Intraventricular Research Articles

Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration

We evaluated the delivery of 14 C -cytosine arabinoside (AraC) to rat brain by: 1) intravenous (IV) bolus, by 2) intrathecal (IT) and 3) intraventricular (IVT) infusion, and by 4) convection-enhanced delivery (CED) into the caudate nucleus. Plasma and brain AraC metabolites were measured with HPLC, and distribution and concentration of 14 C -AraC in brain sections were measured by quantitative autoradiography. After IV administration, the α and β plasma half-lives were 1.9 and 46.5 min, respectively. The blood-to-brain transfer constant of AraC was 2.5±1.4 μl g −1 min −1, compatible with high water solubility. After IT and IVT administration, tissue levels were high at the brain and ventricular surfaces, but declined exponentially into brain. After CED, maximum brain levels were up to 10,000 times higher than the IV group, and the distribution pattern was one of high 14 C -AraC concentration in the convective component, with exponentially declining concentrations outside this region. The rate loss constant from brain was 0.002±0.0004 min −1, suggesting that AraC was accumulating in brain cells. AraC was metabolized into uracil arabinoside within the brain. 14 C -AraC was infused into 1 dog and distributed widely in the ipsilateral hemisphere. These studies suggest that delivery of AraC to brain parenchyma by the IV, IT or IVT routes will be subtherapeutic. Delivery by CED can achieve, and maintain, therapeutic levels of AraC in the brain, and should be further evaluated as a potential method of drug delivery.

Thalamostriate Vasculopathy in Neonates in the MAGnet Trial: Association with Placental Funisitis and Intraventricular Hemmorrhage

Thalamostriate Vasculopathy in Neonates in the MAGnet Trial: Association with Placental Funisitis and Intraventricular Hemmorrhage

This is the first report of an intraventricular perineurioma

This is the first report of an intraventricular perineurioma

Intraventricular naemorrage: treatment with rt-PA intratecally injected

Intraventricular naemorrage: treatment with rt-PA intratecally injected

GABA agonists and neurotransmitters metabolizing enzymes in steroid-primed OVX rats.

The effect of intraventricular (IVT) administration of GABAA receptor agonist muscimol and GABAB receptor agonist, baclofen was examined on the activity of acetylcholinesterase (AChE), monoamine oxidase (MAO) and Na+, K(+)-ATPase in discrete areas of brain from estrogen-progesterone primed ovariectomized rats. AChE enzyme activity was increased in two subcellular fractions (soluble and total particulate) studied, with statistically significant changes in cerebral hemispheres (CH), cerebellum (CB), thalamus (TH) and hypothalamus (HT), Na+, K(+)-ATPase enzyme activity was decreased in both these fractions. MAO activity increased significantly in CH, TH and HT. The presented results suggest a functional relationship between GABAergic (inhibitory), cholinergic and monoaminergic (excitatory) systems by affecting the rate of degradation of the excitatory neurotransmitters and Na+, K(+)-ATPase.

Intraventricular insulin enhances the meal-suppressive efficacy of intraventricular cholecystokinin octapeptide in the baboon.

Chronic intraventricular (IVT) insulin infusion suppresses food intake and body weight in the baboon. It has been hypothesized that one mechanism of this action may be enhancement of the effectiveness of satiety factors that regulate meal size. This hypothesis was supported by prior demonstration of a shift in the meal-suppressive effectiveness of cholecystokinin octapeptide (CCK-8) which was given intravenously. The authors tested the effectiveness of a near threshold dose of CCK-8 (25 ng/kg) given via the lateral ventricles (IVT) prior to a 30-min meal, while baboons were chronically infused with cerebrospinal fluid or insulin (100 microU/day) via the lateral ventricles. IVT CCK-8 infusion resulted in meal size changes of -44 +/- 7% and -75 +/- 9% in the absence and presence of insulin, respectively; this was observed in each of the three animals studied. These results provide further support for the hypothesis that IVT insulin can interact with other, meal-regulatory, peptides.

