Background: The hippocampus is a key brain area for many forms of learning and memory and is particularly sensitive to changes in glucose homeostasis. Aim of the work: To investigate in experimentally induced type 1 and 2 diabetes mellitus in rat model the effect of  diabetes mellitus on cognitive functions and related markers of hippocampal synaptic plasticity, and the possible impact of blocking N-methyl-D-aspartic acid (NMDA) receptors by memantine. Materials and methods: Seven rat groups were included: non-diabetic control and non-diabetic receiving memantine; type-1 diabetic groups - untreated, treated with insulin alone and treated with insulin and memantine; and type 2 diabetic groups - untreated and memantine treated. Cognitive functions were assessed by the Morris Water Maze and passive avoidance test. Biochemical analysis was done for serum glucose, serum insulin and insulin resistance. Routine histological examination was done, together with immunohistochemistry for detection of the hippocampal learning and memory plasticity marker, namely activity regulated cytoskeletal-associated protein (Arc), and the astrocytes reactivity marker, namely glial fibrillary acidic protein (GFAP).  Results: Both type 1 and 2 untreated diabetic groups showed significantly impaired cognitive performance compared to the non-diabetic group. Treating the type 1 diabetic group with insulin alone significantly improved cognitive performance, but significantly decreased GFAP and Arc compared to the untreated type 1 group. In addition, the type 2 diabetic groups showed a significant decrease in hippocampus GFAP and Arc compared to the non-diabetic groups. Blocking NMDA receptors by memantine significantly increased cognitive performance, GFAP and Arc in the type 1 insulin-memantine group compared to the type 1-insulin group and significantly increased Arc in the type 2-memantine group compared to the untreated type 2 diabetic group. The non-diabetic group receiving memantine was, however, significantly adversely affected. Conclusion: Cognitive functions are impaired in both types of diabetes mellitus and can be improved by blockage of NMDA receptors which may spark a future therapeutic role for these receptors in diabetes-associated cognitive dysfunction.

We concluded that ghrelin could represent new therapeutic window in early treatment of sepsis-induced AKI and this could be mainly due to its anti-inflammatory effects.

Ischemia-reperfusion (I/R) cannot be avoided in liver transplantation procedures, and apoptosis is a central mechanism of cell death after liver reperfusion. Protective effect of recombinant erythropoietin (rhEPO) on liver apoptosis has not been clearly investigated. This work investigated intraportal (IP) rhEPO-protective effect in a rat model of hepatic I/R-induced apoptosis and its appropriated time and dose of administration. Eight groups were included (n = 10/group): sham-operated, I/R (45 min ischemia and 2 h reperfusion), preconditioned rhEPO I/R (24 h or 30 min before ischemia), and postconditioned rhEPO I/R (before reperfusion) using two different rhEPO doses (1,000 and 5,000 IU/kg). When compared with the sham-operated group, the I/R group showed significant increase of serum levels of aspartate and alanine aminotransferases (AST, ALT), hepatic caspase-9 activity(894.99 ± 176.90 relative fluorescence units (RFU)/mg/min versus 458.48 ± 82.96 RFU/mg/min), and Fas ligand (FasL) expression, histopathological damages, and significant decrease in the antiapoptotic Bcl-xL/apoptotic Bax ratio(0.38 ± 0.21 versus 3.35 ± 0.77) rhEPO-improved ALT and AST but failed to reduce FasL expression in all groups compared with the I/R group. Thirty minutes and 24 h preconditioning with rhEPO (1,000 IU/kg) increased Bcl-xL/Bax ratio and reduced caspase-9 activity, and the same effect was observed when higher dose was given 24 h before ischemia. Preconditioning was more effective than postconditioning in improving caspase-9 activity, and no dose-dependent effect was observed. In conclusion, single IP rhEPO injection 30 min before ischemia has an advantage over rhEPO postconditioning in improving post-hepatic I/R-induced apoptosis with no additional time- and dose-dependent effects which may provide potentially useful guide in liver transplantation procedures.

