Mast Cells Exert Anti-Inflammatory Effects in an IL10-/- Model of Spontaneous Colitis.

Mast cells are well established as divergent modulators of inflammation and immunosuppression, but their role in inflammatory bowel disease (IBD) remains to be fully defined. While previous studies have demonstrated a proinflammatory role for mast cells in acute models of chemical colitis, more recent investigations have shown that mast cell deficiency can exacerbate inflammation in spontaneous colitis models, thus suggesting a potential anti-inflammatory role of mast cells in IBD. Here, we tested the hypothesis that in chronic, spontaneous colitis, mast cells are protective. We compared colitis and intestinal barrier function in IL10-/- mice to mast cell deficient/IL10-/- (double knockout (DKO): KitWsh/Wsh × IL10-/-) mice. Compared with IL10-/- mice, DKO mice exhibited more severe colitis as assessed by increased colitis scores, mucosal hypertrophy, intestinal permeability, and colonic cytokine production. PCR array analyses demonstrated enhanced expression of numerous cytokine and chemokine genes and downregulation of anti-inflammatory genes (e.g., Tgfb2, Bmp2, Bmp4, Bmp6, and Bmp7) in the colonic mucosa of DKO mice. Systemic reconstitution of DKO mice with bone marrow-derived mast cells resulted in significant amelioration of IL10-/--mediated colitis and intestinal barrier injury. Together, the results presented here demonstrate that mast cells exert anti-inflammatory properties in an established model of chronic, spontaneous IBD. Given the previously established proinflammatory role of mast cells in acute chemical colitis models, the present findings provide new insight into the divergent roles of mast cells in modulating inflammation during different stages of colitis. Further investigation of the mechanism of the anti-inflammatory role of the mast cells may elucidate novel therapies.

Early weaning stress induces chronic functional diarrhea, intestinal barrier defects, and increased mast cell activity in a porcine model of early life adversity.

BACKGROUND: Early life adversity (ELA) is a risk factor for development of gastrointestinal disorders later in life. The underlying mechanisms through which ELA and sex interact to influence disease susceptibility remains poorly understood. METHODS: Utilizing a porcine early weaning stress (EWS) model to mimic ELA, we investigated the long-term effects of EWS on functional diarrhea, ileal permeability, mast cell activity and mast cell relationship with enteric ganglia. KEY RESULTS: Juvenile and adult EWS pigs exhibited chronic, functional diarrhea (EWS 43.6% vs late wean control(LWC) 4.8%, P<.0001), increased intestinal permeability (2 fold increase EWS vs LWC, P<.0001), and mast cell numbers (at 7 weeks and 20 weeks ~1.6 fold increase EWS vs LWC, P<.05). Compared with EWS male castrates (Male-C), females EWS pigs exhibited more frequent diarrhea (58.8% vs 29.9%, P=.0016), and increased intestinal permeability (1-2 fold higher in EWS females, P<.001). Increased mast cell numbers and their enhanced co-localization with neuronal ganglia were observed in both Male-C and female EWS pigs; however, female pigs exhibited greater release of mast cell tryptase upon activation with c48/80 (~1.5 fold increase, P<.05), compared with Male-C pigs. CONCLUSIONS AND INFERENCES: These data demonstrate that pigs exposed to ELA exhibit increased vulnerability to functional diarrhea, intestinal permeability and mast cell activity. Further, these studies also showed that EWS female and Male-C pigs exhibited dimorphic responses to EWS with female piglets exhibited greater susceptibility and severity of diarrhea, intestinal permeability and mast cell tryptase release. Together, these findings mimic some of the key pathophysiologic findings in human functional GI disorders functional gastrointestinal disorders (FGIDs) suggesting that the EWS porcine model could be a valuable preclinical translational model for FGID research associated with ELA.

Early life adversity in piglets induces long-term upregulation of the enteric cholinergic nervous system and heightened, sex-specific secretomotor neuron responses.

