Sitagliptin's renoprotective effect in a diabetic nephropathy model in rats: The potential role of PI3K/AKT pathway.

Management of diabetic nephropathy (DN) is far from satisfactory. There is a rising role of the involvement of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway in the pathogenesis of DN. This study aimed at investigating the renoprotective effects of PI3K/AKT pathway via sitagliptin in a rat model of DN. Thirty-two male Wistar rats were divided into four groups (eight rats each): (I) control, (II) sitagliptin, (III) DN, and (IV) DN + sitagliptin. Fasting blood glucose (FBG), kidney index, and kidney function tests in both blood and urine were measured. The levels of superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-ß) and gene expressions of PI3K, pPI3K, AKT, and pAKT in renal tissue were detected. Renal histopathological and immunohistochemical studies were evaluated. DN + sitagliptin group showed significant decrease in FBG and kidney index, improvement in kidney function tests, and a decrease in levels of TNF-α and TGF-ß in renal tissues compared with DN group. This was associated with significant increase in SOD and gene expressions of PI3K and AKT and their phosphorylated active forms in renal tissue in DN + sitagliptin group compared with DN group. Moreover, DN + sitagliptin group showed apparent decrease in amount of collagen fibers and expression of alpha-smooth muscle actin (α-SMA) compared with DN group. This work shows that sitagliptin improved renal functions and histopathological changes, impeded inflammation, and oxidative stress and upregulated PI3K/AKT pathway which highlights its renoprotective effects in a rat model of DN.

Reduction in TNF alpha and oxidative stress by liraglutide: Impact on ketamine-induced cognitive dysfunction and hyperlocomotion in rats.

BACKGROUND: Diabetes and psychotic disorders are occasionally comorbid. Possible pathophysiologies linking these disorders include inflammation and oxidative stress. Glucagon like peptide-1 (GLP-1) agonists modulate glucose metabolism and may exert neuroprotective effects via central GLP-1 receptors. AIM OF THE WORK: To explore the effects of GLP-1 agonist, liraglutide, on ketamine-induced hyper-locomotion and cognitive dysfunction and the associated inflammation and oxidative stress in normoglycemic and diabetic rats. METHODS: Rats were divided into: Chow fed (non-diabetic) and high fat diet fed/STZ (diabetic) groups: I. non-diabetic/control, non-diabetic/liraglutide, non-diabetic/ketamine, non-diabetic/ketamine/liraglutide groups. II. diabetic/control, diabetic/liraglutide, diabetic/ketamine and diabetic/ketamine/liraglutide groups. Hyperlocomotion and cognitive dysfunction were assessed using open field and water maze tests. Biochemical parameters were measured in serum and hippocampus. RESULTS: Ketamine induced hyperlocomotion and cognitive dysfunction, with hippocampal histopathological changes. Increase in tumour necrosis factor (TNF)-alpha and oxidative stress and reduction in brain-derived neurotrophic factor (BDNF) were noted. These changes were augmented in diabetic compared to non-diabetic rats. Liraglutide significantly improved hyperlocomotion, and cognitive dysfunction and hippocampal histopathological changes in non-diabetic and diabetic rats. Improvement in glucose homeostasis, reduction in TNF alpha and malondialdehyde, and increase in glutathione and BDNF were observed in serum and hippocampus. CONCLUSION: Beneficial effects of liraglutide on ketamine-induced hyperlocomotion and cognitive dysfunction are associated with reduction in TNF alpha and oxidative stress. Since effects of liraglutide occurred in diabetic and non-diabetic rats, glycemic and non-glycemic effects (via central GLP-1 receptors) might be involved. Targeting oxidative stress and inflammation by GLP-1 agonists, may be a promising approach in psychotic patients with diabetes.

Improvement of cognitive function, glucose and lipid homeostasis and serum osteocalcin levels by liraglutide in diabetic rats.

BACKGROUND: Glucose and lipid abnormalities, oxidative stress (OXS) and reduced brain-derived neurotrophic factor (BDNF) are involved in cognitive dysfunction in diabetes. Glucagon like peptide 1 (GLP1) receptors modulate glucose and lipid metabolism, cognitive function and serum osteocalcin. On the other hand, osteocalcin modulates cognitive function and glucose and lipid metabolism. This study investigated whether the GLP 1 agonist liraglutide improves cognitive function via modulation of serum osteocalcin and glucose and lipid metabolism. METHODS: Effects of 4 weeks liraglutide treatment (100 µg/Kg/d and 300 µg/Kg/d) on changes in cognitive function and bone homeostasis, induced by high fat diet/low-dose streptozotocin (HFD-STZ), were determined in rats. Cognitive function was assessed using Morris water maze (MWM) test. Serum and bone biochemical parameters were determined. RESULTS: Liraglutide dose-dependently improved cognitive function in diabetic rats (reduced escape latency, and increased time spent in target quadrant in MWM test, compared to diabetic control). Glucose and lipid abnormalities and the associated changes in serum BDNF and oxidative stress makers were improved. Serum BDNF and glutathione were significantly increased, whereas malondialdehyde level was reduced. Serum osteocalcin was significantly increased and correlated with improvement in cognitive dysfunction. Serum and bone receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin ratios were significantly reduced by liraglutide treatment. CONCLUSION: Improvement of cognitive dysfunction by liraglutide involves modulation of glucose and lipid metabolism and serum osteocalcin. GLP1 agonists may provide an alternative metabolic approach for cognitive dysfunction in diabetes.

Tadalafil versus linaclotide in gastrointestinal dysfunction and depressive behavior in constipation-predominant irritable bowel syndrome.

BACKGROUND: Intestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated. METHODS: 72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days. RESULTS: Both drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide). Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide). CONCLUSION: Systemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.

Trimetazidine potentiates the antiepileptic activity and ameliorates the metabolic changes associated with pentylenetetrazole kindling in rats treated with valproic acid.

Oxidative stress is implicated in epileptogenesis as well as in the metabolic changes associated with increased risk of atherosclerotic vascular disease in epilepsy. The present work investigated the impact of the antioxidant trimetazidine (TMZ) on the antiepileptic activity of valproic acid (VPA) and on the metabolic and histological changes in hippocampal, aortic, and hepatic tissues associated with epilepsy and (or) VPA. Rats were divided into non-pentylenetetrazole (non-PTZ) group subdivided into control and VPA-treated groups, and PTZ-treated group subdivided into PTZ, PTZ/VPA, PTZ/TMZ, and PTZ/VPA + TMZ groups. VPA treatment in PTZ rats resulted in an antioxidant effect with improvement in oxidative stress, metabolic and histopathological changes induced by PTZ in hippocampus, aortic, and hepatic tissues. TMZ exhibited anticonvulsant activity and potentiated the anticonvulsant effect of VPA. Combination of TMZ with VPA induced a greater reduction in oxidative stress, improvement in the metabolic and histopathological changes compared to VPA treatment. In contrast, VPA administration in non-PTZ-treated rats induced a pro-oxidative effect, associated with metabolic and histopathological changes in aortic and hepatic tissues. These findings suggest that co-administration of TMZ with VPA in epilepsy might antagonize not only the oxidative stress associated with epilepsy but might also counteract a potential pro-oxidative effect of VPA.