Effects Of Chronic Intracerebroventricular Infusion Research Articles

Pilot Study of the Effects of Chronic Intracerebroventricular Infusion of Human Anti-IgLON5 Disease Antibodies in Mice.

Background: Anti-IgLON5 disease is a rare late-onset neurological disease associated with autoantibodies against IgLON5, neuronal accumulation of phosphorylated Tau protein (p-Tau), and sleep, respiratory, and motor alterations. Purpose: We performed a pilot study of whether the neuropathological and clinical features of anti-IgLON5 disease may be recapitulated in mice with chronic intracerebroventricular infusion of human anti-IgLON5 disease IgG (Pt-IgG). Methods: Humanized transgenic hTau mice expressing human Tau protein and wild-type (WT) control mice were infused intracerebroventricularly with Pt-IgG or with antibodies from a control subject for 14 days. The sleep, respiratory, and motor phenotype was evaluated at the end of the antibody infusion and at least 30 days thereafter, followed by immunohistochemical assessment of p-Tau deposition. Results: In female hTau and WT mice infused with Pt-IgG, we found reproducible trends of diffuse neuronal cytoplasmic p-Tau deposits in the brainstem and hippocampus, increased ventilatory period during sleep, and decreased inter-lick interval during wakefulness. These findings were not replicated on male hTau mice. Conclusion: The results of our pilot study suggest, but do not prove, that chronic ICV infusion of mice with Pt-IgG may elicit neuropathological, respiratory, and motor alterations. These results should be considered as preliminary until replicated in larger studies taking account of potential sex differences in mice.

Effects of neurosecretory protein GL on food intake and fat accumulation under different dietary nutrient compositions in rats.

We recently identified a novel hypothalamic small protein, named neurosecretory protein GL (NPGL), which is involved in energy homeostasis in birds and mammals. However, whether the action of NPGL is influenced by nutritional composition remains unknown. Thus, we investigated the effect of chronic intracerebroventricular infusion of NPGL for 13 days on feeding behavior and body mass gain under a normal chow (NC) diet, high-fat diet, high-sucrose diet (HSD), and medium-fat/medium-sucrose diet (MFSD) in rats. NPGL stimulated food intake of NC and MFSD, especially during the light period. By contrast, NPGL decreased body mass gain under NC and increased total white adipose tissue mass in HSD- and MFSD-fed rats. These data suggest that the effects of NPGL on feeding behavior, body mass gain, and fat accumulation depend on nutrient type. Among them, sucrose in diets seems to contribute to fat accumulation elicited by NPGL.

β-Arrestin-Biased Agonist Targeting the Brain AT1R (Angiotensin II Type 1 Receptor) Increases Aversion to Saline and Lowers Blood Pressure in Deoxycorticosterone Acetate-Salt Hypertension.

Activation of central AT1Rs (angiotensin type 1 receptors) is required for the increased blood pressure, polydipsia, and salt intake in deoxycorticosterone acetate (DOCA)-salt hypertension. TRV120027 (TRV027) is an AT1R-biased agonist that selectively acts through β-arrestin. We hypothesized that intracerebroventricular administration of TRV027 would ameliorate the effects of DOCA-salt. In a neuronal cell line, TRV027 induced AT1aR internalization through dynamin and clathrin-mediated endocytosis. We next evaluated the effect of chronic intracerebroventricular infusion of TRV027 on fluid intake. We measured the relative intake of water versus various saline solutions using a 2-bottle choice paradigm in mice subjected to DOCA with a concomitant intracerebroventricular infusion of either vehicle, TRV027, or losartan. Sham mice received intracerebroventricular vehicle without DOCA. TRV027 potentiated DOCA-induced water intake in the presence or absence of saline. TRV027 and losartan both increased the aversion for saline-an effect particularly pronounced for highly aversive saline solutions. Intracerebroventricular Ang (angiotensin) II, but not TRV027, increased water and saline intake in the absence of DOCA. In a separate cohort, blood pressure responses to acute intracerebroventricular injection of vehicle, TRV, or losartan were measured by radiotelemetry in mice with established DOCA-salt hypertension. Central administration of intracerebroventricular TRV027 or losartan each caused a significant and similar reduction of blood pressure and heart rate. We conclude that administration of TRV027 a selective β-arrestin biased agonist directly into the brain increases aversion to saline and lowers blood pressure in a model of salt-sensitive hypertension. These data suggest that selective activation of AT1R β-arrestin pathways may be exploitable therapeutically.

Effects of Chronic Intracerebroventricular Infusion of RFamide-Related Peptide-3 on Energy Metabolism in Male Mice.

