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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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All sourcesNASA NTRSDOE OSTI
NASA NTRS1996

Skeletal response to corticosteroid deficiency and excess in growing male rats

The study was designed to investigate bone histomorphometric changes induced by corticosteroid deficiency and supplementation at different dose levels in the rat skeleton. Male rats were adrenalectomized (ADX) or sham-operated and divided into six groups. At 2 days after surgery, sham-operated control rats (CON + PLA) and one group of ADX rats (ADX + PLA) were implanted subcutaneously (s.c.) with placebo pellets. ADX rats in the remaining four groups (ADX + C25, ADX + C50, ADX + C100, and ADX + C300) were implanted sc with corticosterone pellets designed to release 25, 50, 100, or 300 mg of the hormone over a 60 day period. Each ADX rat was also implanted sc with an aldosterone pellet (2.5 mg) similarly designed to release its contents over the same time period. All rats were killed at 3 weeks after implantation of pellets. Terminal blood samples were collected for serum biochemistry and the proximal tibial metaphyses (PTM), tibial diaphyses, and first lumbar vertebrae (LV) were processed undecalcified for quantitative bone histomorphometry. A dose-dependent increase in serum corticosterone concentration was observed in ADX rats implanted with hormone pellets. In comparison to CON + PLA rats, ADX + PLA rats had lower cancellous bone volume associated with a stimulation in longitudinal bone growth, an increase in mineral apposition rate, and a trend for increased osteoclast and osteoblast surfaces in PTM. In contrast, cancellous bone of ADX + C25 rats was preserved at nearly the CON + PLA level. However, the higher doses of corticosterone increased cancellous bone mass, but decreased longitudinal bone growth and all indices of bone resorption and formation in a dose-dependent manner in PTM. Similar cancellous bone changes were observed in the LV of corticosterone-treated rats, with the exception of a lack of an hormonal effect on cancellous bone mass. In the tibial diaphysis, corticosterone inhibited periosteal bone formation in a dose-dependent manner, but did not affect cortical bone mass. The results indicate that corticosteroid deficiency induces cancellous osteopenia, whereas supplementation with a near physiologic dose of the hormone prevents this bone loss in ADX rats. Furthermore, corticosteroid excess inhibits bone growth and bone turnover in a dose-dependent manner, but does not induce cancellous osteopenia in growing male rats.

Non-NASA Center↗
NASA NTRS2004

Calcium balance in mature male rats with unloaded hindlimbs

BACKGROUND: Calcium balances, regulated by the calcium endocrine system, are negative during spaceflight but have not been reported in flight simulation models using fully mature small animals. METHODS: We conducted two calcium (Ca) balance studies in 6-mo-old male rats exposed to a model that unloads the hindlimbs (HU) for 4 wk. Control (C) and HU rats were fed diets with 0.5% Ca in the first and 0.1% Ca in the second study. Housing in metabolic cages enabled daily food and water intake measurements as well as collections of urine and fecal specimens. At necropsy, blood was obtained for measures of Ca-regulating hormones. RESULTS: Both C and HU rats adjusted to housing and diets with decreases in body weight and negative Ca balances during the first week of each experiment. Thereafter, averages of Ca balances were more negative in the unloaded rats than controls: -8.1 vs. -1.6 mg x d(-1) in rats fed 0.5% (p < 0.05). This difference was not due to urinary Ca excretion since it was lower in HU than C rats (1.27 +/- 0.51 mg x d(-1) vs. 2.35 +/- 0.82 mg x d(-1), p < 0.05). Fecal Ca in HU rats exceeded dietary Ca by 4-7%, Restricting dietary Ca to 0.1% was followed by an increase in serum 1,25-dihydroxyvitamin D (1,25-D) and greater intestinal Ca absorption than in rats fed 0.5% Ca. Ca balances in rats fed 0.1% Ca were also more negative in HU than C rats (-2.4 vs. -0.03 mg x d(-1), p < 0.05). Parathyroid hormone (PTH) was suppressed and 1,25-D increased in HU rats fed 0.5% Ca. C rats fed 0.1% Ca had increased PTH and 1,25-D was the same as in the HU group. CONCLUSION: After adaptation, Ca balances were more negative in mature male rats with unloaded hindlimbs than controls, an effect from increased secretion and loss of endogenous fecal Ca associated with increased 1,25-D in Ca-replete and Ca-restricted rats.

