Combined administration of secretin and oxytocin inhibits chronic colitis and associated activation of forebrain neurons.

BACKGROUND: The pathogenesis of inflammatory bowel disease is unknown; however, the disorder is aggravated by psychological stress and is itself psychologically stressful. Chronic intestinal inflammation, moreover, has been reported to activate forebrain neurons. We tested the hypotheses that the chronically inflamed bowel signals to the brain through the vagi and that administration of a combination of secretin (S) and oxytocin (OT) inhibits this signaling. METHODS: Three daily enemas containing 2,4,6-trinitrobenzene sulfonic acid (TNBS), which were given to rats produced chronic colitis and ongoing activation of Fos in brain neurons. KEY RESULTS: Fos was induced in neurons in the paraventricular nucleus of the hypothalamus, basolateral amygdala, central amygdala, and piriform cortex. Subdiaphragmatic vagotomy failed to inhibit this activation of Fos, suggesting that colitis activates forebrain neurons independently of the vagi. When administered intravenously, but not when given intracerebroventricularly, in doses that were individually ineffective, combined S/OT prevented colitis-associated activation of central neurons. Strikingly, S/OT decreased inflammatory infiltrates into the colon and colonic expression of tumor necrosis factor-alpha and interferon-gamma. CONCLUSIONS & INFERENCES: These observations suggest that chronic colonic inflammation is ameliorated by the systemic administration of S/OT, which probably explains the parallel ability of systemic S/OT to inhibit the colitis-associated activation of forebrain neurons. It is possible that S and OT, which are endogenous to the colon, might normally combine to restrict the severity of colonic inflammatory responses and that advantage might be taken of this system to develop novel means of treating inflammation-associated intestinal disorders.

Brain effects of chronic IBD in areas abnormal in autism and treatment by single neuropeptides secretin and oxytocin.

Recent research points to the connection between behavioral and gut disorders. Early adverse events are associated with inflammatory bowel disease (IBD). In animal models, maternal deprivation and social isolation predispose to gastric erosion and brain pathology. This study examined (1) brain effects of chronic gastrointestinal inflammation in a rat model of acquired IBD and (2) whether such changes are resolved by individual secretin (S) or oxytocin (OT) peptide treatment. Neurological manifestations of IBD were mapped by c-fos gene expression in male Sprague-Dawley rats (n = 10) with trinitrobenzene sulfonic acid (TNBS)-induced IBD vs controls (n = 11). IBD was characterized by moderate/severe infiltration of inflammatory cells 10 d after TNBS infusion. Age-matched pairs were processed for immunocytochemical detection of Fos, expressed when neurons are stimulated. S or OT (100 mg/250 mL saline) or equivolume saline was administered iv by Alzet pump for 20 d after disease onset. Degree of resolution of colitis-induced brain activation was assessed by c-fos expression, and mean numbers of Fos-immunoreactive nuclei for each group were compared using Independent Samples T-test. Chronic IBD activated periventricular gray, hypothalamic/visceral thalamic stress axes and cortical domains, and septal/preoptic/amygdala, brain areas abnormal in autism. Single peptide treatment with S or OT did not alter the effects of inflammation on the brain. Brain areas concomitantly activated by visceral inflammation are those often abnormal in autism, suggesting that IBD could be a model for testing treatments of autism. Other single and combined peptide treatments of IBD should be tested. The clinical implications for treating autism, IBD, and concomitant sickness behaviors with peptide therapy, with or without maternal nurturing as a natural equivalent, are presented.

The cardiac-related rhythm in preganglionic sympathetic activities of developing piglets.