The effects of intraventricular injection of β-endorphin on initial estrogen action to induce lordosis behavior

Ovariectomized female rats subcutaneously (SC) injected or intracerebrally implanted with estradiol benzoate (EB), and given progesterone SC were used as experimental animals to assess the effects of the β-endorphin (β-EP) neuronal system on lordosis behavior. In intraventricular (IV) injection of β-EP at the onset of sc EB priming, the lordosis behavior was significantly (p < 0.001) facilitated. In contrast, the lordosis behavior was significantly (p < 0.001) inhibited by IV injection of naloxone, an opioid receptor antagonist. β-EP facilitation of lordosis was observed exclusively within the initial stage of estrogen action. The behavior was significantly (p < 0.001) facilitated by IV injection of β-EP given with an intracerebral implantation of crystalline EB into the septal-preoptic regions. However, the lordosis behavior was significantly (p < 0.001) inhibited by β-EP when EB was implanted into the ventromedial hypothalamus. Animals receiving EB implants into the mesencephalic reticular formation were not affected by β-EP. The present study suggests that the β-EP neuronal system stimulates sexual receptivity through an action on the central nervous system in relation to the site of estrogen-initial activation to induce the lordosis reflex. The sites of β-EP action may be the estrogen receptive septal-preoptic and hypothalamic regions; the former for facilitatory effect and the latter for inhibitory effect.

Intraventricular galanin impairs delayed nonmatching-to-sample performance in rats.

Intraventricular galanin impairs delayed nonmatching-to-sample performance in rats.

The effect of convulsions on the rectification of central nervous system disorders in epileptic mice

Abnormal behavior in epileptic mice (El mice) may be rectified after convulsive seizures. This mechanism was investigated behaviorally through measurements of ethanol-induced sleeping time and locomotor activity, as well as immunohistochemically using a microphotometry system. Decreased ethanol-induced sleeping time and increased ethanol-dependent locomotor activity in El mice as compared to ddY mice (the mother strain of El mice) were rectified by convulsions as well as the intraventricular (IVT) administration of CaCl 2, dopamine, or serotonin. Also, the lower dopamine levels in the neostriatum and nucleus accumbens septi in El mice as compared to ddY mice were improved by convulsions as well as the IVT administration of CaCl 2. We have previously observed that a lower level of serum calcium in El mice causes a decrease in central biogenic amine synthesis through a calmodulin-dependent system. This may increase the susceptibility to epileptic convulsions and induce abnormal behavior. Combining the present results with our previous observations, we suggest that the convulsions in El mice will be induced when the balance of physiological functions is lost, as may be seen when the biogenic amine syntheses are decreased. The serum calcium level in El mice is increased by convulsions, and an elevated serum calcium level enhances brain biogenic amine synthesis through a calmodulin-dependent system. Subsequently, biogenic amines rectify physiological disorders in El mice.

Intraventricular neuropeptide Y injections stimulate food intake in lean, but not obese Zucker rats

We examined the effect of acute third intraventricular (IVT) injections of either saline or NPY (0.95, 3.0, 9.5, or 30.0 μg in 1 μl) on the 1-, 4-, and 22-hour postinjection food and water intake of female obese (fa/fa), heterozygous lean (Fa/fa), and homozygous lean (Fa/Fa) Zucker rats. None of the doses of NPY had an effect on either food or water intake of fa/fa rats. A significant increase of food intake was seen in Fa/Fa rats at 1 and 4 hours after the 3.0 μg injection of NPY and at 1, 4, and 22 hours after the 9.5 μg injection of NPY. Both 3.0 and 9.5 μg of NPY also stimulated 1- and 4-hour postinjection food intake of Fa/fa rats, although this effect was significant only at 4 hours after the 3.0 μg dose. NPY had a less reliable effect on water intake; 3.0 μg of NPY stimulated 1-hour postinjection water intake of Fa/fa rats and 4-hour postinjection water intake of Fa/Fa rats. These results indicate that lean, but not obese Zucker rats, respond by eating more to centrally administered NPY. This deficit is similar to the effects seen with IVT insulin injections and may be a result of a common receptor-mediated mechanism.

