Effects Of Intracerebroventricular Administration Research Articles

Beta-Amyloid and Its Asp7 Isoform: Morphological and Aggregation Properties and Effects of Intracerebroventricular Administration.

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of aggregated beta-amyloid (Aβ) protein in the form of senile plaques within brain tissue. Senile plaques contain various post-translational modifications of Aβ, including prevalent isomerization of Asp7 residue. The Asp7 isomer has been shown to exhibit increased neurotoxicity and induce amyloidogenesis in brain tissue of transgenic mice. The toxicity of Aβ peptides may be partly mediated by their structure and morphology. In this respect, in this study we analyzed the structural and aggregation characteristics of the Asp7 isoform of Aβ42 and compared them to those of synthetic Aβ42. We also investigated the effects of intracerebroventricular (i.c.v.) administration of these peptides, a method often used to induce AD-like symptoms in rodent models. Atomic force microscopy (AFM) was conducted to compare the morphological and aggregation properties of Aβ42 and Asp7 iso-Aβ42. The effects of i.c.v. stereotaxic administration of the proteins were assessed via behavioral analysis and reactive oxygen species (ROS) estimation in vivo using a scanning ion-conductance microscope with a confocal module. AFM measurements revealed structural differences between the two peptides, most notably in their soluble toxic oligomeric forms. The i.c.v. administration of Asp7 iso-Aβ42 induced spatial memory deficits in rats and elevated oxidative stress levels in vivo, suggesting a potential of ROS in the pathogenic mechanism of the peptide. The findings support the further investigation of Asp7 iso-Aβ42 in translational research on AD and suggest its involvement in neurodegenerative processes.

Anandamide modulates the neuroendocrine responses induced by extracellular volume expansion

(1) The aim of the present study was to evaluate the effects of intracerebroventricular administration of anandamide (AEA), an inhibitor of fatty acid amide hydrolase activity (URB597) and a CB1 receptor (CB1 R) antagonist (AM251) on the homeostatic responses elicited by extracellular volume expansion (EVE) in male adult rats. (2) Pretreatment with AEA (100 ng/4 μL) significantly reduced the effect of hypertonic (H-) EVE on plasma concentrations of prolactin (PRL), oxytocin (OT) and corticosterone, but not vasopressin (AVP). Administration of URB597 (20 μg/5 μL) alone significantly reduced PRL, OT, AVP and corticosterone in the H-EVE group. Conversely, URB597 and AEA had no significant effect on basal hormone concentrations. Pretreatment with AM251 (200 ng/2 μL) potentiated OT but did not change AVP plasma levels in the H-EVE group. (3) Hypertonic EVE significantly increased AVP and OT mRNA expression in the supraoptic nucleus (SON), an effect that was blunted in AEA-pretreated rats. Pretreatment with AEA did not change the percentage of vasopressinergic or oxytocinergic neurons colocalizing c-Fos in the SON, but increased nitrate concentrations in the median eminence of animals subjected to H-EVE. (4) The present data suggest that: (i) vasopressinergic and oxytocinergic neurons may be differentially affected by AEA; (ii) activation of CB1 R may restrain the response of the neurohypophyseal system (NHS) to EVE; (iii) the hypothalamic-pituitary-adrenal axis, PRL and the NHS may still be sensitive to AEA after EVE, with these effects probably not dependent on AEA metabolism; and (iv) AEA and nitric oxide could interact in vivo as modulators to directly control stress-induced responses.

P.5.a.006 The effect of intracerebroventricular administration of (25–35)-β-amyloid fragment on EEG and cognition in the rat – a pilot study

P.5.a.006 The effect of intracerebroventricular administration of (25–35)-β-amyloid fragment on EEG and cognition in the rat – a pilot study

Antinociceptive effect of intracerebroventricular administration of d-serine on formalin-induced pain

In a previous study using the tail-flick test, we found that intracerebroventricular administration of D-serine, an endogenous co-agonist at the glycine sites of N-methyl-D-aspartate (NMDA) receptors, elicited an antinociceptive effect on thermal nociception. The purpose of the present study was to evaluate the effect of intracerebroventricular administration of D-serine on nociception induced by tissue damage or inflammation using the formalin test. Infusion of drugs into the third ventricle in rat was performed via indwelling cannulae. Drugs were infused at a volume of 10μl over 2min, and the infusion cannula was left in place for 2min before removal. The formalin test was performed 10min after drug administration. Intracerebroventricular administration of D-serine significantly and dose-dependently decreased the number of flinches in both the early and late phases in the formalin test. This antinociceptive effect was antagonized by intracerebroventricular administration of L-701,324, a selective antagonist at the glycine sites of NMDA receptors. The present data suggest that activation of NMDA receptors via glycine sites at the supraspinal level induces an antinociceptive effect on both acute and tonic pain.