This investigation was performed to determine whether partial spectral analysis of preganglionic sympathetic nerve discharges would reveal age-related differences in the distribution of baroreceptor afferent information to brainstem sympathetic-related neurons. Any influence of baroreceptor afferent activity on ordinary spectra of cervical sympathetic and splanchnic nerves was removed by partialization using the arterial blood pressure signal which represented baroreceptor activity. An absence of statistically significant coherence in partialized nerve spectra would indicate that sympathetic-related neurons receive peripheral baroreceptor afferent input, but are not interconnected, whereas the presence of significant coherence would mean that these neurons are interconnected. Ordinary spectral analysis did not demonstrate age-related differences in the relationship between nerve activity and baroreceptor afferent input. In many animals, large peaks, located at cardiac frequencies (range 2.75-5.6 Hz), were noted in ordinary nerve autopower spectra, and were significantly correlated in ordinary coherence spectra. Partialization of nerve spectra eliminated or reduced cardiac-related peaks in autopower spectra regardless of age, and, in 8 of 10 animals, reduced coherence estimates to non-significant values. In two animals, 19 and 36 days old, significant coherence values remained after partialization. These results demonstrated that cardiac-related peaks in coherence in spectra of preganglionic splanchnic and cervical sympathetic nerves were dependent upon peripheral afferent baroreceptor input in most animals. Further, the finding that significant residual coherence was absent in most cases suggested a paucity of intrabulbar pathways connecting brainstem sympathetic-related neurons.

Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases.

The monoamine oxidase (MAO) metabolites of norepinephrine (NE) or epinephrine (EPI) and of dopamine (DA) are 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively. The toxicity of these catecholamine (CA) MAO metabolites was predicted over 50 years ago. However, until our recent chemical synthesis of these CA aldehyde metabolites, the hypothesis about their toxicity could not be tested. The present paper reviews recent knowledge gained about these compounds. Topics to be reviewed include: chemical synthesis and properties of DOPEGAL and DOPAL; in vitro and in vivo toxicity of CA aldehydes; subcellular mechanisms of toxicity; free radical formation by DOPEGAL versus DOPAL; mechanisms of accumulation of CA aldehydes in Alzheimer's disease (AD) and Parkinson's disease (PD) and potential therapeutic targets in Alzheimer's disease and Parkinson's disease.

Secretin activates visceral brain regions in the rat including areas abnormal in autism.

1. The aim of this study was to determine whether central networks are involved in the presumptive behavioral and autonomic regulatory actions of secretin, a gut hormone that has been reported to have ameliorative effects in autistic children. 2. Central neural responses monitored by regional c-fos gene expression were examined in response to intracerebroventricular secretin injection in awake, freely-moving Sprague-Dawley rats. Tissue sections were incubated in an antibody to the c-fos gene product, Fos, and processed immunohistochemically. 3. Qualitative differences in Fos immunoreactivity in stress adaptation and visceral representation areas of the brain were observed between secretin- and vehicle-infused age-matched pairs (n = 4 pairs). Secretin-activated regions include the area postrema, dorsal motor nucleus, medial region of the nucleus of the solitary tract and its relay station in the lateral tegmentum, locus ceruleus, ventral periaqueductal gray, periventricular thalamic nucleus, paraventricular hypothalamus magnocellularis, medial and central amygdala, lateral septal complex as well as ependymal and subependymal nuclei lining the third ventricle. Specific areas of the cerebral cortex were heavily labeled in secretin-treated rats, as compared to controls: the medial bank of the anterior prefrontal cortex, orbitofrontal cortex, the piriform cortex. and the anterior olfactory nucleus. Secretin attenuated Fos immunoreactivity in the dorsal periaqueductal gray, intralaminar thalamus, medial parvicellular compartment of the hypothalamus, supraoptic nucleus of the hypothalamus, lateral amygdala, motor cortex, and the somatosensory and association areas of the parietal cortex. 4. Secretin alters the activity of structures involved in behavioral conditioning of stress adaptation and visceral reflex reactions. This study predicts a possible cellular mechanism, activation of third ventricular ependymal and subependymal cells, as well as central regulatory actions of secretin. The physiological effects of secretin on behavioral, endocrine, autonomic and sensory neuronal activation patterns, together, contribute to central c-fos activation. Secretin alters the activity of structures involved in behavioral conditioning of stress adaptation and visceral reflex reactions. This study predicts a possible cellular mechanism, activation of third ventricular ependymal and subependymal cells, and central regulatory actions of secretin. The physiological effects of secretin on behavioral, endocrine, autonomic and sensory neuronal activation patterns, together, contribute to central c-fos activation. These findings mandate further investigation of secretin as a brain/gut stress regulatory hormone.

