Key points Tenascin X (TNX) functions in the extracellular matrix of skin and joints where it maintains correct intercellular connections and tissue architecture TNX is associated exclusively with vagal‐afferent endings and some myenteric neurones in mouse and human stomach, respectively. TNX‐deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalized by an inhibitor of vagal‐afferent sensitivity. Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX‐deficient mice. TNX‐deficient patients have upper gastric dysfunction consistent with those in a mouse model. Our translational studies suggest that abnormal gastric sensory function may explain the upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology. TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities, which will enable a better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents‐baclofen could be beneficial in patients. These hypotheses need confirmation via targeted clinical trials. Abstract Tenascin‐X (TNX) is a glycoprotein that regulates tissue structure via anti‐adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers–Danlos syndrome involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal dysfunction. Previously, we have shown that TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX‐deficient patients and mice. We aimed to identify whether TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report that TNX was present in calretinin‐immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABA B receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice, suggesting that vagal afferent responses are probably the result of altered peripheral mechanosensitivity. In TNXB‐deficient patients, significantly greater symptoms of reflux, indigestion and abdominal pain were reported. In the present study, we report the first role for TNX in gastric function. Further studies are required in TNX deficient patients to determine whether symptoms can be relieved usin...

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Transient, global cerebral ischemia (TGCI) causes hippocampal/cortical damage and the persistent loss of welltrained, long-term memory (retrograde amnesia). Fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids, abolishes such amnesia in the absence of neurohistological protection. The present study investigated whether FO prevents ischemia-induced oxidative stress and whether such an action contributes to the lasting effect of FO on memory recovery. In a first experiment, FO was administered for 4 days prior to ischemia, and antioxidant status was subsequently measured after 24 h of reperfusion. In another experiment, naive rats were trained in an eight-arm radial maze until they achieved asymptotic performance and then subjected to TGCI. One group of rats received FO as in the first experiment (i.e., 4 days prior to ischemia), whereas another group received FO for 4 days prior to ischemia plus 6 days postischemia. Retrograde memory performance was assessed 2-5 weeks after ischemia. TGCI depleted the level of antioxidant enzymes and increased the amount of protein carbonylation, indicating oxidative damage. Fish oil reversed oxidative damage to control levels. The same treatment that attenuated oxidative stress after 24 h of reperfusion also prevented retrograde amnesia assessed several weeks later. This antiamnesic effect afforded by short preischemia treatment was comparable to 10 days of treatment but not as consistent. These data indicate that an antioxidant action in the hyperacute phase of ischemia/reperfusion may contribute to the long-term, antiamnesic effect of FO.

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A series of our previous studies demonstrated that fish oil (FO), equivalent to 300mg/kg docosahexahenoic acid (DHA), facilitates memory recovery after transient, global cerebral ischemia (TGCI) in the aversive radial maze (AvRM). The present study sought to address two main issues: (i) whether the memory-protective effect of FO that has been observed in the AvRM can be replicated in the passive avoidance test (PAT) and object location test (OLT) and (ii) whether FO at doses that are lower than those used previously can also prevent TGCI-induced memory loss. In Experiment 1, naive rats were trained in the PAT, subjected to TGCI (4-vessel occlusion model), and tested for retrograde memory performance 8 and 15days after ischemia. Fish oil (300mg/kg/day DHA) was given orally for 8days. The first dose was delivered 4h postischemia. In Experiment 2, the rats were subjected to TGCI, treated with the same FO regimen, and then trained and tested in the OLT. In Experiment 3, the rats were trained in the AvRM, subjected to TGCI, administered FO (100, 200, and 300mg/kg DHA), and tested for memory performance up to 3weeks after TGCI. At the end of the behavioral tests, the brains were examined for neurodegeneration and neuroblast proliferation. All of the behavioral tests (PAT, OLT, and AvRM) were sensitive to ischemia, but only the AvRM was able to detect the memory-protective effect of FO. Ischemia-induced neurodegeneration and neuroblast proliferation were unaffected by FO treatment. These results suggest that (i) the beneficial effect of FO on memory recovery after TGCI is task-dependent, (ii) doses of FO<300mg/kg DHA can protect memory function in the radial maze, and (iii) cognitive recovery occurs in the absence of neuronal rescue and/or hippocampal neurogenesis.

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