Impairment of brain redox homeostasis caused by the major metabolites accumulating in hyperornithinemia–hyperammonemia–homocitrullinuria syndrome in vivo

Ornithine, ammonia and homocitrulline are the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.

Changes in Cell Proliferation in the Subventricular Zone of the Brain in Adult Rats Given β-Amyloid Peptide (25–35)

The effects of intracerebroventricular administration of fragment (25-35) of beta-amyloid peptide [Abeta(25-35)] on cell proliferation in the subventricular zone of the dentate gyrus of the hippocampus in adult rats were analyzed. Animals received doses of 15 nmol of pre-aggregated Abeta(25-35) or the Abeta(35-25) control peptide, or solvent (sterile water) into the lateral ventricles. On post-injection days 1-5, rats received intraperitoneal injections of the thymidine analog 5-bromo-2'-deoxyuridine (BrdU). BrdU incorporated into DNA was detected immunohistochemically on frontal brain sections six and 12 days after peptide administration. At six days, the numbers of BrdU-containing cells in the subventricular zone showed no differences between the study groups. At 12 days, the total number of BrdU-positive cells decreased significantly in all study groups. At the same time, the number of labeled cells in rats given Abeta(25-35) was significantly greater in this brain zone than in animals given water or the control peptide. Thus, Abeta(25-35) significantly increased cell proliferation in the subventricular zone after intracerebroventricular administration.

Relationships between the sedative and hypnotic effects of intracerebroventricular administration of L-serine and its metabolites, pyruvate and the derivative amino acids contents in the neonatal chicks under acute stressful conditions

Intracerebroventricular (i.c.v.) injection of L-serine was shown to have sedative and hypnotic effects on neonatal chicks under acute stressful conditions. To clarify the central mechanism of these effects of L-serine, two experiments were done. First, we focused on the glycogenic pathway in which L-serine is converted into pyruvate and finally glucose. I.c.v. administration of pyruvate (0.84 micromol) did not induce any behavioral and endocrinological changes, while L-serine and glucose triggered sedative and hypnotic effects. Secondly, the relationship between the sedation by L-serine and the metabolism into other amino acids which have sedative effects was investigated in the telencephalon and diencephalon. In both brain areas, a dose-dependent increase was seen in L-serine, although other amino acids were not changed. In the present study, it was concluded that the sedative action of L-serine was not due to the action of its metabolite pyruvate, or to the action of other amino acids.

Effects of intracerebroventricular administration of ultra low doses of histaminergic drugs on morphine state-dependent memory of passive avoidance in mice

The effects of intracerebroventricular (i.c.v.) administration of ultra low doses (ULDs) of histamine, clobenpropit and pyrilamine are studied on morphine state-dependent (STD) memory in mice. Although pre-test administration of different doses of histamine and clobenpropit showed no effect on impairment of memory induced by pre-training morphine, when the above drugs were co-administered with morphine, they inhibited the restoration of memory by morphine. These effects were opposite to microgram doses of the same drugs.

Evaluation of neuromedin U actions in energy homeostasis and pituitary function.

The brain-gut peptide neuromedin U (NMU) has been identified recently as a physiological regulator of food intake. To further investigate the central role of NMU in energy homeostasis, we examined the distribution of NMU transcript and the effect of intracerebroventricular administration on several physiological parameters and on the pattern of c-Fos activation. Here we report that intracerebroventricular administration of NMU to 24-h fasted rats resulted in a decrease in subsequent food intake and body weight gain. NMU administration activated neurons in several brain regions implicated in the regulation of feeding behavior. Activated cells included catecholaminergic neurons of the arcuate nucleus and brain stem. Distribution studies revealed NMU expression in the caudal brain stem (nucleus of the solitary tract and inferior olive) and pituitary, with significant levels in the pars tuberalis. This contradicts earlier published observations. In obese (fa/fa) Zucker rats, decreases in NMU expression were detected in the nucleus of the solitary tract, pars tuberalis, and pars distalis, whereas in the fasted rat, a decrease in NMU transcript was detected in the pars distalis. These results confirm the effects of NMU on feeding and suggest additional roles for NMU in neuroendocrine function.

