GM1 ganglioside therapy in acute ischemic stroke. Italian Acute Stroke Study--Hemodilution + Drug

Eleven of 31 clinical centers participating in the Italian Acute Stroke Study--Hemodilution carried out a preliminary study on the effectiveness of ganglioside GM1 in acute stroke; 502 patients were randomized to GM1 (GM1, n = 121), GM1 plus hemodilution (GM1 + H, n = 128), placebo (P, n = 130), or placebo plus hemodilution (P + H, n = 123) groups less than or equal to 12 hours after onset of a hemispheric cerebral infarct. The patients were treated for 15 days and were evaluated on Days 21 and 120 after the onset of stroke. Intention-to-treat analysis failed to show any differences in neurologic deficit, mortality, or neurologic disability among the groups. Efficacy analysis showed a significantly higher degree of neurologic improvement in GM1 group patients compared with patients in the P group during the first 15 days. GM1-treated patients (GM1 and GM1 + H groups) showed a significantly higher degree of neurologic improvement during the first 10 days compared with the placebo-treated patients (P and P + H groups). These differences were no longer statistically significant at Day 120. Our results provide a rationale for the planning of a larger, multicenter trial of GM1 ganglioside in acute stroke.     

Irbesartan restores the in-vivo insulin signaling pathway leading to Akt activation in obese Zucker rats

BACKGROUND: Angiotensin II (AII) has been shown to contribute to the pathogenesis of hypertension and insulin resistance. In addition, the administration of selective AII type 1 receptor blockers has been shown to improve insulin sensitivity. However, only a few studies have addressed the molecular mechanisms involved in this association. Furthermore, in a previous study we illustrated that obese Zucker rats (OZR) present increased serine 994 (Ser994) phosphorylation of hepatic insulin receptor, and this event seems to be implicated in the regulation of the intrinsic IRK in this model of insulin resistance. OBJECTIVE AND DESIGN: We examined the effects of chronic treatment with irbesartan (50 mg/kg a day for 6 months) on the hepatic insulin signaling system of OZR. METHODS: The extent of phosphorylation of several components of the insulin signaling system was assessed by immunoprecipitation, followed by immunoblotting with phosphospecific antibodies. In addition, liver AII levels and fat deposits were determined by immunohistochemistry and Oil red O, respectively. RESULTS: OZR displayed a marked attenuation in the in-vivo phosphorylation of several components of the insulin signaling pathways in the liver, together with significantly higher hepatic AII levels and hepatic steatosis when compared with lean Zucker rats. We found that in the livers of OZR long-term administration of irbesartan is associated with: (i) increased insulin-stimulated insulin receptor tyrosine phosphorylation; (ii) decreased insulin receptor Ser994 phosphorylation; (iii) augmented insulin receptor substrate (IRS) 1 and 2 abundance and tyrosine phosphorylation; (iv) augmented association between IRS and the p85 regulatory subunit of phosphatidylinositol 3-kinase; (v) increased insulin-induced Akt phosphorylation; and (vi) decreased hepatic steatosis. CONCLUSION: The present study provides substantial information that demonstrates that long-term selective AII blockade by irbesartan improves insulin signaling and is associated with decreased insulin receptor Ser994 phosphorylation in the liver of a representative animal model of the human metabolic syndrome.