Hindlimb Suspension/physiology↗
DOE OSTI2012

Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The limited mitochondrial adducts in rats are insufficient to trigger cell necrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

A diet containing the soy phytoestrogen genistein causes infertility in female rats partially deficient in UDP glucuronyltransferase

Soy beans contain genistein, a natural compound that has estrogenic effects because it binds the estrogen receptor with relatively high affinity. Genistein is therefore the most important environmental estrogen in the human diet. Detoxification of genistein is mediated through conjugation by UDP-glucuronyltransferase 1 and 2 (UGT1 and UGT2) isoenzymes. Gunn rats have a genetic deficiency in UGT1 activity, UGT2 activities are not affected. Because our Gunn rats stopped breeding after the animal chow was changed to a type with much higher soy content, we examined the mechanism behind this soy diet induced infertility. Gunn and control rats were fed diets with and without genistein. In these rats, plasma levels of genistein and metabolites, fertility and reproductive parameters were determined. Enzyme assays showed reduced genistein UGT activity in Gunn rats, as compared to wild type rats. Female Gunn rats were completely infertile on a genistein diet, wild type rats were fertile. Genistein diet caused a persistent estrus, lowered serum progesterone and inhibited development of corpora lutea in Gunn rats. Concentrations of total genistein in Gunn and control rat plasma were identical and within the range observed in humans after soy consumption. However, Gunn rat plasma contained 25% unconjugated genistein, compared to 3.6% in control rats. This study shows that, under conditions of reduced glucuronidation, dietary genistein exhibits a strongly increased estrogenic effect. Because polymorphisms that reduce UGT1 expression are prevalent in the human population, these results suggest a cautionary attitude towards the consumption of large amounts of soy or soy supplements. -- Highlights: ► Gunn rats are partially deficient in detoxification by UDP glucuronyltransferases. ► Female Gunn rats are infertile on a soy containing diet. ► Soy contains genistein, a potent phytoestrogen. ► Inefficient glucuronidation of genistein causes female infertility.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

SU-E-T-492: Implementing a Method for Brain Irradiation in Rats Utilizing a Commercially Available Radiosurgery Irradiator

Purpose: The purpose of the study was to implement a method for accurate rat brain irradiation using the Gamma Knife Perfexion unit. The system needed to be repeatable, efficient, and dosimetrically and spatially accurate. Methods: A platform (“rat holder”) was made such that it is attachable to the Leskell Gamma Knife G Frame. The rat holder utilizes two ear bars contacting bony anatomy and a front tooth bar to secure the rat. The rat holder fits inside of the Leskell localizer box, which utilizes fiducial markers to register with the GammaPlan planning system. This method allows for accurate, repeatable setup.A cylindrical phantom was made so that film can be placed axially in the phantom. We then acquired CT image sets of the rat holder and localizer box with both a rat and the phantom. Three treatment plans were created: a plan on the rat CT dataset, a phantom plan with the same prescription dose as the rat plan, and a phantom plan with the same delivery time as the rat plan. Results: Film analysis from the phantom showed that our setup is spatially accurate and repeatable. It is also dosimetrically accurate, with an difference between predicted and measured dose of 2.9%. Film analysis with prescription dose equal between rat and phantom plans showed a difference of 3.8%, showing that our phantom is a good representation of the rat for dosimetry purposes, allowing for +/- 3mm diameter variation. Film analysis with treatment time equal showed an error of 2.6%, which means we can deliver a prescription dose within 3% accuracy. Conclusion: Our method for irradiation of rat brain has been shown to be repeatable, efficient, and accurate, both dosimetrically and spatially. We can treat a large number of rats efficiently while delivering prescription doses within 3% at millimeter level accuracy.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1993