Both cerebral GABA(A) receptors and spinal GABA(A) receptors modulate the capacity of isoflurane to produce immobility.

We previously demonstrated that intrathecal administration of the noncompetitive gamma-aminobutyric acid type A (GABA(A)) receptor antagonist picrotoxin increased isoflurane MAC (the minimum alveolar concentration of anesthetic producing immobility in 50% of animals) by a maximum (ceiling effect) of approximately 40%. We also found that IV administration of picrotoxin increased MAC by more than 60%, without evidence of a ceiling effect. The larger increase with IV administration suggested a role of cerebral GABA(A) receptors. Accordingly, in this study we examined the effect of intracerebroventricular administration of picrotoxin in rats, finding that picrotoxin infusion into the third ventricle increased isoflurane MAC by a maximum of approximately 40%, without finding a ceiling effect. In addition, we concurrently infused picrotoxin into the intrathecal and intracerebroventricular spaces, producing an increase in MAC in excess of 70%, also with no evidence of a ceiling effect. The dose-response relationship for the intrathecal-intraventricular infusion paralleled that of the IV infusion but was shifted to the left by an order of magnitude. We conclude that both cerebral and spinal GABA(A) receptors modulate the capacity of inhaled anesthetics to produce immobility. Because other studies have shown that the spinal cord, and not the brain, mediates the capacity of inhaled anesthetics to produce immobility, these results call into question the relevance of GABA(A) receptors to the immobilizing action of isoflurane.

Intracerebroventricular infusion of fibroblast growth factor-1 increases Fos immunoreactivity in periventricular astrocytes in rat hypothalamus

When released into the third ventricle of the brain, fibroblast growth factor (FGF)-1 acts as a feeding suppressor. To identify the cells that respond to FGF-1 in this process, we investigated the effects of intracerebroventricular administration of FGF-1 on Fos protein expression in the rat hypothalamus. Two hours after infusion of FGF-1, significantly more Fos signals were observed in the periventricular zone of the third ventricle and its surroundings. Double immunohistochemical studies using antibodies against Fos, glial fibrillary acidic protein, and neuronal nuclei revealed that the FGF-1-induced Fos signals in the periventricular zone were in astrocytes, not in neurons. FGF-1-induced Fos expression was not found in neurons in such hypothalamic nuclei as the lateral hypothalamic area, paraventricular nucleus, ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, or arcuate nucleus. These results suggest a possible involvement of periventricular astrocytes in the early stages of FGF-1-induced feeding suppression.

Role of cholinergic and GABAergic neurotransmission in the opioids-mediated GnRH release mechanism of EBP-primed OVX rats.

The effect of intracerebroventricular administration of mu-opioid agonist, morphine (a drug of potential abuse), and its antagonist, naloxone, followed by morphine was studied on the metabolism of acetylcholine and gamma amino butyric acid in seven discrete regions of brain from EBP-primed ovariectomized rats. We also assayed serum luteinizing hormone and follicle stimulating hormone after morphine and naloxone + morphine treatments. Cholineacetyltransferase and acetylcholinesterase, gamma-aminobutyric acid transaminase, succinic semialdehyde dehydrogenase and glutamate dehydrogenase activities were found to decrease significantly in hypothalamic as well as other brain regions studied. Naloxone given prior to morphine injection was seen to reverse the effect of morphine on enzymes activities. Our study provides evidence that opioidergic modulation of GnRH release is mediated through cholinergic and GABAergic neurotransmission besides monoaminergic control and the results may further help to elucidate the basis of neuronal dysfunction in opiate addicts.

The anesthetic interaction between adenosine triphosphate and N-methyl-D-aspartate receptor antagonists in the rat.

Modulation of synaptic neurotransmission through the ligand-gated ion channel is probably involved in the mechanisms of analgesic and anesthetic actions. In the central nervous system, adenosine triphosphate and glutamate are fast excitatory neurotransmitters through their effects on P2X and N-methyl-D-aspartate (NMDA) receptors respectively. To examine the anesthetic interaction between adenosine triphosphate and NMDA receptor antagonists, we studied the effect of intracerebroventricular administration of P2 and/or NMDA antagonists on the minimum alveolar concentration (MAC) of sevoflurane in rats. Intracerebro- ventricular administration of phosphonopentanoic acid azophenyl-2',4'-disulfonate and D (-)-2-anino-5-phophonopentanoic acid, P2 and NMDA antagonists, significantly reduced the MAC of sevoflurane. The reduction of the MAC by both phosphonopentanoic acid azophenyl-2',4'-disulfonate and D (-)-2-anino-5-phophonopentanoic acid was dose-dependent. The effect of coadministration of both antagonists was additive in the reduction of sevoflurane minimum alveolar concentration. These results suggest that P2 and NMDA receptors mediate nociceptive/anesthetic processing as inhibition of these receptors resulted in analgesic and anesthetic effects. However the pathway mediated through each receptor may be different postsynaptically and/or one of these presynaptic receptors may modulate the neurotransmitter release of the other.