BACKGROUND: Early life adversity (ELA) is a risk factor for the later-life onset of gastrointestinal (GI) diseases such as irritable bowel syndrome (IBS); however, the mechanisms are poorly understood. Here, we utilized a porcine model of ELA, early weaning stress (EWS), to investigate the influence of ELA on the development and function of the enteric nervous system (ENS). METHODS: Female and castrated male (Male-C) piglets were weaned from their sow either at 15 days of age (EWS) or 28 days of age (late weaning control, LWC). At 60 and 170 days of age, ileal mucosa-submucosa preparations were mounted in Ussing chambers and veratridine- and corticotropin releasing factor (CRF)-releasing factor-evoked short circuit current (Isc ) responses were recorded as indices of secretomotor neuron function. Enteric neuron numbers and the expression of select neurotransmitters and their receptors were also measured. KEY RESULTS: Compared with LWC pigs, female, but not Male-C EWS, pigs exhibited heightened veratridine-induced Isc responses at 60 and 170 days of age that were inhibited with tetrodotoxin and atropine. Ileum from EWS pigs had higher numbers of enteric neurons that were choline acetyltransferase positive. Markers of increased cholinergic signaling (increased acetylcholinesterase) and downregulated mucosal muscarinic receptor 3 gene expression were also observed in EWS pigs. CONCLUSIONS & INFERENCES: This study demonstrated that EWS in pigs induces lasting and sex-specific hypersensitivity of secretomotor neuron function and upregulation of the cholinergic ENS. These findings may represent a mechanistic link between ELA and lifelong susceptibility to GI diseases such as IBS.

Serological, genomic and structural analyses of the major mite allergen Der p 23.

BACKGROUND: Der p 23 was recently identified in a European population as a major allergen and potentially a chitin binding protein. OBJECTIVE: This study sought to assess the importance of Der p 23 among other Dermatophagoides allergens in a North American population and to determine the structure for functional characterization. METHODS: IgE binding to Der p 23, Der p 1, Der p 2, Der p 5, Der p 7 and Der p 8 was measured by ELISA. RNA-seq data from D. pteronyssinus were compared as estimates of allergen expression levels. The structure was analysed by X-ray crystallography and NMR. RESULTS: Despite a high prevalence of Der p 23, (75% vs. 87% and 79% for Der p 1 and Der p 2, respectively), the anti-Der p 23 IgE levels were relatively low. The patient response to the 6 allergens tested was variable (n = 47), but on average anti-Der p 1 and anti-Der p 2 together accounted for 85% of the specific IgE. In terms of abundance, the RNA expression level of Der p 23 is the lowest of the major allergens, thirty fold less than Der p 1 and sevenfold less than Der p 2. The structure of Der p 23 is a small, globular protein stabilized by two disulphide bonds, which is structurally related to allergens such as Blo t 12 that contain carbohydrate binding domains that bind chitin. Functional assays failed to confirm chitin binding by Der p 23. CONCLUSIONS AND CLINICAL RELEVANCE: Der p 23 accounts for a small percentage of the IgE response to mite allergens, which is dominated by Der p 1 and Der p 2. The prevalence and amount of specific IgE to Der p 23 and Der p 2 are disproportionately high compared to the expression of other Dermatophagoides allergens.

Early-life dietary spray-dried plasma influences immunological and intestinal injury responses to later-life Salmonella typhimurium challenge.

Increasing evidence supports the concept that early-life environmental influences, including nutrition and stress, have an impact on long-term health outcomes and disease susceptibility. The objective of the present study was to determine whether dietary spray-dried plasma (SDP), fed during the first 2 weeks post-weaning (PW), influences subsequent immunological and intestinal injury responses to Salmonella typhimurium challenge. A total of thirty-two piglets (age 16-17 d) were weaned onto nursery diets containing 0, 2·5 % SDP (fed for 7 d PW) or 5 % SDP (fed for 14 d PW), and were then fed control diets (without SDP), for the remainder of the experiment. At 34 d PW (age 50 d), pigs were challenged with 3 × 109 colony-forming units of S. typhimurium. A control group (non-challenged) that was fed 0 % SDP in the nursery was included. At 2 d post-challenge, the distal ileum was harvested for the measurement of inflammatory, histological and intestinal physiological parameters. S. typhimurium challenge induced elevated ileal histological scores, myeloperoxidase (MPO), IL-8 and TNF, and increased intestinal permeability (indicated by reduced transepithelial voltage (potential difference) and elevated 4 kDa fluorescein isothiocyanate dextran (FD4) flux rates). Compared with S. typhimurium-challenged controls (0 % SDP), pigs fed the 5 % SDP-14 d diet exhibited reduced ileal histological scores, MPO levels, IL-8 levels and FD4 flux rates. Pigs fed the 5 % SDP-14 d nursery diet exhibited increased levels of plasma and ileal TNF-α in response to the challenge, compared with the other treatments. These results indicate that inclusion of SDP in PW diets can have an influence on subsequent immunological and intestinal injury responses induced by later-life S. typhimurium challenge.