Neuropeptide K (NPK) suppresses copulatory behavior in male rats

Recent studies show that neuropeptide K (NPK), a member of the tachykinin family of neuropeptides, is found in various hypothalamic sites implicated in the control of gonadotropin secretion, food intake and sexual behavior. Since our previous studies showed that NPK inhibited feeding and gonadotropin secretion in rats, we have now assessed the effects of NPK on sexual behavior in male rats. Copulatory behavior was recorded subsequent to injection of different doses of NPK either into the third ventricle of the brain or intraperitoneally in sexually experienced male rats. We observed that intraventricular (IVT) administration of 0.125 nmol NPK produced only a slight effect on behavior as indicated by a significant increase in intromission latency. However, a four-fold higher dose of 0.5 nmol of NPK completely eliminated copulatory behavior. These rats displayed no overt locomotor deficit but ignored the receptive females, rarely approaching them during the test period. Only two mounts and no intromissions were observed in 6 rats during the test period. In contrast, neither the same dose of 0.5 nmol nor a higher dose of 3.14 nmol injected intraperitoneally produced any discernible effect on sexual performance. These results show that NPK acts centrally to inhibit sexual behavior in male rats and that hypothalamic NPK may be an important part of the neural circuit that regulates reproduction and related behaviors.

A mechanism of cadmium poisoning: The cross effect of calcium and cadmium in the calmodulin-dependent system

The effects of the intraventricular (IVT) administration of cadmium on the amount of dopamine (DA) in various regions of the mice brain were analyzed immunohistochemically using a microphotometry system. DA levels in the neostriatum and nucleus accumbens were increased by approximately 30% (p less than 0.01) by the IVT administration of CdCl2 (1 mumol/kg). This effect was abolished by the calmodulin antagonist, W-7 (4.2 micrograms/mouse, IVT). The effects of cadmium on DA levels in the brain were very similar to those seen with calcium. Combining these results with our previous finding that calmodulin does not have the ability to distinguish between calcium and cadmium, a mechanism of cadmium poisoning is suggested in which cadmium activates catecholamine synthesizing enzyme and numerous other enzymes through calmodulin-dependent systems, thereby disturbing many functions in the organism.

Development of ethanol tolerance not altered by 6-OHDA lesions of dorsal bundle

It has been demonstrated via intraventricular (IVT) 6-OHDA infusions that central nervous system norepinephrine is necessary for the development of tolerance to ethanol (ETOH) in the mouse. Because 6-OHDA IVT infusions are not specific, we tested the effects of destruction of a specific NE pathway on development of ETOH tolerance. Rats received 6-OHDA lesions of the dorsal noradrenergic bundle (DB) and the development of ethanol tolerance was measured using the sleeptime test. The time between loss and recovery of the righting reflex was determined after an acute challenge dose of ETOH. Rats were then placed on ETOH diet for 13 days followed by a repeat of the sleeptime test. Sham and 6-OHDA-DB-lesioned rats exhibited the same sleeptime prior to ETOH diet, over the course of 13 days, and exhibited similar significantly ( p<0.0005) shorter sleeptimes after ETOH diet. Our data suggest that destruction of the DB does not alter development of ETOH tolerance as measured by the sleeptime test.

IVT CCK-8 is more effective than IV CCK-8 at decreasing meal size in the baboon

In this study, we compared the effectiveness of intravenous (IV) vs. intraventricular (IVT) cholecystokinin octapeptide (CCK-8) to decrease single meal size over a dose range of 0.1 to 4.0 μ-g/kg in a population of overnight fasted baboons. IV CCK did not decrease meal size significantly at doses of 0.5, 1, and 4 μg/kg (84 ± 22%, 78 ± 12%, and 89 ± 33% of paired control meal sizes respectively). IVT CCK significantly decreased single meal size at all doses tested (40 ± 18%, 26 ± 10%, 37 ± 15%, 26 ± 12%, and 12 ± 6% of paired control meal sizes at 0.1, 0.25, 0.5, 1, and 2 μg/kg respectively). Meal suppression with IVT CCK was significantly greater than that achieved with IV CCK at doses of 1 and 2 μg/kg. We conclude that in the baboon, CCK may have a direct effect at the central nervous system to suppress single meal size.