Metabolic responses to head-down suspension in hypophysectomized rats

Rats exposed to head-down suspension (HDS) exhibit reductions in maximal O2 consumption (VO2max) and atrophy of select hindlimb muscles. This study tested the hypothesis that an endocrine-deficient rat exposed to HDS would not exhibit reductions in VO2max or hindlimb muscle mass. Hypophysectomized (HYPX) and sham-operated (SHAM) rats were tested for VO2max before and after 28 days of HDS or cage control (CC) conditions. No significant reductions in VO2max were observed in HYPX rats. In contrast, SHAM-HDS rats exhibited a significant reduction in absolute (-16%) and relative (-29%) measures of aerobic capacity. Time course experiments revealed a reduction in VO2max in SHAM-HDS rats within 7 days, suggesting that cardiovascular adjustments to HDS occurred in the 1st wk. HDS was associated with atrophy of the soleus (-42%) in SHAM rats, whereas HYPX rats exhibited atrophy of the soleus (-36%) and plantaris (-13%). SHAM-HDS rats had significantly lower (-38%) soleus citrate synthase activities per gram muscle mass than SHAM-CC, but no significant differences existed between HYPX-HDS and -CC rats. HDS rats had an impaired ability to thermoregulate, as indicated by significantly greater temperature increases per unit run time, compared with their CC counterparts. Pretreatment plasma epinephrine levels were significantly lower in HYPX than in SHAM rats. Norepinephrine concentration was similar for all groups except HYPX-HDS, in which it was significantly higher. HDS had no significant effect on thyroxine or triiodothyronine. SHAM-HDS rats had significantly lower concentrations of testosterone and growth hormone.(ABSTRACT TRUNCATED AT 250 WORDS).

NASA Discipline Number 14-10↗
NASA NTRS2003

The response of Dahl salt-sensitive and salt-resistant female rats to a space flight model

Vitamin D metabolism in the Dahl salt-sensitive (S) rat, a model of salt-induced hypertension, differs from that in the Dahl salt-resistant (R) rat. We have tested the hypothesis that differences in vitamin D metabolism would render the Dahl S rat more susceptible than the Dahl R rat to the effects of a space flight model. Dahl female rats were tail suspended (hind limb unloaded) for 28 days, while fed a low salt (3 g/kg sodium chloride) diet. Plasma 25-OHD concentrations of S rats were significantly lower than that of R rats. Plasma 1,25-(OH)2D concentration was 50% lower in unloaded than in loaded S rats, but was unaffected in unloaded R rats. The left soleus muscle weight and breaking strength of the left femur (torsion test) were 50% and 25% lower in unloaded than in loaded S and R rats. The mineral content of the left femur, however, was significantly lower (by 11%) only in unloaded S rats. We conclude that female S rats are more vulnerable than female R rats to decreases in plasma 1,25-(OH)2D concentration and femur mineral content during hind limb unloading, but equally vulnerable to muscle atrophy and reduced breaking strength of the femur.