Identification of Maillard reaction products on peanut allergens that influence binding to the receptor for advanced glycation end products.

BACKGROUND: Recent immunological data demonstrated that dendritic cells preferentially recognize advanced glycation end product (AGE)-modified proteins, upregulate expression of the receptor for AGE (RAGE), and consequently bias the immune response toward allergy. METHODS: Peanut extract was characterized by mass spectrometry (MS) to elucidate the specific residues and specific AGE modifications found in raw and roasted peanuts and on rAra h 1 that was artificially glycated by incubation with glucose or xylose. The binding of the RAGE-V1C1 domain to peanut allergens was assessed by PAGE and Western analysis with anti-Ara h 1, 2, and 3 antibodies. IgE binding to rAra h 1 was also assessed using the same methods. RESULTS: AGE modifications were found on Ara h 1 and Ara h 3 in both raw and roasted peanut extract. No AGE modifications were found on Ara h 2. Mass spectrometry and Western blot analysis demonstrated that RAGE binds selectively to Ara h 1 and Ara h 3 derived from peanut extract, whereas the analysis failed to demonstrate Ara h 2 binding to RAGE. rAra h 1 with no AGE modifications did not bind RAGE; however, after AGE modification with xylose, rAra h 1 bound to RAGE. CONCLUSIONS: AGE modifications to Ara h 1 and Ara h 3 can be found in both raw and roasted peanuts. Receptor for AGE was demonstrated to selectively interact with AGE-modified rAra h 1. If sensitization to peanut allergens occurs in dendritic cells via RAGE interactions, these cells are likely interacting with modified Ara h 1 and Ara h 3, but not Ara h 2.

Neurophysiologic evaluation of cyclosporine toxicity associated with bone marrow transplantation.

INTRODUCTION: Cortical blindness, a rare form of cyclosporine (CSA) neurotoxicity, has previously been described in only nine bone marrow transplant (BMT) recipients. METHODS: Our institution averages 35 allogeneic BMT's per year. In the past year we have seen two women with reversible cortical blindness secondary to CSA toxicity. RESULTS: Age (years) (Case 1; Case 2): 32; 22. Day post-BMT: 41; 50. Peak CSA level (ng/ml): 1159; 632. Both had a history of renal toxicity requiring adjustment of CSA dosage. MRI - both with diffuse while matter changes. EEG - both with moderate to severe generalized slowing. Visual evoked potentials were markedly prolonged in both. Auditory evoked potentials: minimally abnormal; normal. Somatosensory evoked potentials - both normal. Prompt improvement occurred with discontinuation of CSA. Followup neurophysiologic evaluations were normal, however structural changes remained on MRI. CONCLUSION: As neurophysiologic studies closely follow the clinical status they should be included in the evaluation and followup of CSA neurotoxicity.

Neurophysiologic evaluation of cyclosporine toxicity associated with bone marrow transplantation.

INTRODUCTION: Cortical blindness, a rare form of cyclosporine (CSA) neurotoxicity, has previously been described in only nine bone marrow transplant (BMT) recipients. METHODS: Our institutions averages 35 allogeneic BMT's per year. In the past year we have seen two women with reversible cortical blindness secondary to CSA toxicity. RESULTS: Age (years) (Case 1; Case 2): 32; 22. Day post-BMT: 41: 50. Peak CSA level (ng/ml): 1159; 632. Both had a history of renal toxicity requiring adjustment of CSA dosage. MRI - both with diffuse white matter changes. EEG-both with moderate to severe generalized slowing. Visual evoked potentials were markedly prolonged in both. Auditory evoked potentials: minimally abnormal; normal. Somatosensory evoked potential - both normal. Prompt improvement occurred with discontinuation of CSA. Followup neurophysiologic evaluations were normal, however structural changes remain on MRI. CONCLUSION: As neurophysiologic studies closely follow the clinical status they should be included in the evaluation and followup of CSA neurotoxicity.

Anorectal function in fluctuating (on-off) Parkinson's disease: evaluation by combined anorectal manometry and electromyography.