Central dopamine-synthesis regulation by the calcium-calmodulin-dependent system

The effects of the intraventricular (IVT) administration of calcium on the amount of dopamine (DA) in various regions of the mouse brain were analyzed immunohistochemically by using a microphotometry system. The DA levels in the nucleus accumbens and the lateral part of the neostriatum were increased by approximately 45% ( p < 0.01) and 25–35% ( p<0.01), respectively, by the IVT administration of CaCl 2 (10 μmol/kg). It was also found that this effect was abolished by the calmodulin antagonist, W-7 (4.2 μg/mouse, IVT). The brain regions in which the amount of DA was increased by calcium were areas where high levels of calmodulin and tyrosine hydroxylase are distributed. These findings suggest that the synthesis of central DA is regulated by calcium through a calmodulin-dependent system.

Morphologic alterations in rat brain following systemic and intraventricular methotrexate injection: light and electron microscopic studies.

To determine the morphological substrate of acute methotrexate (MTX) encephalopathy, light and electron microscopic studies were performed on rat brains after short-term intraperitoneal (IP) and intraventricular (IV) injections of MTX. In both models, Alzheimer type II astrocytosis was the initial and major pathologic alteration seen by light microscopy. The neurons, oligodendrocytes, myelin and endothelial cells were relatively spared. Ultrastructural studies showed pleomorphism and condensation of mitochondria, membrane-bound vacuoles, prominent stacks of sparsely granular, rough endoplasmic reticulum and progressive hydropic swelling of astrocytic perikarya and their processes. The astroglial alterations were reversible after cessation of the drug but persisted for a longer time with repeated IP administration. Gastrointestinal complications and overall mortality were also greater with higher doses and increasing frequency of IP MTX injection. White matter necrosis was noted only after IV injection of high-dose MTX. The neuropathologic changes of MTX leukoencephalopathy can be replicated in an animal model by IV injection of the drug. The reversibility of the changes that were seen following IP administration correlates with the transient neurologic deficits observed in some patients after high-dose systemic MTX therapy. The initially selective astroglial effect suggests that astrocytes might be a target for MTX toxicity, although other central nervous system components may also be adversely affected by the drug.

Continuous intraventricular infusion of neuropeptide Y evokes episodic food intake in satiated female rats: Effects of adrenalectomy and cholecystokinin

In these studies the pattern of feeding behavior during continuous intraventricular (IVT) infusion of NPY for 4 hr in the satiated female rat was monitored. Whereas saline infusion was ineffective, each of the three doses of NPY (117, 470 or 1175 pmol/hr) increased feeding during the entire 4 hr infusion and 2 hr postinfusion period. The cumulative food intake at the end of 4 hr of NPY infusion was enhanced in a dose-related fashion between 0, 117 and 470 pmol/hr; at 1175 pmol/hr food intake plateaued. In addition, the latency to initiate feeding response decreased in a dose-related fashion and feeding occurred in discrete (35–45) episodes during the 4 hr infusion period. Further, the total time feeding and local eating rate (g/min) increased significantly in response to the higher rates of NPY infusion. Concurrent infusion of cholecystokinin (CCK) at either equimolar or 2.5 × NPY dose, affected neither the NPY-induced cumulative food intake nor any other parameter of feeding behavior. On the other hand, cumulative food intake was significantly decreased in adrenalectomized rats in response to NPY infusion (470 pmol/hr); a response due primarily to a marked suppression in some, and almost complete cessation of food consumption in other rats during the second 2 hr period of NPY infusion. These studies show that continuous central infusion of NPY can produce sustained, intermittent feeding behavior and adrenalectomy significantly curtailed the duration of NPY effectiveness. These observations are in line with the view that an increase in NPY secretion in relevant brain site(s) may be responsible for the intermittent high rate of food consumption during the dark phase of the daily light-dark cycle in the rat.

The effects of the novel anti-anginal compound RS 43285 on myocardial conduction in the anaesthetized dog.