RFamide-related peptide-3 (RFRP-3), the mammalian ortholog of avian gonadotropin-inhibitory hormone (GnIH), plays a crucial role in reproduction. In the present study, we explored the other functions of RFRP-3 by investigating the effects of chronic intracerebroventricular infusion of RFRP-3 (6 nmol/day) for 13 days on energy homeostasis in lean male C57BL/6J mice. The infusion of RFRP-3 increased cumulative food intake and body mass. In addition, the masses of brown adipose tissue (BAT) and the liver were increased by the administration of RFRP-3, although the mass of white adipose tissue was unchanged. On the other hand, RFRP-3 decreased O2 consumption, CO2 production, energy expenditure, and core body temperature during a short time period in the dark phase. These results suggest that the increase in food intake and the decrease in energy expenditure contributed to the gain of body mass, including the masses of BAT and the liver. The present study shows that RFRP-3 regulates not only reproductive function, but also energy metabolism, in mice.

Effects of chronic intracerebroventricular infusion of neurosecretory protein GL on body mass and food and water intake in chicks

Recently, we discovered a novel cDNA encoding the precursor of a small secretory protein, neurosecretory protein GL (NPGL), in the chicken mediobasal hypothalamus. In this study, immunohistochemical analysis revealed that NPGL was produced in the infundibular and medial mammillary nuclei of the mediobasal hypothalamus, with immunoreactive fibers also detected in the hypothalamus and the median eminence. As it is known that these regions are involved in feeding behavior in chicks, we surveyed the effects of chronic intracerebroventricular infusion of NPGL on feeding behavior and body mass for a period of two weeks. NPGL stimulated food and water intake, with a concomitant increase in body mass. However, NPGL did not influence mRNA expression of several hypothalamic ingestion-related neuropeptides. Our data suggest that NPGL may be a novel neuronal regulator involved in growth processes in chicks.

Increasing Angiotensin-(1–7) Levels in the Brain Attenuates Metabolic Syndrome–Related Risks in Fructose-Fed Rats

We evaluated effects of chronic intracerebroventricular infusion of angiotensin (Ang)-(1-7) on cardiovascular and metabolic parameters in fructose-fed (FF) rats. After 6 weeks of fructose intake (10% in drinking water), Sprague-Dawley rats were subjected to intracerebroventricular infusion of Ang-(1-7) (200 ng/h; FF+A7 group) or 0.9% sterile saline (FF group) for 4 weeks with continued access to fructose. Compared with control rats, FF rats had increased mean arterial pressure and cardiac sympathetic tone with impaired baroreflex sensitivity. FF rats also presented increased circulating triglycerides, leptin, insulin, and glucose with impaired glucose tolerance. Furthermore, relative weights of liver and retroperitoneal adipose tissue were increased in FF rats. Glycogen content was reduced in liver, but increased in muscle. In contrast, fructose-fed rats subjected to chronic intracerebroventricular infusion of Ang-(1-7) presented reduced cardiac sympathetic tone with normalized mean arterial pressure, baroreflex sensitivity, glucose and insulin levels, and improved glucose tolerance. Relative weight of liver, and hepatic and muscle glycogen contents were also normalized in FF+A7 rats. In addition, FF+A7 rats had reduced mRNA expression for neuronal nitric oxide synthase and NR1 subunit of N-methyl-d-aspartate receptor in hypothalamus and dorsomedial medulla. Ang-(1-7) infusion did not alter fructose-induced hyperleptinemia and increased relative weight of retroperitoneal adipose tissue. There were no differences in body weights, neither in liver mRNA expression of phosphoenolpyruvate carboxykinase or glucose-6-phosphatase among the groups. These data indicate that chronic increase in Ang-(1-7) levels in the brain may have a beneficial role in fructose-fed rats by ameliorating cardiovascular and metabolic disorders.

Chronic inhibition of brain phospholipase A2 in rats as a model to investigate Alzheimer-related alterations: a preliminary study

Altered membrane-associated phospholipase A2 (PLA2) activities have been correlated with several forms of chronic brain injury, in particular Alzheimer's disease (AD). Several studies suggest that persistent inhibition of PLA2 (particularly cPLA2 and iPLA2 isoforms) may play a central role in memory deficits as well as β-amyloid production in AD, thus participating in the neurodegenerative process. In order to validate a reversible animal model which is suitable for the study of Alzheimer-related alterations and treatments, we investigated in rats the effect of chronic intracerebroventricular infusion (using 3-days mini-osmotic pumps) of the dual cPLA2 and iPLA2 inhibitors PACOCF3 (reversible) and MAFP (irreversible), or minimal DMSO (vehicle), on the activity of the enzyme in the dorsal hippocampus and pre-frontal cortex. Both 500µM and 5 mM PACOCF3 did not cause any inhibition of PLA2 in relation to vehicle (n=3/group). 1 mM MAFP showed a trend towards inhibition of PLA2 in both hippocampus and cortex when compared to vehicle (n=4/group). Finally, 3 mM MAFP did significantly inhibit PLA2 (p<0.05; t-test) by 21% in hippocampus and 26% in cortex when compared to vehicle (n=3/group). The findings of lack of inhibition by PACOCF3 and greater inhibition power of MAFP, even at lower concentrations than PACOCF3, point to the viability of using the irreversible inhibitor MAFP to study the effects of chronic inhibition of cerebral PLA2 in vivo.