NASA Program Biomedical Research and Countermeasur↗
DOE OSTI2013

Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor which plays a role in the development of multiple tissues and is activated by a large number of ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In order to examine the roles of the AHR in both normal biological development and response to environmental chemicals, an AHR knockout (AHR-KO) rat model was created and compared with an existing AHR-KO mouse. AHR-KO rats harboring either 2-bp or 29-bp deletion mutation in exon 2 of the AHR were created on the Sprague–Dawley genetic background using zinc-finger nuclease (ZFN) technology. Rats harboring either mutation type lacked expression of AHR protein in the liver. AHR-KO rats were also insensitive to thymic involution, increased hepatic weight and the induction of AHR-responsive genes (Cyp1a1, Cyp1a2, Cyp1b1, Ahrr) following acute exposure to 25 μg/kg TCDD. AHR-KO rats had lower basal expression of transcripts for these genes and also accumulated ∼ 30–45-fold less TCDD in the liver at 7 days post-exposure. In untreated animals, AHR-KO mice, but not AHR-KO rats, had alterations in serum analytes indicative of compromised hepatic function, patent ductus venosus of the liver and persistent hyaloid arteries in the eye. AHR-KO rats, but not AHR-KO mice, displayed pathological alterations to the urinary tract: bilateral renal dilation (hydronephrosis), secondary medullary tubular and uroepithelial degenerative changes and bilateral ureter dilation (hydroureter). The present data indicate that the AHR may play significantly different roles in tissue development and homeostasis and toxicity across rodent species. - Highlights: • An AHR knockout rat was generated on a Sprague–Dawley outbred background. • AHR-KO rats lack expression of AHR protein. • AHR-KO rats are insensitive to TCDD-mediated effects. • Data suggests difference in the role of AHR in tissue development of rats and mice. • Abnormalities in vascular development are observed in AHR-KO mouse, but not rat. • Renal pathology is observed in AHR-KO rat, but not mouse.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1990

Fed, but not Fasted, Adrenalectomized Rats Survive the Stress of Hemorrhage and Hypovolemia

We have recently shown that conscious adrenalectomized rats exhibit nearly normal recovery of arterial blood pressure during the 5 h after hemorrhage. In those experiments, it appeared that a previous reduction in food intake might have compromised the recovery of blood pressure and increased mortality. These experiments were designed to test in conscious sham-adrenalectomized (control) and adrenalectomized rats prepared with indwelling arterial and venous cannulae: 1. The effects of a 20- to 24-h fast (compared to rats fed ab libitum) on the mobilization of plasma substrates and recovery of arterial blood pressure after a 15 ml/kg - 5 min hemorrhage, and 2. Vascular responsivity to pressor agents in fed or fasted groups before or 2 h after hemorrhage. In all rats hemorrhage resulted in decreased arterial pressure and heart rate. Arterial pressure recovered to near normal in both fed and fasted control groups and in the led adrenalectomized rats, and all of these rats survived for 24 h after stress. By contrast, in the fasted adrenalectomized rats, arterial pressure recovered only during the first 1.5 - 2 h and then failed, resulting in 100% mortality by 3-5 h. Compared to the other three groups, in which substrate levels either increased or remained fairly stable, plasma glucose and beta-hydoxybutyrate concentrations fell steadily, from 1.5-2 h after hemorrhage until death occurred in the fasted adrenalectomized rats. Basal ACTH concentrations were elevated cormpared to control values in both adrenalectomized groups (fed and fasted). Hemorrhage caused increases in plasma ACTH in all groups; the magnitude of the responses did not differ among the groups. The dilution of Evans' blue dve after hemorrhage (used as an index of fluid movement into the vascular space) was not different in contol and adrenalectomized rats (either fed or fasted). There were no differences in pressor responses to phenylephrine, vasopressin, or angiotensin-II between the fed and fasted condition in the control rats either before or after hemorrhage. There was a fasting-associated decrease in vascular responsivity, to vasopressin, but normal responsivity to phenylephrine and angiotensin-II, in the adrenal-ectomized rats both before and after hemorrhage. We conclude that: (1) since fed adrenalectomized rats all survived the stress, adrenal hormones are not required for survival unless fasting is a prior condition; (2) vascular responsiveness to phenylephrine and angiotensin-II is not altered by fasting and is, therefore, probably not the proximate cause of cardiovascular svstem failure; and (3) from these data we cannot distinguish between a failure in substrate supply and a failure in some component of the cardiovascular svstem, other than vascular responsivity, that results in death after hemorrhage in fasted adrenalectomized rats.