Obesity is an important risk factor for heart disease. This study investigated the effects of omega-3 (omega-3) on reversal of high fat (HF) diet-induced changes in the expression of the cardiac adiponectin and adiponectin receptors R1 and R2. Male rats were fed low-fat (LF; 10% energy from fat) or HF (45% energy from fat) for 16 weeks, LF-omega-3 or a HF-omega-3 (LF or HF for 16 weeks supplemented by omega-3 as 36 g/kg diet for the last 6 weeks, respectively) and a HF diet for 10 weeks to demonstrate HF effect before omega-3 administration. HF diet induced obesity, glucose intolerance, increased heart end systolic and diastolic volumes, decreased serum adiponectin, reduced expression of cardiac and adipose tissue adiponectin and adipo R1 & R2 with elevated serum tumour necrosis factor-alpha (TNF-alpha) compared to the LF diet. On the other hand, the HF-omega-3 group compared with the HF group had improved glucose tolerance (area under the glucose curve 837.14 +/- 45.7 versus 1158.5 +/- 69.8) and insulin resistance with a significant increase in serum adiponectin (4.22 +/- 0.39 versus 2.82 +/- 0.69 ng/ml) and a significant decrease in serum TNF-alpha (129.84 +/- 13.63 versus 209.8 +/- 16.42 pg/ml) and triglycerides independent of obesity. Also the data showed significant increases in the expression of cardiac and adipose tissue adiponectin and adiponectin R1 and adipose tissue adipo R2 as well as cardiac pAMP kinase with improvement in end-systolic and -diastolic volumes. These parameters were also improved compared to initial values in HF-10-week group. In conclusion, dietary omega-3 supplementation has a beneficial effect on fat-induced cardiac dysfunction and insulin resistance partly through increasing adiponectin and adiponectin receptors expression in heart and adipose tissue.

Type 2 diabetes mellitus is one of the common metabolic disorders that ultimately afflicts large number of individuals. Adrenomedullin (AM) is a potent vasodilator peptide; previous studies reported development of insulin resistance in aged AM deficient mice. In this study, we employed a gene delivery approach to explore its potential role in insulin resistance. Four groups were included: control, diabetic, non-diabetic injected with the AM gene and diabetic injected with the AM gene. One week following gene delivery, serum glucose, insulin, triglycerides, leptin, adiponectin and corticosterone were measured as well as the insulin resistance index (HOMA-IR). Soleus muscle glucose uptake and RT-PCR of both AM and glucose transporter-4 (GLUT 4) gene expressions were assessed. A single tail vein injection of adrenomedullin gene in type 2 diabetic rats improved skeletal muscle insulin responsiveness with significant improvement of soleus muscle glucose uptake, HOMA-IR, serum glucose, insulin and triglycerides and significant increase in muscle GLUT 4 gene expression (P < 0.05) compared with the non-injected diabetic rats. The beneficial effects of AM gene delivery were accompanied by a significant increase in the serum level of adiponectin (2.95 ± 0.09 versus 2.33 ± 0.17 lg/ml in the non-injected diabetic group) as well as a significant decrease in leptin and corticosterone levels (7.51 ± 0.51 and 262.88 ± 10.

The role of nitric oxide (NO) in ventillatory muscle contractile function has been under debate for several years. Moreover little is known about NO role under hypoxic conditions and the contribution of inducible nitric oxide synthetase (iNOS) in its generation. The aim of this study was to investigate the effect of NO on the force generation and fatigue resistance of the rat diaphragm muscle under acute in vitro hypoxia and to compare these effects to those under hyperoxic conditions. The effects of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA), the NO scavenger hemoglobin, and the NO donor Na nitroprusside on the maximal twitch force (Ft), submaximal tetanic force (F30), maximal tetanic force (F0) and isotonic endurance time under hyperoxic and hypoxic conditions were evaluated. Also diaphragm iNOS activity and nitrotyrosine level as a marker of peroxynitrite were measured. Inhibition of NO production and its scavenging using L-NMMA and Hb respectively had no effect on the diaphragm isometric contraction, the recruitment of its muscle fibers and fatigue resistance under hyperoxic condition. Hypoxia significantly reduced Ft, F30 , F0 and fatigue resistance with increased diaphragm iNOS activity and nitrotyrosine level. Hypoxia significantly reduced Ft and F0 in L-NMMA group compared to hyperoxic control one. While L-NMMA significantly increased F30 and decreased isotonic fatigability during hypoxia concomitant with reduction of iNOS activity and nitrotyrosine level compared to hypoxic control group. Moreover Hb induced similar results with additional significant improvement of Ft and F0. The effects of L-NMMA were prevented by co-administration with the NOS substrate L-arginine. On the other hand, Excessive exogenous NO production by Na nitroprusside markedly decreased isometric contractile and fatigue properties during both hyperoxia and hypoxia. In conclusion the results of this study showed that the iNOS is activated in the diaphragm under hypoxia and may contribute partially to NO generation in hypoxia. Also they indicate that NO has a more prominent role in rat diaphragm under in vitro hypoxia compared to hyperoxic condition and that it contributes to the depression of force generation in the hypoxic diaphragm in vitro. Inhibition of NO generation during hypoxia may have a protective effect which could be a target in clinical conditions.