Tachykinin-induced stimulation of neuropeptide Y gene expression in the rat arcuate nucleus.

Previous neurocytochemical data indicate the presence of synaptic contacts between tachykinergic terminals and neuropeptide Y (NPY) neurons in the arcuate nucleus of the rat suggesting that tachykinins may regulate NPY neuronal activity. To examine the functional signification of such regulation, the effect of intracerebroventricular administration of neurokinin A on NPY mRNA levels was studied using in situ hybridization. Repeated treatment with NKA (40 microg/day for 3 days) induced a 44% increase in NPPY mRNA expression compared with saline-injected control animals. These results demonstrate a positive effect of tachykinins on NPY gene expression and suggest either a direct or indirect control of arcuate NPY neurons by endogenous tachykinins.

Antinociceptive effect of intracerebroventricular administration of cholecystokinin antagonist in nerve-ligated mice.

In the present study we investigated the effects of intracerebroventricular injection of caerulein, the cholecystoki nin receptor agonist and proglumide, the receptor antagonist on morphine response in the sciatic nerve ligation in mice. Subcutaneous administration of morphine induced antinociception in the both intact and ligated mice, however, the response of the opioid was lower in the ligated mice as compared with the intact animals. Caerulein induced antinociception in the non-ligated but not in the nerve-ligated animals. Combination of caerulein with morphine elicited higher response in ligated animals, however, the response induced in ligated animals was much more prominent. Proglumide alone did not elicit any response in both animal groups. The antagonist decreased the response of caerulein in the nonligated mice. Low doses of proglumide in the combination with caerulein induced antinociception in the ligated mice. We conclude that cholecystokinin receptor mechanism(s) may alter morphine resistance induced by nerve ligation.

Effects of different periods of lithium pretreatment and aminoglycoside antibiotics on apomorphine-induced yawning in rats.

Interactive effects of intracerebroventricular administration of the aminoglycoside antibiotics, amikacin and gentamicin, and different duration of lithium pretreatment on apomorphine-induced yawning were investigated in male rats. The study was designed to investigate whether the hypothesis that the aminoglycoside antibiotics, amikacin and gentamicin, via their effects on phosphoinositide pathways and calcium channel might influence dopaminergic mechanisms as manifested in the yawning effect. Lithium is known to interact with phosphoinositide metabolism and was also tested after chronic studies on the apomorphine yawning model. Subcutaneous administration of apomorphine (0.1, 0.2 and 0.4 mg/kg) to rats induced yawning in a biphasic manner. However the maximum response was obtained by 0.2 mg/kg of the drug. Intracerebroventricular administration of aminoglycoside antibiotics amikacin (25 microg/rat) increased and gentamicin (10 and 20 microg/rat) decreased apomorphine-induced yawning. Pretreatment of animals with lithium (600 mg/l) in drinking water for 7, 14 and 21 days reduced yawning induced by apomorphine. Administration of lithium for 28 days did not induce any significant effect on yawning response. Amikacin and gentamicin function via the same mechanism on phosphoinositide cascade. Since amikacin and gentamicin did not affect the yawning response similarly, they apparently do not involve inositol trisphosphate level in the alterations of dopaminergic-induced yawning. Probably, the effect of lithium pretreatment on the number of yawns is also time-dependent and some tolerance to the inhibitory effect of lithium might occur after 28 days' treatment.

Central losartan blocks natriuretic, vasopressin, and pressor responses to central hypertonic NaCl in sheep.