Darlington, Daniel N.↗
NASA NTRS2001

Effects of Cage Type and NASA Rodent Food Bar in Male Sprague-Dawley Rats

Early prototype caging for the rodent Advanced Animal Habitat (P-AAH) for the International Space Station (ISS) is currently being tested. In this five week study, effects of the wire-bottom P-AAH cages and specialized NASA rodent food bars (FB) were compared to standard vivarium cages (VIV) with corn-cob, litter-filled bottoms, and standard Purina rat chow (CH). Ninety-six male Sprague-Dawley rats were divided into four treatment groups (24 rats/treatment): Group 1) VIV+CH, Group 2) P-AAH+CH, Group 3) VIV+FB, and Group 4) P-AAH+FB. Each VIV and P-AAH cage housed three and six rats, respectively. After five weeks of treatment rats were weighed, euthanized, and blood samples were collected. Weights of liver (LIV), kidney (KID), brain (BRN), epididymal fat (EPI), and perirenal fat (PERI) were also measured. Statistical analysis to compare differences between groups was performed by standard analysis of variance procedures (ANOVA) with a significance level of pLO.05. Results indicated P-AAH housed rats had significantly lower body weights (BW), LIV weights, and LIV/BW than VIV housed rats. FB fed rats had significantly lower blood urea nitrogen (BUN) levels and LIV/BW than CH fed rats. In addition, FB fed rats had significantly higher cholesterol (CHOL) levels, EPI/BW, PERI/BW, and total fat (EPI+PERI)/BW than CH fed rats. The P-AAH+FB group had significantly lower EPI, BRN, and total fat than VIV+FB rats. VIV+FB rats had significantly higher BRN, EPI, PERI, and total fat than VIV+CH rats. Triglycerides (TG), KID, KID/BW, and BRN/BW were not significantly different among treatment groups. These findings provide valuable information regarding cage design and food bar suitability for long-term use on the ISS.

Lau, Angela↗
NASA NTRS2003

The Effects of Spaceflight on the Rat Circadian Timing System

Two fundamental environmental influences that have shaped the evolution of life on Earth are gravity and the cyclic changes occurring over the 24-hour day. Light levels, temperature, and humidity fluctuate over the course of a day, and organisms have adapted to cope with these variations. The primary adaptation has been the evolution of a biological timing system. Previous studies have suggested that this system, named the circadian (circa - about; dies - a day) timing system (CTS), may be sensitive to changes in gravity. The NASA Neurolab spaceflight provided a unique opportunity to evaluate the effects of microgravity on the mammalian CTS. Our experiment tested the hypotheses that microgravity would affect the period, phasing, and light sensitivity of the CTS. Twenty-four Fisher 344 rats were exposed to 16 days of microgravity on the Neurolab STS-90 mission, and 24 Fisher 344 rats were also studied on Earth as one-G controls. Rats were equipped with biotelemetry transmitters to record body temperature (T(sub b)) and heart rate (HR) continuously while the rats moved freely. In each group, 18 rats were exposed to a 24-hour light-dark (LD 12:12) cycle, and six rats were exposed to constant dim red-light (LL). The ability of light to induce a neuronal activity marker (c-fos) in the circadian pacemaker of the brain, the suprachiasmatic nucleus (SCN), was examined in rats studied on flight days two (FD2) and 14 (FD14), and postflight days two (R+1) and 14 (R+13). The flight rats in LD remained synchronized with the LD cycle. However, their T(sub b), rhythm was markedly phase-delayed relative to the LD cycle. The LD flight rats also had a decreased T(sub b) and a change in the waveform of the T(sub b) rhythm compared to controls. Rats in LL exhibited free-running rhythms of T(sub b), and HR; however, the periods were longer in microgravity. Circadian period returned to preflight values after landing. The internal phase angle between rhythms was different in flight than in one-G. Compared with control rats, the flight rats exhibited no change in HR. Finally, the LD FD2 flight rats demonstrated a reduced sensitivity to light as shown by significantly reduced c-fos expression in the SCN in comparison with controls. These findings constitute the first demonstration that microgravity affects the fundamental properties of the mammalian circadian timing system, specifically by influencing the clock's period, and its ability to maintain temporal organization and phase angle of synchronization to an external LD cycle.