Chronic intracerebroventricular infusion of MCH causes obesity in mice. Melanin-concentrating hormone.

Melanin-concentrating hormone (MCH) is a cyclic amino acid neuropeptide localized in the lateral hypothalamus. Although MCH is thought to be an important regulator of feeding behavior, the involvement of this peptide in body weight control has been unclear. To examine the role of MCH in the development of obesity, we assessed the effect of chronic intracerebroventricular infusion of MCH in C57BL/6J mice that were fed with regular or moderately high-fat (MHF) diets. Intracerebroventricular infusion of MCH (10 microg/day for 14 days) caused a slight but significant increase in body weight in mice maintained on the regular diet. In the MHF diet-fed mice, MCH more clearly increased the body weight accompanied by a sustained hyperphagia and significant increase in fat and liver weights. Plasma glucose, insulin, and leptin levels were also increased in the MCH-treated mice fed the MHF diet. These results suggest that chronic stimulation of the brain MCH system causes obesity in mice and imply that MCH may have a major role in energy homeostasis.

Chronic intracerebroventricular infusion of angiotensin II increases brain AT1 receptor expression in young rats

The aim of the present study was to determine the effect of chronic intracerebroventricular infusion of angiotensin II (ANG II) on the expression of brain AT1 receptors in young (3–4 weeks) rats. One week of icv ANG II infusion produced a significant increase in brain AT1 receptor protein (Western blot) and mRNA (relative RT-PCR) expression. These data raise the possibility that ANG II may play a role in postnatal expression of brain AT1 receptors.

Physiological and behavioral effects of chronic intracerebroventricular infusion of corticotropin-releasing factor in the rat.

The present study was conducted to investigate the long-term effects of chronic elevation of centrally circulating levels of corticotropin-releasing factor (CRF) on behavior and physiology. For this purpose ovine CRF was infused continuously for a period of 10 days into the lateral ventricle of rats with the aid of osmotic pumps (calculated CRF delivery was 4.9 micrograms/day). Changes in daily rhythms in body temperature and home cage motor activity were recorded telemetrically during the infusion period. The most prominent physiological findings were a delayed body weight gain and a long-lasting hyperthermia following CRF infusion. The peptide treatment furthermore increased adrenal weight and suppressed the weight of the thymus at the end of the experiment. Behaviorally, CRF administration elicited a short-lasting increase in activity during the light phase and an increased anxiety in an elevated plus-maze 1 week after the start of infusion. The similarities between the present results and the long-term changes previously described in behaviorally stressed rats indicate that chronically elevated levels of CRF in the brain might play an important role in the induction and persistence of stress-related behavioral and physiological disorders.

Effect of Chronic Intracerebroventricular Infusion of Corticotropin-Releasing Factor on Circadian Corticosterone Rhythm in the Rat.

The effects of chronic (14 day) intracerebroventricular infusion of various amounts of ovine corticotropin-releasing factor (oCRF) on the circadian blood corticosterone rhythm in male rats were examined. Control (saline-infused) rats showed distinct blood corticosterone rhythms over 48 h with nadirs at 0900 h and peaks at 2100 h on days 6-7 and 13-14. oCRF at 3 pmol/h did not affect the circadian corticosterone rhythm on these days. When oCRF was infused at a rate of 12 pmol/h, blood corticosterone was increased throughout the 48 h periods. A significant circadian rhythm remained at days 6-7, but continuous infusion for an additional 7 days disrupted the rhythm. Higher doses of oCRF (48 and 240 pmol/h) obliterated the rhythm during both periods; the disruption was characterized by an increase in corticosterone during the lights-on period without a substantial change in the evening maximum. Thus, the blood corticosterone concentration was eventually confined within a narrow range, not exceeding the normal circadian peak, over a wide dose range of centrally administered CRF. Significant effects of oCRF on body and adrenal weight were observed only at the two highest doses used. These findings may provide some insight into the state of the hypothalamic-pituitary-adrenal axis in animals exposed to chronic stress and in patients with depression.

Effect of chronic intracerebroventricular infusion of cholecystokinin on respiration and sleep.

We investigated the effect of chronic intracerebroventricular infusion of the sulfated cholecystokinin octapeptide (CCK-8S) on sleep pattern and respiratory rate. The results indicate a depression of respiratory rate during Non-REM and REM sleep as well as an increase in the number of REM periods occurring per hour of Non-REM sleep. It is suggested that central release of CCK-8S is capable of modulating the automatic regulation of respiration during sleep and altering the normal sleep-waking pattern.