Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats

<p>Abstract</p> <p>Background</p> <p>Intracerebral hemorrhage (ICH) remains a serious clinical problem lacking effective treatment. Urocortin (UCN), a novel anti-inflammatory neuropeptide, protects injured cardiomyocytes and dopaminergic neurons. Our preliminary studies indicate UCN alleviates ICH-induced brain injury when administered intracerebroventricularly (ICV). The present study examines the therapeutic effect of UCN on ICH-induced neurological deficits and neuroinflammation when administered by the more convenient intraperitoneal (i.p.) route.</p> <p>Methods</p> <p>ICH was induced in male Sprague-Dawley rats by intrastriatal infusion of bacterial collagenase VII-S or autologous blood. UCN (2.5 or 25 μg/kg) was administered i.p. at 60 minutes post-ICH. Penetration of i.p. administered fluorescently labeled UCN into the striatum was examined by fluorescence microscopy. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. Blood-brain barrier (BBB) disruption was assessed using the Evans blue assay. Hemorrhagic volume and lesion volume were assessed by Drabkin's method and morphometric assay, respectively. Pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) expression was evaluated by enzyme-linked immunosorbent assay (ELISA). Microglial activation and neuronal loss were evaluated by immunohistochemistry.</p> <p>Results</p> <p>Administration of UCN reduced neurological deficits from 1 to 7 days post-ICH. Surprisingly, although a higher dose (25 μg/kg, i.p.) also reduced the functional deficits associated with ICH, it is significantly less effective than the lower dose (2.5 μg/kg, i.p.). Beneficial results with the low dose of UCN included a reduction in neurological deficits from 1 to 7 days post-ICH, as well as a reduction in brain edema, BBB disruption, lesion volume, microglial activation and neuronal loss 3 days post-ICH, and suppression of TNF-α, IL-1β, and IL-6 production 1, 3 and 7 days post-ICH.</p> <p>Conclusion</p> <p>Systemic post-ICH treatment with UCN reduces striatal injury and neurological deficits, likely via suppression of microglial activation and inflammatory cytokine production. The low dose of UCN necessary and the clinically amenable peripheral route make UCN a potential candidate for development into a clinical treatment regimen.</p

Uncoupling proteins, dietary fat and the metabolic syndrome

There has been intense interest in defining the functions of UCP2 and UCP3 during the nine years since the cloning of these UCP1 homologues. Current data suggest that both UCP2 and UCP3 proteins share some features with UCP1, such as the ability to reduce mitochondrial membrane potential, but they also have distinctly different physiological roles. Human genetic studies consistently demonstrate the effect of UCP2 alleles on type-2 diabetes. Less clear is whether UCP2 alleles influence body weight or body mass index (BMI) with many studies showing a positive effect while others do not. There is strong evidence that both UCP2 and UCP3 protect against mitochondrial oxidative damage by reducing the production of reactive oxygen species. The evidence that UCP2 protein is a negative regulator of insulin secretion by pancreatic β-cells is also strong: increased UCP2 decreases glucose stimulated insulin secretion ultimately leading to β-cell dysfunction. UCP2 is also neuroprotective, reducing oxidative stress in neurons. UCP3 may also transport fatty acids out of mitochondria thereby protecting the mitochondria from fatty acid anions or peroxides. Current data suggest that UCP2 plays a role in the metabolic syndrome through down-regulation of insulin secretion and development of type-2 diabetes. However, UCP2 may protect against atherosclerosis through reduction of oxidative stress and both UCP2 and UCP3 may protect against obesity. Thus, these UCP1 homologues may both contribute to and protect from the markers of the metabolic syndrome