Anorectal dysfunction and constipation are well recognized in Parkinson's disease and may reflect the direct involvement of the gastrointestinal tract by the primary Parkinson's disease process. We hypothesized, therefore, that anorectal function would alter in parallel with fluctuations in motor function related to on- and off-periods in Parkinson's disease, and employed combined anorectal manometry and electromyography to investigate anorectal function during both on- and off-periods in patients with Parkinson's disease. Manometric recordings revealed a deterioration in voluntary sphincter squeeze during off-periods (squeeze index, on versus off, mean +/- SEM: 46.4 +/- 11.1 versus 29.6 +/- 7.9 mm Hg, p < 0.05); correspondingly, simultaneous electromyographic (EMG) recordings showed poor recruitment of external anal sphincter and puborectalis muscles during off-periods. A hypercontractile ("paradoxical") rectosphincteric reflex response occurred during both on- and off-periods, and was associated with an increase in EMG activity in the external sphincter and/or the puborectalis muscle. These changes in manometric and EMG parameters paralleled changes in overall motor function. These findings provide further support for the involvement of the pelvic floor musculature in the Parkinson's disease process and also provide EMG correlates for some of the manometric abnormalities described in Parkinson's disease.

Cervical dystonia: a review the role of botulinum toxin.

Cervical dystonia, although rare in the general population, can severely affect the lives of those afflicted with the disease. Throughout history several theories have been proposed regarding its etiology and pathophysiology, from underlying mental disorders to post-infectious to altered basal ganglia and brainstem function. However, CD remains poorly understood. Because of its similarity to Idiopathic Torsion Dystonia a genetic basic is suspected, but is not proven. Without a true understanding of the disease treatment remains symptomatic, and begins with physical therapy and medications and progresses to consideration of surgery. These treatment strategies have provided some relief, which is usually less than satisfactory within a short period of time. Recently, the use of botulinum toxin has provided significant symptomatic relief of pain in CD and has been associated with subjective and objective improvement in head posture. This newest therapy, although symptomatic, restores a more normal head posture and pain relief enabling the individuals with CD to continue to be active and productive participants in life, providing a ray of hope to these people as we continue to search for a better understanding of the disease process and the development of more effective treatment strategies.

Characterization of swallowing and defecation in Parkinson's disease.

UNLABELLED: Despite the high prevalence of Parkinson's disease, the pathophysiology of its gastrointestinal symptoms remains poorly understood. OBJECTIVES: to evaluate swallowing and defecatory function in patients with Parkinson's disease and age- and sex-matched controls and to correlate objective findings with subjective symptoms. METHODS: The following studies were performed on 13 patients with Parkinson's disease and seven controls: extrapyramidal function assessment, gastrointestinal symptom survey, videoesophagram, colon transit study, defecography, and anorectal manometry. RESULTS: Abnormal salivation (frequency, %, control vs. Parkinson's disease: 14 vs. 77, p < 0.05), dysphagia (14 vs. 77, p < 0.05), constipation (14 vs. 31, p < 0.05), and defecatory dysfunction (29 vs. 77, p < 0.05) were more common among Parkinsonian patients. However, videoesophagographic abnormalities were equally common in both groups. Colon transit time was significantly prolonged in the Parkinson's disease group. Altered puborectalis function was noted on defecography in 31% of Parkinson's disease subjects, but in none of the controls (p < 0.05). Anorectal manometry identified several abnormalities in the Parkinson's disease group, which included decreased basal anal sphincter pressures, prominent phasic fluctuations on squeeze, and a hyper-contractile external sphincter response to the rectosphincteric reflex. Many patients exhibited both slow transit and manometric abnormalities, and symptoms were poor predictors of test results. CONCLUSION: In this group of patients with mild to moderate Parkinson's disease, videoesophagographic abnormalities were not confined to the patients with Parkinson's disease. Studies of colonic and anorectal function, in contrast, identified a number of abnormalities. Therefore, colonic and anorectal dysfunction appears to be an early gastrointestinal manifestation of Parkinson's disease, and may represent the direct involvement of the gut by this disease process.

Defecatory function in Parkinson's disease: response to apomorphine.

We evaluated the effects of the dopaminergic agent apomorphine on defecation and anorectal function in patients with Parkinson's disease (PD). A gastrointestinal symptom survey, extrapyramidal assessment, defecating proctogram, and anorectal manometric study were performed in 8 subjects with PD. Basal studies showing abnormalities were repeated following apomorphine administration. Prior defecographic abnormalities were normalized following apomorphine injection in 1 of 3 subjects and significant improvements in manometric parameters were observed in all 5 subjects who underwent repeat anorectal manometry. We conclude that apomorphine can correct anorectal dysfunction in PD, and that these abnormalities may be a consequence of dopamine deficiency secondary to the PD process. These findings may also have therapeutic implications.

Gastrointestinal dysfunction in Parkinson's disease: frequency and pathophysiology.