Cardiac ischemia is considered to be one of the deleterious injury increasing the risk of cardiac morbidity and mortality. Remote protection of the heart via ischemiareperfusion of non-vital organs (Remote ischemic preconditioning RIPC) was suggested by many studies as one of the possible cardioprotective intervention. The aim of the present study was to examine the role of inducible nitric oxide synthase (iNOS) and glutathione peroxidase (GPx) in RIPC of the heart prior to ischemiareperfusion injury, and the possibility of protecting cardiac performance and reducing cardiac damage. Four groups of male rabbits (n= 10/group) were included in this study: Control sham operated group (group I); Remote ischemic preconditioning (RIPC) group (group II); ischemia-reperfusion (I/R) group (group III) and RIPC+I/R group (group IV). RIPC was performed in rabbits of group II and IV by repeated four cycles of 10 min each ,of ischemia-reperfusion of femoral artery alternating with intervals of 10 minutes of reperfusion. After 24 hours, groups III and IV were subjected to 30 minutes pre-ischemic perfusion then 30 minutes of left coronary artery occlusion followed by 60 minutes of post-ischemic reperfusion. Serum creatine kinase (CK) was measured and the size of myocardial infarction was estimated at the end of the ischemic phase (as an index of myocardial ischemic injury). Glutathione peroxidase activity and mRNA iNOS expression were assessed in the cardiac tissue of the four groups. RIPC was found to have no significant effect on the left ventricular cardiac performance of normal heart. However, RIPC improved significantly the percentage recovery of the left ventricular developed pressure in group IV following ischemia-reperfusion compared to group III with no significant difference in the percentage recovery of both the contractility index and the heart rate. As regards glutathione peroxidase activity, it was significantly increased in group II compared to group I, and also as a consequence of cardiac ischemia reperfusion, GPx activity was significantly increased in group III compared to group I and II. RIPC and I/R increased significantly the GPx activity in group IV compared to other groups. Moreover, it was found that group IV had a significant increase in cardiac iNOS gene expression compared to group III, associated with a significant improvement of cardiac damage including serum creatine kinase and infraction size. Also, a significant positive correlation was found between GPx activity and iNOS gene expression in group IV. In conclusion, RIPC from skeletal muscles enhanced Bull. Egypt. Soc. Physiol. Sci. 26 (2) 2006 Younan et al. 212the recovery of the heart developed pressure, reduced the post-ischemic CK level, reduced the myocardial infarction size and was accompanied by an increase of glutathione peroxidase activity and enhanced iNOS gene expression providing a possible potential target for the development of novel cardioprotective strategies during I/R injury.

Impaired renal sodium excretion has been observed in fat induced obesity and was claimed to be multifactorial. Interestingly the subsequently developed hypertension can respond to one drug treatment, the angiotensin-converting enzyme inhibitor (ACE-I), suggesting a relationship between different causes of such impaired renal sodium excretion. This study aimed to elucidate such relationship and included six groups; group 1: rats fed the standard chow, group 2: moderately high fat diet (MHFD) fed rats, group 3: high salt fed (HSD) rats (4% Nacl for 1 week), group 4: MHFD+HSD, group 5: HSD+ACE-I and group 6: MHFD+HSD+ACE-I. It was found that 10 weeks of MHFD significantly increased the obesity index in groups 2, 4 and 6 compared to groups 1, 3 and 5 respectively and the systolic blood pressure in response to HSD in group 4 compared to group 3. Moreover MHFD led to significant albuminuria with significant reduction in urinary sodium excretion. Also MHFD increased significantly the renal malondialdehyde level (MDA) as an index of oxidative stress and angiotensinogen (AG) gene expression with significant decrease in urinary nitrites excretion and renal neuronal nitric oxide synthase (nNOS) expression in group 2 compared to group 1 and in group 4 compared to group 3. While HSD for one week did not have an impact on these previous parameters as evident by their non-significant differences between groups 3 and 1 and between groups 4 and 2. However, ACE inhibition in group 6 decreased significantly its urine albumin content, renal AG and MDA and significantly increased its urinary Na and nitrites excretion as well as its renal nNOS compared to group 4. Also ACE-I improved renal AG and nNOS in group 6 to be insignificantly different from those of group 5. These previous results suggest that a link coexist between renal angiotensinogen upregulation and renal oxidative stress mediated decrease in NO availability. In conclusion the MHF fed rats exhibited salt sensitivity accompanied by upregulation of renal angiotensinogen expression, increased oxidative stress and decreased nNOS expression, all of which could contribute to salt retention and hypertension.