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Overactivation of angiotensin-converting enzyme/angiotensin 2/angiotensin receptor-1 (ACE/Ang2/AT1) axis provokes amyloid-β-induced apoptosis and neurodegeneration in Alzheimer's disease (AD). Moreover, activation of AT1 impairs the survival pathway phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). Interestingly, the coupling between ACE2/Ang(1-7)/Mas receptor (MasR) axis and PI3K/Akt activation opposes AT1-induced apoptosis. However, the effect of in vivo stimulation of MasR against AD and its correlation to PI3K/Akt is not yet elucidated. Thus, the present study aimed to investigate the relationship between PI3K/Akt pathway and the activation of ACE2/MasR in the AD model of D-galactose-ovariectomized rats. AD features were induced following 8-week injection of D-galactose (150 mg/kg, i.p.) in ovariectomized female rats. The ACE2 activator dimenazine (15 mg/kg, i.p.) was daily administered for 2 months. DIZE administration boosted the hippocampal expression of ACE2 and Mas receptors while suppressing AT1 receptor. Notably, dimenazine enhanced the expression of phosphorylated survival factors (PI3K, Akt, signal transducer, and activator of transcription-3) and neuroplasticity proteins such as cyclic adenosine monophosphate-responsive element-binding protein and brain-derived neurotrophic factor along with nicotinic and glutamatergic receptors. Such effects were accompanied by suppressing phosphorylated tau and glycogen synthase kinase3β along with caspase-3, cytochrome-c, nuclear factor kappa B, tumor necrosis factor alpha, and glial fibrillary acidic protein contents. Dimenazine ameliorated the histopathological damage observed in D-galactose-ovariectomized rats and improved their learning and recognition memory in Morris water maze and novel object recognition tests. In conclusion, dimenazine-induced stimulation of ACE2/Ang(1-7)/Mas axis subdues cognitive deficits in AD most probably through activation of PI3K/Akt pathway.

The present study investigated the possible relationship between pro-inflammatory cytokines and programmed nigral neuronal death in rotenone model of Parkinson's disease (PD). Sitagliptin and liraglutide efficacy to inhibit the inflammatory-apoptotic degenerative process were investigated, too. The experimental PD were induced in male albino rats by ten subcutaneously injections of rotenone (3 mg/kg/day, s.c). All treatment drugs were administered for 16 days after induction of Parkinson rat's model. Sitagliptin and liraglutide were administered in three different dose levels (10-20-30 mg/kg, p.o), (25-50-100 μg/kg, s.c), respectively. Cylindrical and catalepsy tests were used to detect the optimum dose response of each drug. Sitagliptin (30 mg/kg/day, p.o) and liraglutide (50 μg/kg, s.c.) showed statistically significant (p ≤ 0.05) effect on behavioral activity. Where both doses improved the motor performance significantly in comparison with other doses in both cylindrical and catalepsy tests. Furthermore, they reversed rotenone-induced nigral neuronal loss, associated with marked decrease of pro-inflammatory cytokines: interleukin (IL)-1β, IL-6, transforming growth factor (TGF)-β1, together with a significant increase of striatal dopamine, nigral glial cell line-derived neurotrophic factor (GDNF), and tyrosine hydroxylase positive (TH+) cells. Moreover, the pro-apoptotic environment in nigrostriatal tissues was abrogated significantly, as the pro-apoptotic protein Bax decreased along with the anti-apoptotic protein Bcl-2 increased. In conclusion, sitagliptin and liraglutide represent a promising strategy to mitigate the progression of PD by their anti-inflammatory, anti-apoptotic neurotrophic and neurogenic mechanistic activities.

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PurposeAn herbal preparation, STW 5, used clinically in functional dyspepsia and irritable bowel syndrome, has been shown to possess properties that may render it useful in inflammatory bowel disease (IBD). The present work was conducted to study its effectiveness in a rat model of IBD.MethodsAn experimental model reflecting ulcerative colitis in man was adopted, whereby colitis was induced in Wistar rats by feeding them 5 % dextran sulfate sodium (DSS) in drinking water for one week. STW 5 and sulfasalazine (as a reference standard) were administered orally daily for 1 week before colitis induction and continued during DSS feeding. The animals were then sacrificed, and the severity of colitis was evaluated macroscopically and microscopically. Colon samples were homogenized for determination of reduced glutathione, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-3 as well as myeloperoxidase, glutathione peroxidase, and superoxide dismutase. In addition, colon segments were suspended in an organ bath to test their reactivity towards carbachol, KCl, and trypsin.ResultsSTW 5 and sulfasalazine were both effective in preventing the shortening of colon length and the increase in both colon mass index and total histology score as well as the changes in biochemical parameters measured except changes in dismutase activity. DSS-induced colitis led to marked depression in colonic responsiveness to the agents tested ex vivo, an effect which was normalized by both drugs.ConclusionsThe findings point to a potential usefulness of STW 5 in the clinical setting of ulcerative colitis.

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