Although more extensive research is required to fully characterize the pathophysiology of the gastrointestinal symptoms in PD, much of the presently available data suggest that the primary PD process is the major factor in the etiology of gut dysfunction in this patient population. This may be mediated by both central and peripheral mechanisms. Involvement of the dorsal motor nucleus of the vagus might produce dysfunction of muscles controlling deglutition and esophageal motility, thereby leading to drooling, dysphagia, and gastroesophageal reflux. The presence of Lewy bodies, the primary neuropathologic finding in the CNS in PD, in the myenteric plexus of both the esophagus and colon suggests that the PD process may also affect the enteric nervous system and contribute to the development of esophageal dysmotility and constipation through this peripheral mechanism. Dopamine receptors have been identified in the lower esophageal sphincter and the esophageal body of animals. If similarly present in humans, involvement of this dopaminergic system could contribute to the development of dysphagia and nausea of PD. Constipation may reflect both peripheral involvement, indicated by Lewy bodies in the colonic myenteric plexus, leading to colonic inertia, and central mechanisms, leading to pelvic floor dysfunction.

Gastrointestinal symptoms in Parkinson's disease.

We have investigated the prevalence of gastrointestinal (GI) symptoms in 98 individuals with Parkinson's disease (PD) and in a control group of 50. Seventy-nine of those with PD were being treated with dopaminergic medications and 19 were untreated. Those symptoms occurring more frequently in PD patients than in controls included abnormal salivation, dysphagia, nausea, constipation, and defecatory dysfunction. Except for defecatory dysfunction, symptoms did not correlate with treatment but instead correlated with disease severity. This suggests that the GI symptoms of PD reflect direct involvement in the GI tract by the primary disease process.

Amino acid uptake in isolated, perfused liver: effect of trauma and sepsis.

To examine alterations in amino acid metabolism after trauma and sepsis, male Sprague-Dawley rats underwent no operation (control, CON), celiotomy (trauma, TRA), or cecal ligation and puncture (sepsis, CLP). After 16 hr, plasma amino acid concentrations were determined. A second group of similarly prepared animals underwent isolated liver perfusion, and net amino acid uptake or release was determined over 30 min. Sepsis significantly decreased total amino acid concentration in portal plasma (CON, 3486 +/- 156 nmole/ml; TRA, 3407 +/- 150 nmole/ml; CLP, 2738 +/- 148 nmole/ml). Glutamine concentrations were uniformly lower in portal plasma than in arterial plasma in all states. There were depressed concentrations of the branched chain amino acids (BCAA) in portal plasma after trauma but not sepsis. In the isolated liver perfusion model, a marked increase in amino acid uptake was induced by sepsis (CON, 39.9 +/- 7.9 mumol/g liver protein; TRA, 49.5 +/- 17.3 mumol/g liver protein; CLP, 124 +/- 11 mumol/g liver protein). In addition, there was significantly greater uptake of threonine, asparagine, proline, methionine, tyrosine, and arginine. Although the BCAA isoleucine and valine were taken up to a greater extent in sepsis, the overall BCAA uptake was not significantly greater in sepsis than in control (CON 6.92 +/- 2.15 mumol/g liver protein vs CLP 15.8 +/- 1.9 mumol/g liver protein). The greatest increase in uptake following sepsis was among the gluconeogenic precursor amino acids alanine, glycine, threonine, and serine (CON, 27.0 +/- 4.2 mumol/g liver protein, TRA, 38.8 +/- 8.9 mumol/g liver protein; CLP, 62.8 +/- 6.0 mumol/g liver protein).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of different intravenous nutritional regimens on renal function during acute renal failure in the rat.

Acute renal failure in the surgical patient is accompanied by a state of hypermetabolism and increased catabolism. Nutritional therapy is therefore directed at the preservation of body cell mass and protein synthesis for repair of wounds and damaged renal tubuli and for maintenance of host defense mechanisms. We examined the effect of two levels of protein intake (18.4 +/- 1.4 and 30.8 +/- 2.4 mg N/100 g BW/day) and three different amino acid formulations (Freamine III, Nephramine, and a made-up mixture of Nephramine + Freamine HBC) on renal function following mercury chloride-induced acute renal failure in the rat. All animals suffered severe renal failure manifested by increased plasma urea and creatinine levels, decreased creatinine clearance, and increased fractional excretion of sodium. On day 4 of acute renal failure, rats receiving low dose amino acids had better-preserved renal function than those receiving high dose amino acids. However, the type of solution infused did not affect recovery of renal function.