Anatomical basis for the fastigial pressor response.

Electrical stimulation of rostromedial portion of cerebellar fastigial nucleus elicits integrated cardiovascular effects, which are neurally and humorally mediated. In this study, we sought to demonstrate the anatomical substrates of the fastigial pressor response (FPR) in the rat. The response was electrophysiologically localized in anesthetized, paralyzed-ventilated rats. Anterograde transport techniques were used to study the efferent projections of the fastigial pressor area; the distribution of efferent projection cells were then mapped by injecting retrograde tracers into anterogradely labeled sites. Electrolytic lesions were then placed bilaterally in selected brainstem areas in the attempt to block the pressor response. Sites of cerebellar stimulation and of brainstem lesions were subsequently histologically identified. The following lesions abolished the FPR: in nine animals lesions involved portions of the nucleus gigantocellularis dorsalis (NGCd), paramedian reticular formation (PMN) and the nucleus tractus solitarii (NTS) (in two animals fairly selectively the caudal NTS); in two other animals lesions destroyed the rostral ventrolateral medulla (C1 area) and in one animal the area encompassing the dorsal convexity of the superior cerebellar peduncle bordering the locus coeruleus-lateral parabrachial complex; partially effective were unilateral lesions of NGCd and NTS (three), bilateral lesions confined to NGCd and PMN (two), to vestibular complex and uncinate fasciculus (UF) (three), to UF and locus coeruleus (three) and to nucleus reticularis ventralis (two). Ineffective lesions involved A1 area, the nucleus gigantocellularis ventralis (NGCv), the spinal trigeminal nucleus and nucleus reticularis parvocellularis, the A5 area of the ventrolateral pons, the central gray and lateral mesencephalic tegmentum. It seems therefore that the pressor response elicited by stimulation of the cerebellar fastigial nucleus utilizes central specific pathways, as lesions involving other brainstem regions also known to participate in cardiovascular control do not affect the response. Furthermore, the FPR persisted after midbrain decerebration, thus demonstrating that it is organized beneath the midbrain.

Developmental changes in heart rate variability during exposure to prolonged hypercapnia in piglets.

The hypothesis that hypercapnia-induced differences in heart rate variability (HRV) would emerge during early maturation was tested using a developing porcine model. Piglets were randomly assigned to either exposed (10% CO2 for 1 h) or control (100% O2) conditions, and then to one of three study groups: (a) 5-8 days old, (b) 13-15 days old, (c) 26-34 days old. Experiments were performed on pairs of age-and litter-matched animals that were anesthetized, paralyzed, and artificially ventilated. HRV was evaluated using power spectral analysis, SD of differences between successive RR intervals, and cardiac interval analysis. Statistical comparisons of simultaneously studied animals were made at baseline, 15 and 55 min after onset of hypercapnia, and 2 h after offset of hypercapnia. Our analyses revealed that only HRV of 26-34-day-old animals differed significantly from values of control animals. Cardiac intervals of those animals were distributed in such a manner that hypercapnia likely elicited coactivation of sympathetic and parasympathetic systems. Comparison of the distribution of cardiac intervals for other animals showed that 5-8-day-old animals had high frequency of balanced intervals at baseline that remained so during hypercapnia. Given that such coactivation may be neuroprotective, the paucity of balanced intervals in 13-15-day-old animals could mean that the end of the second postnatal week is associated with increased vulnerability.