Funkcionális és morfológiai változások jellemzése krónikus agyi hipoperfúzió során patkányban = Characterization of functional and morphological changes is the hypoperfused rat brain

Az igen gyakori krónikus agyi hipoperfúzió feltehetően ok-okozati összefüggésben áll az időskori kognitív zavarok kialakulásával. Az állapot széleskörben elfogadott állatkísérletes modellje patkányban a permanens kétoldali carotis comm. okklúzió (2VO). Ennek hatására neuronális károsodás, microglia aktiváció és memória zavar alakul ki. Eredményeink megerősítették, hogy a károsító folyamatok sokrétűek, közöttük kulcs szerepet játszik a pro-és antioxidáns enzimek (pl. COX-2 vagy az eNOS) megváltozott indukciója. Az antioxidáns hatásáról ismert alfa tokoferol használatával jelentősen csökkenthető volt a 2VO által előidézett memóriakárosodás. A hipoperfúzió károsan hat a retinára is. Modellünkben egy szelektív mitochondriális ATP-függő K+csatornanyitó vegyülettel eredményesen csökkentettük a retinakárosodást. Eredményeink rámutattak arra is, hogy szelektív COX-2 gátló szerekkel meggátolható a tanulási folyamat nagymértékű károsodása. A hipoperfúzió és a migrén összefüggéseinek tanulmányozása során rámutattunk a COX-2 enzim lehetséges szerepére a migrén pathomechanizmusában. Továbbá bizonyítottuk, hogy az NMDA patkányban kúszó kérgi depolarizáción (CSD) keresztül okoz kérgi hiperaemiát. A krónikus hipoperfúzió és az öregedés egyaránt csökkenti az agykéreg érzékenységét a CSD kiváltásával szemben. Kutatási eredményeink számos területen hozzájárultak a krónikus agyi hipoperfúzió által okozott morfológiai és funkcionális károsodások mechanizmusának megértéséhez. | Chronic cerebral hypoperfusion is a mild ischemic condition associated with a cognitive decline which is prevalent during senescence. Its experimental animal model compromises permanent occlusion of the common carotid arteries (2VO) in rats, which results in neuronal damage, microglia activation and memory dysfunction. Our studies indicate that various mechanisms, including oxidative stress (e.g.: elevated COX-2 and eNOS levels), have been proposed to be involved in this process. Alpha-tocopherol ?a well known antioxidant- moderates the 2VO-induced learning impairment even when used after the 2VO onset. 2 VO results in severe degeneration of all retinal layers that could be counteracted by stimulation of mitochondrial ATP sensitive potassium channels. We have reported that selective COX-2 inhibition prevents the hypoperfusion-induced memory impairment. Our findings suggest that COX-2, but not COX-1 derived metabolites play a significant role in the induction of migraine. We have demonstrated NMDA elicits dose-dependent increases in cortical blood flow that are composed of cortical spreading depression (CSD)-dependent and -independent components. Our results point out reduced sensitivity of the cortex to CSD elicitation with early aging, and a less responsive cerebrovascular system with chronic hypoperfusion. Our experimental studies provided several pieces of evidence for understanding of the causative role played by cerebral hypoperfusion in neurodegenerative diseases

Faecal Matrix Metalloprotease-9 Is a More Sensitive Marker For Diagnosing Pouchitis Than Faecal Calprotectin – Results From a Pilot Study

Background. Potential non-invasive markers of pouchitis would have a great deal of significance within clinical practice. This study is aimed at assessing the diagnostic accuracy of faecal calprotectin and matrix metalloprotease-9 as potential markers in patients both with and without pouchitis. Patients and methods. Stool and blood samples were collected from 33 ileal pouch-anal anastomosis patients before a follow-up pouchoscopy. Biopsy samples were taken for histological purposes. The presence of cuffitis and stenosis was evaluated with an endoscopy. Calprotectin and matrix metalloprotease-9 were quantified with an enzyme-linked immunosorbent assay. Results. Pouchitis was detected in 30.3% of the patients. The levels of faecal calprotectin and matrix metalloprotease-9 increased significantly in patients with pouchitis. The sensitivity and specificity of matrix metalloprotease-9 was higher than that of faecal calprotectin. Only matrix metalloprotease-9 correlated significantly with the severity of pouchitis. Conclusions. Faecal matrix metalloprotease-9 has a high specificity in the diagnosis of pouchitis

Optimal Endpoint of Therapy in IBD: An Update on Factors Determining a Successful Drug Withdrawal

Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory disorders, which require long term treatment to achieve remission and to prevent relapses and cancer. While current therapies are effective in most cases, they can have rare but serious side effects and are often associated with high costs. On the other hand, early discontinuation of an effective treatment may lead to a quick relapse and to complications at the restart of therapy. Therefore it is essential to determine the optimal duration of maintenance therapy, but clear guidelines are missing. The most important questions when deciding whether to continue or withdraw therapy in quiescent UC and CD patients are the efficacy of the continuous treatment to maintain remission in the long term, the frequency and severity of side effects, and the chance of relapse after discontinuation of therapy. This review summarizes the current knowledge on these topics with respect to 5-aminosalicylates, thiopurines, methotrexate, and biological therapies and collects information regarding when and in which specific patient groups, in the absence of risk factors, can withdrawal of therapy be considered without a high risk of relapse. Additionally, the particular aspect of colorectal cancer prevention by current therapies will also be discussed

Role of antispasmodics in the treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a long-lasting, relapsing disorder characterized by abdominal pain/discomfort and altered bowel habits. Intestinal motility impairment and visceral hypersensitivity are the key factors among its multifactorial pathogenesis, both of which require effective treatment. Voltage-gated calcium channels mediate smooth muscle contraction and endocrine secretion and play important roles in neuronal transmission. Antispasmodics are a group of drugs that have been used in the treatment of IBS for decades. Alverine citrate, a spasmolytic, decreases the sensitivity of smooth muscle contractile proteins to calcium, and it is a selective 5-HT(1A) receptor antagonist. Alverine, in combination with simethicone, has been demonstrated to effectively reduce abdominal pain and discomfort in a large placebo-controlled trial. Mebeverine is a musculotropic agent that potently blocks intestinal peristalsis. Non-placebo-controlled trials have shown positive effects of mebeverine in IBS regarding symptom control; nevertheless, in recent placebo-controlled studies, mebeverine did not exhibit superiority over placebo. Otilonium bromide is poorly absorbed from the GI tract, where it acts locally as an L-type calcium channel blocker, an antimuscarinic and a tachykinin NK2 receptor antagonist. Otilonium has effectively reduced pain and improved defecation alterations in placebo-controlled trials in IBS patients. Pinaverium bromide is also an L-type calcium channel blocker that acts locally in the GI tract. Pinaverium improves motility disorders and consequently reduces stool problems in IBS patients. Phloroglucinol and trimethylphloroglucinol are non-specific antispasmodics that reduced pain in IBS patients in a placebo-controlled trial. Antispasmodics have excellent safety profiles. T-type calcium channel blockers can abolish visceral hypersensitivity in animal models, which makes them potential candidates for the development of novel therapeutic agents in the treatment of IBS

Diazoxide and dimethyl sulphoxide alleviate experimental cerebral hypoperfusion-induced white matter injury in the rat brain

Aging and dementia are accompanied by cerebral white matter (WM) injury, which is considered to be of ischemic origin. A causal link between cerebral ischemia and WM damage has been demonstrated in rats; however, few attempts appear to have been made to test potential drugs for the alleviation of ischemia-related WM injury. We induced cerebral hypoperfusion via permanent, bilateral occlusion of the common carotid arteries of rats. A mitochondrial ATP-sensitive potassium channel opener diazoxide (5 mg/kg) or its solvent dimethyl sulphoxide (DMSO) was administered i.p. (0.25 ml) on 5 consecutive days after surgery. Sham-operated animals served as control for surgery, and non-treated rats as controls for treatments. Thirteen weeks after surgery, the animals were sacrificed and astrocytes and microglia were labeled immunocytochemically in the internal capsule, the corpus callosum and the optic tract. The astrocytic proliferation was enhanced by cerebral hypoperfusion in the optic tract, and reduced by diazoxide in DMSO, but not by DMSO alone in the corpus callosum. After carotid artery occlusion, microglial activation was enhanced two-fold in the corpus callosum and four-fold in the optic tract. DMSO decreased microglial activation in the optic tract, while diazoxide in DMSO, but not DMSO alone, restored microglial activation to the control level in the corpus callosum. In summary, the rat optic tract appeared to be particularly vulnerable to ischemia, while the effect of diazoxide was restricted to the corpus callosum. We conclude that diazoxide dissolved in DMSO can moderate ischemia-related neuroinflammation by suppressing glial reaction in selective cerebral WM areas.