Chronic N-acetylcysteine treatment alleviates acute lipopolysaccharide-induced working memory deficit through upregulating caveolin-1 and synaptophysin in mice.

RATIONALE: Working memory (WM) is a dynamic encoding process and an active representation of information over a short time. The ability to guide forthcoming behavior would be disrupted if WM was impaired by various factors including inflammation, stress, free radicals, and disease states such as schizophrenia. However, the mechanism underlying acute working memory impairment remains to be defined. OBJECTIVES: In this study, we tested the hypothesis that decreased caveolin-1 (Cav-1) and synaptophysin (SYP) accounted for the WM impairment challenged with acute intraperitoneally lipopolysaccharide (LPS), which mimicked neuroinflammation. Delayed alternation T-maze task (DAT) was used to assess working memory of adult male C57BL/6 mice, and western blot and immunostaining were used to detect protein expression and distribution in medial prefrontal cortex (mPFC) and hippocampus. RESULTS: Our results showed that LPS dose-dependently induced working memory deficit accompanied by the decrease of Cav-1 and SYP in mPFC but not hippocampus. In addition, LPS significantly decreased protein level of Cav-1 and SYP in neurons by activating microglia cells. More important, 2-week N-acetylcysteine (NAC) treatment dose-dependently inhibited LPS-induced working memory deficit by improving the ability to use Lose-shift but not Win-shift strategy and significantly inhibited LPS-induced downregulation of Cav-1 and SYP in mPFC. CONCLUSIONS: Taken together, our findings demonstrate that chronic NAC treatment alleviates acute LPS-induced working memory deficit through upregulating Cav-1 and SYP in mice.

Expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in ulcerative colitis.

AIM: To examine the expression of metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the colonic mucosa of patients with ulcerative colitis (UC). METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to study the expression of MMP-1 and TIMP-1 at both mRNA and protein levels in patients with UC and controls. The relationship between MMP-1 mRNA, TIMP-1 mRNA, MMP-1 mRNA/TIMP-1 mRNA ratio and the severity of clinical symptoms of the patients with UC were also analyzed. RESULTS: The expression of MMP-1 mRNA and TIMP-1 mRNA in the ulcerated and inflamed colonic mucosa was significantly higher than that in the non-inflamed colonic mucosa (P < 0.001), but there was no statistically significant difference in the non-inflamed colonic mucosa of UC patients and normal controls (P > 0.05). The mRNA expression of MMP-1 and TIMP-1 in ulcerated colonic mucosa of UC patients was increased by 80-fold and 2.2-fold, respectively when compared with the normal controls. In the inflamed colonic mucosa, the increase was 30-fold and 1.6-fold, respectively. Immunohistochemical analysis showed that among the ulcerated, inflamed, and non-inflamed colonic mucosae of UC patients and the normal controls, the positive rate of MMP-1 expression was 87%, 87%, 40% and 35% respectively, and the positive rate of TIMP-1 expression was 89%, 89%, 80% and 75%, respectively. Furthermore, the expression of MMP-1 mRNA, TIMP-1 mRNA and the MMP-1 mRNA/ TIMP-1 mRNA ratio were correlated with the severity of clinical symptoms (P <0.05). CONCLUSION: Excessive expression of MMP-1 in the diseased colonic mucosa causes excessive hydrolysis of the extracellular matrix (ECM) and ulceration in UC patients. MMP-1 mRNA, TIMP-1 mRNA and MMP-1 mRNA/TIMP-1 mRNA ratio can be used as biomarkers to judge the severity of clinical symptoms in patients with UC. Exogenous TIMP-1 or MMP-1 inhibitor therapy is a novel treatment for patients with UC.