO and ARC-VMH neurons. However, in OVX-EBP-primed rats, while still markedly inhibiting ARC-VMH units, NE failed to depress MUA recorded in DBB-MPO sites (some units were actually excited by NE), perhaps reflecting the higher ratio of LHRH neurons/inhibitory neurons in DBB-MPO.

Action Potentials↗

PubMed1992

bFGF promotes the survival of entorhinal layer II neurons after perforant path axotomy.

Infusion of basic fibroblast growth factor (bFGF) prevents the loss of cholinergic neurons in the septum/diagonal band of broca following fimbria-fornix transection. However, an in vivo test of whether bFGF will also rescue injured non-cholinergic or cortical neurons has not been carried out. Previous studies have shown that the majority of layer II stellate neurons utilize an excitatory amino acid as their neurotransmitter. In order to determine if bFGF acts on non-cholinergic cortical neurons, a paradigm was developed to examine whether or not bFGF could spare layer II entorhinal stellate cells from axotomy induced death or atrophy. Axotomy of the medial entorhinal cortex fibers projecting to the dentate gyrus of the hippocampal formation via the perforant path lead to retrograde cell loss in entorhinal cortex. Fourteen or thirty days after a unilateral knife cut axotomy of the perforant path, layer II of medical entorhinal cortex showed a 28% decrease in large stellate neurons as well as many weakly stained, hollow cells compared to the non-lesioned side or naive controls. Layer IV neurons, however, which do not project via the perforant path, showed little detectable change in the number of cells ipsilateral to the knife-cut as compared to the contralateral side. Intraventricular infusion of bFGF over a period of 14 days reduced the 28% cell loss to less than 6%. Thus, bFGF is capable of preventing cortical neuronal loss and/or atrophy associated with retrograde degeneration of non-cholinergic neurons following axotomy.

Animals↗

PubMed1983

Effects of intraventricular administration of catecholamines on luteinizing hormone release in morphine-treated rats.

Morphine (M) treatment has been shown to suppress LH release in rats. These studies were undertaken to determine whether a decrease in the response of LHRH neurons to excitatory neurotransmitters may be responsible for the depressed LH secretion in M-treated rats. Ovariectomized rats bearing permanent cannulae in the third ventricle of the brain were primed with estradiol benzoate and progesterone; 3 days later, they received M (20 mg/kg, sc) or saline (controls). The effects of two intraventricular (Ivt) 2-min pulses delivered 80 min apart of vehicle (artificial cerebrospinal fluid), dopamine, norepinephrine, or epinephrine (E) on LH release were assessed. Basal blood LH levels were undisturbed by Ivt administration of vehicle in saline-treated rats. Intraventricular infusions of dopamine (5.3 micrograms/pulse) also failed to evoke LH release in saline-treated rats. However, similar pulse norepinephrine or E infusions (5.3 micrograms/pulse) readily elicited well defined episodes of LH hypersecretion. The magnitude and temporal pattern of LH responses in the control and M-treated rats were quite similar. In another experiment, the progesterone-induced afternoon LH surge was blocked by M treatment of estradiol benzoate-primed rats. In these blocked rats, Ivt administration of E evoked rapid and substantial LH secretion. Thus, our results failed to demonstrate any evidence of diminution in the response of LHRH neurons to excitatory neurotransmitters in M-treated rats. On the other hand, they lend credence to the view that a decreased influx of adrenergic signals in the vicinity of the LHRH neurons may result in the suppression of LH release after M administration.

Animals↗