Fuller, Charles A.↗
NASA NTRS1993

Influence of simulated microgravity on the VO2 max of nontrained and trained rats

Head-down suspension (HDS) of rats has evolved as a useful model for the simulation of a microgravity environment. Previous HDS experiments with rats have shown an impaired capacity to perform aerobic exercise as demonstrated by reductions in maximum oxygen consumption (VO2 max), treadmill run time (RT), and mechanical efficiency (ME) of treadmill running at submaximal conditions. To determine whether endurance training (TR) before HDS would modify exercise performance, male Sprague-Dawley rats were assigned to nontrained (NT) or TR groups for 6 wk and exposed to HDS or cage control (CC) conditions for 29 days. The rats were tested for VO2 max, RT, and ME before treatment and on days 7, 14, 21, and 28. In addition, water and electrolyte excretion was measured on days 1 and 21 of the experimental period. Before HDS, the TR rats had significantly higher measures of VO2 max (15%) and RT (22%) than the NT rats. On day 28, HDS was associated with significant reductions in absolute VO2 max (ml/min) in TR (-30%) and NT (-14%) rats. Relative VO2 max (ml.min-1.kg-1) was significantly reduced in TR (-15%) but not NT rats. Similar reductions in RT occurred in TR (-37%) and NT (-35%) rats by day 28. ME was reduced 22% in both TR and NT rats after 28 days of suspension. HDS elicited diuresis, natriuresis, and kaliuresis in TR rats after 21 days but not after 24 h. In contrast, HDS-NT rats exhibited no diuretic, natriuretic, or kaliuretic responses.(ABSTRACT TRUNCATED AT 250 WORDS).

Non-NASA Center↗
DOE OSTI2014

Aliskiren toxicity in juvenile rats is determined by ontogenic regulation of intestinal P-glycoprotein expression

Juvenile rat toxicity studies with the direct renin inhibitor aliskiren were initiated to support treatment in the pediatric population. In Study 1, aliskiren was administered orally to juvenile rats at doses of 0, 30, 100 or 300 mg/kg/day with repeated dosing from postpartum day (PPD) 8 to PPD 35/36. In-life, clinical pathology, anatomic pathology, and toxicokinetics evaluations were performed. In Study 2, single oral doses of aliskiren (0, 100 or 300 mg/kg) were given to 14-, 21-, 24-, 28-, 31- or 36-day-old rats; in-life data and toxicokinetics were evaluated. Study 3 was a single dose (3 mg/kg i.v.) pharmacokinetic study in juvenile rats on PPD 8, 14, 21 and 28. In Study 4, naïve rats were used to investigate ontogenic changes of the multidrug-resistant protein 1 (MDR1) and the organic anion transporting polypeptide (OATP) mRNA in several organs. Oral administration of aliskiren at 100 and 300 mg/kg caused unexpected mortality and severe morbidity in 8-day-old rats. Aliskiren plasma and tissue concentrations were increased in rats aged 21 days and younger. Expression of MDR1 and OATP mRNA in the intestine, liver and brain was significantly lower in very young rats. In conclusion, severe toxicity and increased exposure in very young rats after oral administration of aliskiren are considered to be the result of immature drug transporter systems. Immaturity of MDR1 in enterocytes appears to be the most important mechanism responsible for the high exposure. - Highlights: • Aliskiren was orally administered to juvenile rats. • Unexpected severe toxicity and acute mortality occurred in rats aged 8 days. • Toxicity was associated with increased aliskiren plasma and tissue exposure. • Developmental changes of exposure correlated with ontogeny of transporters. • Immaturity of MDR1 in enterocytes causes increased exposure in very young rats.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CART peptide activates the Nrf2/HO-1 antioxidant pathway and protects hippocampal neurons in a rat model of Alzheimer's disease