1. A pentobarbitone-anaesthetized canine model of myocardial conduction was developed to evaluate drug effects on intra-atrial (I-A), intra-ventricular (I-V) and atrioventricular (A-V) conduction parameters, both at rest and during electrical pacing of the right atrium or ventricle. Drug effects on the ability of the sino-atrial (SA) node to re-establish sinus rhythm on switching off electrical pacing were also considered. The effects of the novel anti-anginal compound RS 43285-193 ((+/-)-N-(2,6-dimethyl-phenyl)-4[2-hydroxy-3-(2-methoxyphenoxy)propyl] -1-piperazine acetamide dihydrochloride) were compared to those of the standard anti-anginal compounds nicardipine, nifedipine and verapamil. 2. In the dose range 15-7000 micrograms kg-1, RS 43285 had no significant effects on I-A, I-V or A-V conduction either at rest or during electrical pacing and did not affect the re-establishment of sinus rhythm. 3. Nicardipine had no effects on conduction parameters at resting heart rate. There were no effects on I-A or I-V conduction on electrical pacing but A-V conduction was increased at 200-500 micrograms kg-1 (with a 2:1 A-V conduction block in two out of six dogs); this was accompanied by a prolongation of the interval to reversion of sinus rhythm. 4. Nifedipine had no significant effects on I-A or I-V conduction but significantly prolonged A-V conduction at 1000 micrograms kg-1 and this dose also increased the interval to SA node recovery. 5. Verapamil did not effect I-A or I-V conduction. However, A-V conduction was affected with a significant prolongation occurring at resting heart rate at 100-400 Atg kg-' and a 2:1 A-V block in one dog at rest. During right atrial pacing verapamil significantly increased A-V conduction at 50- 400 fig kg-'. All dogs exhibited a 2:1 A-V conduction block at the highest frequency at 400 jig kg-'.

Analgesia induced by N-acetylserotonin in the central nervous system

The relationship between N-acetylserotonin (NAS) in the central nervous system (CNS) and responses to pain was investigated. Using the rat tail-flick model, we initially replicated the work of others showing that intraventricular (IVC) injection of a dipeptide structurally similar to both NAS and serotonin was capable of inducing analgesia in the rat. We then showed that IVC-NAS, but not serotonin elicited analgesia in much the same manner as the dipeptide. This effect proved to be very specific as it required the presence of both an acetyl group on the terminal side chain amine as well as a hydroxyl group on the C-5 position of the indole ring. Substitution of the C-5 hydroxyl by a methoxyl group (melatonin) abolished the analgesic effect. Similarly, removing the N-acetyl substitution (serotonin) also eliminated the analgesia. IVC injection of highly specific antiserum to NAS induced hyperalgesia. Furthermore, an interaction was found between NAS and opiate systems. We demonstrated that while naloxone, the opiate antagonist, has no hyperalgesic properties of itself, it did counteract the analgesia induced by NAS. Similarly, NAS antiserum reversed the analgesia induced by the opiate morphine. This work provides evidence that NAS is an endogenously active substance within the CNS pain network.

Cardiac abnormalities in myotonic dystrophy: Electrocardiographic and echocardiographic findings in 65 patients and 34 of their unaffected relatives. Relation with age and sex and relevance for gene detection

Sixty-five patients with a definite diagnosis of myotonic dystrophy (MD) and 34 of their presumably unaffected relatives were examined cardiologically, including ECG in all and echocardiography in 61 and 32 persons respectively, in order to investigate the frequency of cardiac abnormalities, their clinical importance and their potential value as a preclinical marker in the diagnosis of MD. Atrioventricular conduction (AVC) abnormalities were found in 18 33 (54%) of affected males and in only 5 32 (16%) of affected females ( P = 0.0025). Intraventricular (IVC) conduction abnormalities were encountered with similar frequency in both sexes: in 12 33 (36%) of affected males and 10 32 (31%) of affected females. Mitral valve prolapses (MVP) were seen more often in affected females: 9 31 (29%) of affected males vs 15 30 (50%) of affected females have MVP ( P = 0.16). A previously undescribed finding was that of pericardial effusions in 5 affected and in 1 unaffected person. All affected males with MVP also had conduction abnormalities, but cardiac findings were not interrelated otherwise. None of the cardiac abnormalities mentioned were age-related. Only 8 65 (12%) of patients had cardiac symptoms, all of which were the result of conduction defects. As far as can be judged from a transversal study, the value of cardiac examination of this kind as a preclinical test for the diagnosis of MD is modest. It is argued that IVC-abnormalities, but not AVC-disturbances or MVP, in clinically unaffected relatives may indicate that they are preclinical heterozygotes. The significance of pericardial effusion for the diagnosis of MD awaits further evaluation.