Impaired Insulin Signaling Alters Mediators of Hippocampal Synaptic Dynamics/Plasticity: A Possible Mechanism of Hyperglycemia-Induced Cognitive Impairment.

Alzheimer's disease (AD) is a neurological condition that affects the elderly and is characterized by progressive and irreversible neurodegeneration in the cerebral cortex [...].

Early time course of oxidative stress in hippocampal synaptosomes and cognitive loss following impaired insulin signaling in rats: Development of sporadic Alzheimer's disease.

Oxidative stress, caused by impaired insulin signaling, plays a pivotal role in the pathogenesis of sporadic Alzheimer's disease (sAD). We investigated the oxidative stress parameters in the synaptosomes prepared from the hippocampus tissue in order to identify their potential role in sAD development in intraperitoneal (IP) and intracerebroventricular (ICV) streptozotocin (STZ) injections models of insulin signaling impairment. Rats were harvested 1, 3, or 6 weeks post treatment. Spatial learning and memory, several antioxidants and oxidative stress markers were analyzed. Results showed a significant deficit in learning and memory in rats injected with STZ through IP and ICV routes. Glutathione, glutathione/oxidized glutathione, glutathione S-transferase, glutathione peroxidase, glutathione reductase, catalase, superoxide dismutase(SOD)-total, Zn/Cu(SOD), Mn/Fe(SOD) are significantly decreased in IP-STZ and ICV-STZ groups at 1, 3, and 6 weeks after STZ injection. Oxidized glutathione, thiobarbituric acid reactive species, glucose 6-Phosphate dehydrogenase, protein carbonyls, 4-Hydroxynonenal, and 3-Nitrotyrosine are significantly increased in IP-STZ and ICV-STZ groups at 1,3, and 6 weeks after STZ injection. Changes in oxidative stress parameters in ICV-STZ groups are greater than IP-STZ groups. STZ treatment induced cognitive impairments by 3-W and 6-W, and it was significantly correlated with the extent of oxidative damage. In conclusion, STZ administration through ICV route is deleterious in causing early synaptosomal oxidative damage that exacerbated with time and correlated with cognitive impairments. Our data implicate the involvement of oxidative stress as an early feature of sAD and provide insights into the behavioral and biochemical changes over the course of disease development.

Understanding pacing postconditioning-mediated cardiac protection: a role of oxidative stress and a synergistic effect of adenosine.

We and others have demonstrated a protective role for pacing postconditioning (PPC) against ischemia/reperfusion (I/R) injury in the heart; however, the underlying mechanisms behind these protective effects are not completely understood. In this study, we wanted to further characterize PPC-mediated cardiac protection, specifically identify optimal pacing sites; examine the role of oxidative stress; and test the existence of a potential synergistic effect between PPC and adenosine. Isolated rat hearts were subjected to coronary occlusion followed by reperfusion. PPC involved three, 30 s, episodes of alternating left ventricular (LV) and right atrial (RA) pacing. Multiple pacing protocols with different pacing electrode locations were used. To test the involvement of oxidative stress, target-specific agonists or antagonists were infused at the beginning of reperfusion. Hemodynamic data were digitally recorded, and cardiac enzymes, oxidant, and antioxidant status were chemically measured. Pacing at the LV or RV but not at the heart apex or base significantly (P < 0.001) protected against ischemia-reperfusion injury. PPC-mediated protection was completely abrogated in the presence of reactive oxygen species (ROS) scavenger, ebselen; peroxynitrite (ONOO-) scavenger, uric acid; and nitric oxide synthase inhibitor, L-NAME. Nitric oxide (NO) donor, snap, however significantly (P < 0.05) protected the heart against I/R injury in the absence of PPC. The protective effects of PPC were significantly improved by adenosine. PPC-stimulated protection can be achieved by alternating LV and RA pacing applied at the beginning of reperfusion. NO, ROS, and the product of their interaction ONOO- play a significant role in PPC-induced cardiac protection. Finally, the protective effects of PPC can be synergized with adenosine.

Loss of Anticontractile Effect of Perivascular Adipose Tissue on Pregnant Rats: A Potential Role of Tumor Necrosis Factor-α.

The present investigation examined the effect of pregnancy on the anticontractile effect of perivascular adipose tissue (PVAT) on the rat. Ring segments of the aorta, with and without PVAT, were set up in organ baths for isometric tension recording. In both groups, concentration-response curves to 5-hydroxytryptamine (5-HT) were displaced to the right with a reduction of the maximum response in aorta segments with PVAT. The anticontractile effect of PVAT was attenuated on segments from pregnant rats. 4-Aminopyridine (4-AP), an inhibitor of voltage-gated potassium (Kv) channels, enhanced 5-HT-induced contractions of aorta segments from pregnant and nonpregnant rats only when PVAT was attached. There was no difference in the effect of 4-aminopyridine on 5-HT-induced contractions of aorta segments with PVAT from pregnant and nonpregnant rats. There was also no significant difference in the expression of Kv7.4 channels in aorta segments (with PVAT) between pregnant and nonpregnant rats. Tumor necrosis factor-α (TNF-α) was detected in PVAT from pregnant and nonpregnant rats. The level of TNF-α was significantly greater in PVAT from pregnant rats. Treatment of pregnant rats with pentoxyphyline significantly reduced the level of TNF-α in the PVAT and restored the anticontractile effect of PVAT on aorta segments from pregnant rats. Finally, TNF-α (10 ng/mL) potentiated 5-HT-induced contractions of PVAT-containing pregnant rat aorta. These results would suggest that the loss of anticontractile effect of PVAT in pregnant rat aorta could be due to enhanced production of TNF-α in the PVAT in these rats.

High density lipoprotein stimulated migration of macrophages depends on the scavenger receptor class B, type I, PDZK1 and Akt1 and is blocked by sphingosine 1 phosphate receptor antagonists.

HDL carries biologically active lipids such as sphingosine-1-phosphate (S1P) and stimulates a variety of cell signaling pathways in diverse cell types, which may contribute to its ability to protect against atherosclerosis. HDL and sphingosine-1-phosphate receptor agonists, FTY720 and SEW2871 triggered macrophage migration. HDL-, but not FTY720-stimulated migration was inhibited by an antibody against the HDL receptor, SR-BI, and an inhibitor of SR-BI mediated lipid transfer. HDL and FTY720-stimulated migration was also inhibited in macrophages lacking either SR-BI or PDZK1, an adaptor protein that binds to SR-BI's C-terminal cytoplasmic tail. Migration in response to HDL and S1P receptor agonists was inhibited by treatment of macrophages with sphingosine-1-phosphate receptor type 1 (S1PR1) antagonists and by pertussis toxin. S1PR1 activates signaling pathways including PI3K-Akt, PKC, p38 MAPK, ERK1/2 and Rho kinases. Using selective inhibitors or macrophages from gene targeted mice, we demonstrated the involvement of each of these pathways in HDL-dependent macrophage migration. These data suggest that HDL stimulates the migration of macrophages in a manner that requires the activities of the HDL receptor SR-BI as well as S1PR1 activity.