Highlights: • CART peptide reduced the accumulation of Aβ in the hippocampus of AD rats. • CART peptide improved the cognitive function of AD rats. • CART peptide attenuated the oxidative stress damage in the hippocampus of AD rats. • CART activated the Nrf2/HO-1 pathway to exert antioxidation. • CART inhibit the apoptosis of hippocampal neurons. The accumulation of amyloid-beta (Aβ) and oxidative stress damage in the brain are recognized as early features of Alzheimer's disease (AD). The cocaine- and amphetamine-regulated transcript (CART) peptide may possibly play an antioxidative role in neurons. The aim of this study was to investigate the potential antioxidant mechanism of CART peptide in a rat model of AD. We microinjected of Aβ{sub 1-42} (2μl/4μg/hemisphere) into rat hippocampus to set a rat model of AD. A pre-microinjection of CART peptide (1μl/0.02μg/hemisphere) into rat hippocampus was administered for five consecutive days before Aβ{sub 1-42} treatment. We found that Aβ{sub 1-42} microinjection led to reduction of endogenous CART level in rat hippocampus. CART pretreatment improved the spatial memory and locomotor ability of AD rats. CART peptide decreased the Aβ{sub 1-42} and Aβ production-associated enzyme BACE1 levels. Moreover, CART peptide attenuated the oxidative stress damage with a concrete manifestation of increased MDA as well as decreased T-SOD, GSH and ATP levels in the hippocampus of Aβ{sub 1-42}-treated rat, which may be causatively implicated the activating of Nrf2/HO-1 signaling pathway. Furthermore, CART peptide attenuated neuronal apoptosis with decreased Bax, caspase-9 and caspase-3 levels and increased Bcl-2 level in rat hippocampus. Our results therefore indicate that CART peptide could serve as an antioxidant in early therapy for AD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

MicroRNA changes in rat mesentery and serum associated with drug-induced vascular injury

Regulatory miRNAs play a role in vascular biology and are involved in biochemical and molecular pathways dysregulated during vascular injury. Collection and integration of functional miRNA data into these pathways can provide insight into pathogenesis at the site of injury; the same technologies applied to biofluids may provide diagnostic or surrogate biomarkers. miRNA was analyzed from mesentery and serum from rats given vasculotoxic compounds for 4 days. Fenoldopam, dopamine and midodrine each alter hemodynamics and are associated with histologic evidence of vascular injury, while yohimbine is vasoactive but does not cause histologic evidence of vascular injury in rat. There were 38 and 35 miRNAs altered in a statistically significant manner with a fold change of 2 or greater in mesenteries of fenoldopam- and dopamine-dosed rats, respectively, with 9 of these miRNAs shared. 10 miRNAs were altered in rats given midodrine; 6 were shared with either fenoldopam or dopamine. In situ hybridization demonstrated strong expression and co-localization of miR-134 in affected but not in adjacent unaffected vessels. Mesenteric miRNA expression may provide clarity or avenues of research into mechanisms involved in vascular injury once the functional role of specific miRNAs becomes better characterized. 102 miRNAs were altered in serum from rats with drug-induced vascular injury. 10 miRNAs were commonly altered in serum from dopamine and either fenoldopam or midodrine dosed rats; 18 of these 102 were also altered in mesenteries from rats with drug-induced vascular injury, suggesting their possible utility as peripheral biomarkers. -- Highlights: ► Mesentery and serum were examined from rats given vasoactive compounds for 4 days. ► 72 miRNAs were altered in mesenteries from rats with vascular injury. ► miR-134 was localized to affected but not adjacent unaffected vessels. ► 102 miRNAs were changed in serum from rats with vascular injury. ► 18 miRNAs changed in both mesenteries and serum from rats with vascular injury.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1997

Myogenic regulatory factors during regeneration of skeletal muscle in young, adult, and old rats