This study investigated the effect of intracerebroventricular administration of the angiotensin AT1 receptor antagonist losartan on the natriuresis, pressor effect, and arginine vasopressin (AVP) secretion caused by intracerebroventricular infusion of either ANG II, hypertonic saline, or carbachol. Losartan (1 mg/h) or artificial cerebrospinal fluid (CSF) was infused into the lateral ventricle before, during, and after infusions of either ANG II at 10 microg/h for 1 h, 0.75 mol/l NaCl at 50 microl/min for 20 min, or carbachol at 1.66 microg/min for 15 min. Intracerebroventricular infusions of ANG II, 0.75 mol/l NaCl, or carbachol caused increases in renal Na+ and K+ excretion, arterial pressure, and plasma AVP levels. Increases in arterial pressure, Na+ excretion, and plasma AVP concentration ([AVP]) in response to intracerebroventricular ANG II or intracerebroventricular 0.75 mol/l NaCl were either abolished or attenuated by intracerebroventricular infusion of losartan but not by intracerebroventricular infusion of artificial CSF or intravenous losartan. Intracerebroventricular losartan did not reduce the increase in plasma [AVP] or arterial pressure in response to intracerebroventricular carbachol, but it did attenuate the natriuretic response to intracerebroventricular carbachol. We conclude that an intracerebroventricular dose of losartan (1 mg/h) that inhibits responses to intracerebroventricular ANG II also inhibits vasopressin secretion, natriuresis, and the pressor response to intracerebroventricular hypertonic saline. These results suggest that common neural pathways are involved in the responses induced by intracerebroventricular administration of ANG II and intracerebroventricular hypertonic NaCl. We propose that intracerebroventricular infusion of hypertonic saline activates angiotensinergic pathways in the central nervous system subserving the regulation of fluid and electrolyte balance and arterial pressure in sheep.

Central injection of physostigmine attenuates exercise-induced pressor response in conscious cats

The effects of intracerebroventricular administration of physostigmine, a cholinesterase inhibitor, on the cardiovascular responses evoked by static voluntary exercise were investigated using conscious cats. Four cats were trained to press a bar (200-650 g) with one forelimb for at least 20 s. The changes in mean arterial pressure (MAP), heart rate (HR), and developed force during the first five trials in 30 min by each individual cat were averaged, and a mean of the four values was then calculated. After the cats exercised for 30 min, either artificial cerebrospinal fluid (CSF) or physostigmine (5 micrograms) was administered intracerebroventricularly. Before physostigmine, exercise trials by the cats increased MAP and HR by 17 +/- 3 mmHg and 42 +/- 4 beats/min, respectively. Administration of physostigmine did not alter the resting MAP and HR but attenuated the MAP and HR responses to exercise (5-30 min postphysostigmine: MAP = 8 +/- 3 mmHg, HR = 25 +/- 7 beats/min; 30-60 min postphysostigmine: MAP = 4 +/- 3 mmHg, HR = 19 +/- 8 beats/min). Intracerebroventricular administration of CSF had no effect on the cardiovascular responses to static exercise. Pretreatment with the muscarinic antagonist, atropine (25 micrograms icv), blocked the attenuating effects of subsequent intracerebroventricular administration of physostigmine. These results demonstrate that stimulation of central muscarinic receptors attenuates the cardiovascular responses to static exercise by conscious cats. In addition, the present study suggests that there is no tonic effect of central muscarinic receptors on the cardiovascular responses to voluntary exercise.

Effect of Intracerebroventricular Administration of Vasopressin on Stress-Induced Hyperthermia in Rats

Effect of Intracerebroventricular Administration of Vasopressin on Stress-Induced Hyperthermia in Rats

Effects of intracerebroventricular administration of ethylcholine aziridinium (AF64A) on dopaminergic nervous systems

Changes in dopaminergic activities were investigaed after the intracerebroventricular (icv) administration of ethylcholine aziridium (AF64A) in rats. The levels of dopamine (DA) and metabolites, the activities of tyrosine hydroxylase (TH) and monoamine oxidase (MAO), and the specific binding sites of dopamine receptors in striata, hippocampus, and frontal cortex were assessed 6 days after the AF64A treatment with 3 nmol/each ventrcle. In frontal cortex, the levels of DA and metabolites were significantly decreased without changes in metabolites/DA ratios in the AF64A-treated groups. In contrast, the ratios of metabolites/DA were significantly decreased in striatum and hippocampus in the AF64A treatment. The activity of TH in frontal cortex was significantly decreased. However, that in other areas was not changed. Also the activity of MAO-A was not changed in the studied brain regions. However, the activity of MAO-B in striatum was significantly increased with no change in other areas. The specific binding sites of dopamine D1 and D2 receptors were increased in AF64A-treated frontal cortex. However, those were not changed in striatum and hippocampus except the small decreased specific binding sites of dopamine D-1 receptors in striatum after AF64A treatment. These results indicate that the dopaminergic activity was altered in AF64A treatment. Furthermore, it suggests that the decreased dopaminergic activities in each brain regions might be differently affected by AF64A treatment.