Determination of the source of increased serotonin (5-HT) concentrations in blood and peritoneal fluid of colic horses with compromised bowel.

REASONS FOR PERFORMING STUDY: Increased plasma (5-HT) concentrations are reported in horses predisposed to develop laminitis and after i.v. infusion of endotoxins. In the equine jejunum contractile 5-HT1A-like receptors show tachyphylaxia upon prolonged activation with 5-HT. Therefore, increased systemic 5-HT release in colic horses could play a possible role in the pathophysiology of ileus. OBJECTIVE: To investigate possible increased systemic release of 5-HT in colic horses with compromised bowel and to identify the source of 5-HT overload. METHODS: Concentrations of 5-HT were determined in plasma and peritoneal fluid (PF) of healthy horses (n = 10), strangulating small intestinal colic horses (n = 18), nonsurgical colic horses (n = 10) and cryptorchid stallions (n = 6). It was attempted to identify the source of 5-HT overload by comparing the blood and PF 5-HT concentrations within horses and by assessing the in vivo platelet activation through determination of the beta-thromboglobulin (beta-TG)/platelet factor 4 (PF4) ratio. RESULTS: All horses in the strangulating small intestinal colic group had plasma (P = 0.006) and PF (P = 0.01) 5-HT concentrations above those found in the control group. Plasma beta-TG/PF4 ratio in these horses exceeded 2 in all cases, indicating in vivo platelet activation. Concentrations of 5-HT in PF of colic horses with compromised bowel were significantly lower than the corresponding plasma concentrations (P = 0.005). POTENTIAL RELEVANCE: In horses with compromised bowel, significant amounts of 5-HT can be released into the systemic circulation, through massive release of platelet-stored 5-HT. 5-HT is a very potent proinflammatory, vasoconstrictive and immunomodulatory agent. In view of the rapid and prolonged tachyphylaxia, shown for the jejunal 5-HT1A-like receptors, this increased systemic 5-HT release could play a role in the pathophysiology of ileus in horses.

Coexpression of GSK-3beta corrects phenotypic aberrations of dorsal root ganglion cells, cultured from adult transgenic mice overexpressing human protein tau.

Coexpression of constitutively active GSK-3beta[S9A] rescued the axonal pathology induced by overexpression of human tau in transgenic mice (Spittaels et al., (2000) J. Biol. Chem. 275, 41340-41349). We isolated dorsal root ganglion (DRG) neuronal cultures from adult tau4R- and tau4R x GSK-3beta-transgenic mice to define the mechanisms at the cellular and subcellular level. DRG from tau4R-transgenics showed a reduced sprouting capacity while density and stability of microtubules in the axonal processes were significantly increased. Video-enhanced contrast microscopy demonstrated a dramatic inhibition of fast axonal transport. Coexpression of GSK-3beta increased tau phosphorylation and reversed the effects on microtubule stability and saltatory motion. In DRG from GSK-3beta single transgenics, increased tau phosphorylation was evident without any major effects on microtubule stability or axonal transport. These observations support the hypothesis that excess tau competed with motor-proteins for binding to microtubules and/or that a rigid microtubular system inhibits axonal transport.