Myogenic factor mRNA expression was examined during muscle regeneration after bupivacaine injection in Fischer 344/Brown Norway F1 rats aged 3, 18, and 31 mo of age (young, adult, and old, respectively). Mass of the tibialis anterior muscle in the young rats had recovered to control values by 21 days postbupivacaine injection but in adult and old rats remained 40% less than that of contralateral controls at 21 and 28 days of recovery. During muscle regeneration, myogenin mRNA was significantly increased in muscles of young, adult, and old rats 5 days after bupivacaine injection. Subsequently, myogenin mRNA levels in young rat muscle decreased to postinjection control values by day 21 but did not return to control values in 28-day regenerating muscles of adult and old rats. The expression of MyoD mRNA was also increased in muscles at day 5 of regeneration in young, adult, and old rats, decreased to control levels by day 14 in young and adult rats, and remained elevated in the old rats for 28 days. In summary, either a diminished ability to downregulate myogenin and MyoD mRNAs in regenerating muscle occurs in old rat muscles, or the continuing myogenic effort includes elevated expression of these mRNAs.

Non-NASA Center↗
NASA NTRS1985

Rat maintenance in the Research Animal Holding Facility during the flight of Space Lab 3

To test the husbandry capabilities of the Research Animal Holding Facility (RAHF) during space flight, 24 male rats were flown on Spacelab 3 for 7 days. Twelve large rats (400 g, LF), 5 of which had telemetry devices implanted (IF), and 12 small rats (200 g, SF) were housed in the RAHF. Examination 3 hr after landing (R + 3) revealed the rats to be free of injury, well nourished, and stained with urine. At R + 10 the rats were lethargic and atonic with hyperemia of the extremities and well groomed except for a middorsal area stained with urine and food. Both LF and SF rats showed weight gains comparable to their IG controls; IF rats grew less than controls. Food and water consumption were similar for flight and control groups. Plasma concentrations of total protein, sodium, albumin and creatinine did not differ between flight and control groups. LF and SF rats had elevated plasma glucose, and SF rats had increased blood urea nitrogen, potassium and glutamic pyruvic transaminase. These observations indicate that rats maintained in the RAHF were healthy, well nourished and experienced minimal stress; physiological changes in the rats can thus be attributed to the effects of space flight.

Fast, T.↗
NASA NTRS1996

NASA Rat Acoustic Tolerance Test 1994-1995: 8 kHz, 16 kHz, 32 kHz Experiments

Adult male Sprague-Dawley rats were exposed to chronic applied sound (74 to 79 dB, SPL) with octave band center frequencies of either 8, 16 or 32 kHz for up to 60 days. Control cages had ambient sound levels of about 62 dB (SPL). Groups of rats (test vs. control; N=9 per group) were euthanized after 0. 5. 14, 30, and 60 days. On each euthanasia day, objective evaluation of their physiology and behavior was performed using a Stress Assessment Battery (SAB) of measures. In addition, rat hearing was assessed using the brain stem auditory evoked potential (BAER) method after 60 days of exposure. No statistically significant differences in mean daily food use could be attributed to the presence of the applied test sound. Test rats used 5% more water than control rats. In the 8 kHz and 32 kHz tests this amount was statistically significant(P less than .05). This is a minor difference of questionable physiological significance. However, it may be an indication of a small reaction to the constant applied sound. Across all test frequencies, day 5 test rats had 6% larger spleens than control rats. No other body or organ weight differences were found to be statistically significant with respect to the application of sound. This spleen effect may be a transient adaptive process related to adaptation to the constant applied noise. No significant test effect on differential white blood cell counts could be demonstrated. One group demonstrated a low eosinophil count (16 kHz experiment, day 14 test group). However this was highly suspect. Across all test frequencies studied, day 5 test rats had 17% fewer total leukocytes than day 5 control rats. Sound exposed test rats exhibited 44% lower plasma corticosterone concentrations than did control rats. Note that the plasma corticosterone concentration was lower in the sound exposed test animals than the control animals in every instance (frequency exposure and number of days exposed).

Mele, Gary D.↗