CYSTEAMINE CAN INDUCE DUODENAL ULCERATION IN RATS WITHOUT DEPLETION OF IMMUNOREACTIVE SOMATOSTATIN

Single subcutaneous administration of cysteamine (2-aminoethanethiol, CSH) produces duodenal ulceration in rats within 24 h. Depletion of circulating and tissue somatostatin (SOM), hypergastrinemia and gastric acid hypersecretion have all been postulated as the pathophysiological response to CSH leading to ulceration. The purpose of this study was to analyze the synthesis, storage and secretion of gastrin and SOM as well as structural changes in SOM peptide after CSH treatment. Injection of 300 mg/kg (s.c.) of CSH caused macroscopic duodenal ulcers in seven out of eight rats at 24 h. Hypergastrinemia was seen within 30 min (from 23 +/- 4 to 74 +/- 20 pmol/l), and persisted for 4 h. Antral gastrin content was elevated at 30 min (2539 +/- 114 pmol/g) when compared to saline controls (1589 +/- 101 pmol/g). Plasma SOM did not change over the 24 h but antral SOM increased at 30 min (from 120 +/- 3 to 230 +/- 23 pmol/g) and remained elevated at 2 h (374 +/- 48 pmol/g) and 4 h (357 +/- 37 pmol/g). Fundic and duodenal SOM followed a similar pattern. Antral SOM mRNA was also elevated over the first 4 h (3-fold increase, P less than 0.05). HPLC analysis of antral tissue extracts revealed the presence of additional molecular forms of SOM which, however, differed from the major products of in vitro reduction with either CSH or dithiothreitol. Thus, the in vivo effect of CSH on SOM cannot be solely explained by a reductive opening of the disulphide bond. These results suggest that duodenal ulceration in rats treated with CSH is not related in a simple fashion to depletion of immunoreactive SOM. Early induction of hypergastrinemia may be important in the onset of ulceration. The value of CSH as a SOM depleting tool in gastrointestinal tissue must remain in doubt

Visual guidance of landing behaviour when stepping down to a new level

When stepping down from one level to another, the leading limb has to arrest downward momentum of the body and subsequently receive and safely support bodyweight before level walking can begin. Such step downs are performed over a wide range of heights and predicting when and where contact between the landing limb and the lower level will be made is likely a critical factor. To determine if visual feedback obtained after movement initiation is habitually used in guiding landing behaviour, the present study determined whether pre-landing kinematics and the mechanics of landing would be modulated according to the type of visual feedback available during the stepping down phase. Ten healthy participants (32.3 ± 7.9 years) stepped, from a standing position, down from three different heights onto a forceplatform, either coming immediately to rest or proceeding directly to walking across the laboratory. Repeated trials were undertaken under habitual vision conditions or with vision blurred or occluded 2¿3 s prior to movement initiation. Pre-landing kinematics were assessed by determining, for the instant of landing, lead-limb knee and ankle angle, stepping distance, forwards positioning of the body CM within the base of support and the forwards and downwards body CM velocity. Landing mechanics for the initial contact period were characterized using lead limb vertical loading and stiffness, and trail limb un-weighting. When vision was occluded movement time, ankle plantarflexion and knee flexion were significantly increased compared to that determined for habitual vision, whereas forwards body CM positioning and velocity, vertical loading and stiffness, and trail limb un-weighting, were significantly reduced (p < 0.05). Similar adaptations were observed under blurred conditions, although to a lesser extent. Most variables were significantly affected by stepping task and step height. Subjects likely reduced forwards CM position and velocity at instant of landing, in order to keep the CM well away from the anterior border of the base of support, presumably to ensure boundary margins of safety were high should landing occur sooner or later than expected. The accompanying increase in ankle plantarflexion at instant of landing, and increase in single limb support time, suggests that subjects tended to probe for the ground with their lead limb under modified vision conditions. They also had more bodyweight on the trail limb at the end of the initial contact period and as a consequence had a prolonged weight transfer time. These findings indicate that under blurred or occluded vision conditions subjects adopted a cautious strategy where by they ¿sat back¿ on their trail limb and used their lead limb to probe for the ground. Hence, they did not fully commit to weight transfer until somatosensory feedback from the lead limb confirmed they had safely made contact. The effect of blurring vision was not identical to occluding vision, and led to several important differences between these conditions consistent with the use of impoverished visual information on depth. These findings indicate that online vision is customarily used to regulate landing behaviour when stepping down