The effect of indomethacin on muscle and liver protein synthesis and on whole-body protein degradation during abdominal sepsis in the rat.

It has been recently suggested that increased muscle protein degradation during injury or infection is at least partially mediated by the increased production of prostaglandin E2 in muscle, and some have suggested that cyclooxygenase inhibitors might decrease protein loss in injured or septic patients. In these experiments, fractional synthesis rates of mixed muscle and liver protein and whole-body tyrosine flux were measured by constant intravenous infusion of tyrosine labeled with carbon 14 in 17 rats with sham operations and 15 severely septic rats with or without indomethacin treatment (20 mg/kg/d). Fractional synthesis rates in muscle and liver were decreased in late sepsis and were lowest in the septic group receiving indomethacin. Unlike the fractional synthesis rate, which was affected by indomethacin in septic rats only, tyrosine flux was significantly lower in indomethacin-treated rats with sham operations and those with sepsis. Although indomethacin reduced total-body protein breakdown during sepsis, it was also associated with lower plasma albumin levels and with decreased protein synthesis in muscle and liver at a time when the survival of the septic host may be dependent on its ability to produce new protein for a variety of vital functions. These results do not support the use of indomethacin in sepsis.

Efficacy of two elemental diets: a pair feeding study.

The efficacy and side effects of two elemental diets were studied. Twenty young Sprague-Dawley rats were fed one of three different diets. Group I (n = 7) was fed Vivonex-HN (VIV) ad lib; group II (n = 7) was given Criticare-HN (CRI), pair-fed to group I (the two elemental diets were given in glass bottles); group III was fed regular rat chow and served as control (CON). Body weight (WT), food intake, and nitrogen balance (NB) were measured daily. After 21 days, change in body weight was similar in the three groups (VIV = 64.9 +/- 3.2%; CRI = 59.6 +/- 3.3%; CON = 63.9 +/- 4.8%). Cumulative nitrogen balance was also similar in the two groups fed elemental diets (VIV = 4788 +/- 277 mg N; CRI = 4690 +/- 118 mg N), but in both these groups it was less than the control group fed chow (8060 +/- 85 mg N). Blood urea nitrogen (BUN) on the last day was higher in the VIV group (12.9 +/- 1.22 mg/dl) than in the CRI group (9.43 +/- 0.43 mg/dl), but in both study groups it was lower than in the CON group (17.2 +/- 1.08 mg/dl), although nitrogen intake was higher in the control (ad lib) group. SGPT was similar in the two elemental diets but higher than in CON. Liver weights were higher in the CRI group, probably abnormally so and likely due to increased fat content. Both diets had similar efficacy in nutritional support.

Behavioral depression after intraventricular infusion of octopamine in rats.

The behavioral and neurochemical effects of four intraventricular infusions of octopamine (3,200 micrograms), tryptophan (800 micrograms), and octopamine plus tryptophan delivered over 6 hours was studied in rats after performing a portacaval anastomosis or a sham operation. After each infusion, each animal was rated for neurologic depression with a 17 point test battery. Although overt coma was not induced, octopamine infusions severely depressed neurologic function. Concentrations of norepinephrine, dopamine, and serotonin in the brain were significantly decreased after the infusion of octopamine. Levels of norepinephrine in the brain were significantly correlated with neurologic status and greater depletion of norepinephrine was associated with greater neurologic depression. These studies demonstrate that infusing large amounts of the trace amine octopamine depresses behavior in the rat and this depression is most closely associated with depletion of stores of norepinephrine in the brain.

Infusion of branched-chain amino acids and ammonium salts in rats with portacaval shunts.

During infusion into rats with a portacaval shunt of either ammonium (NH4+) salts alone or NH4+ salts combined with the three branched-chain amino acids (BCAAs) in equimolar quantities, we assessed neurologic function and measured plasma and brain ammonia and amino acid levels and the brain content of amine neurotransmitters and their metabolites. Survival was lengthened and neurologic function was preserved longer in rats receiving BCAAs. Infusion of BCAAs resulted in lower plasma and brain ammonia concentrations compared with rats receiving NH4+ salts alone. Plasma glutamine and alanine levels were higher in rats receiving BCAAs, suggesting increased ammonia detoxification. Loss of neurologic function, regardless of which solution was infused, eventually occurred and corresponded with decreased brain norepinephrine and increased brain alanine levels. These results suggest that BCAAs can protect against hyperammonemia by stimulating the peripheral detoxification of ammonia.