Mustafa., A. M., M. A. Rabie, H. F. Zaki, and A. M. Shaheen, "Inhibition of Brain GTP Cyclohydrolase I Attenuates 3-Nitropropionic Acid-Induced Striatal Toxicity: Involvement of Mas Receptor/PI3k/Akt/CREB/ BDNF Axis", Frontiers in Pharmacology, vol. 12, pp. 740966, 2021.
Elgebaly, S. A., R. Todd, D. L. Kreutzer, R. Christenson, N. El-Khazragy, R. K. Arafa, M. A. Rabie, A. F. Mohamed, L. A. Ahmed, and N. S. El Sayed, "Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure.", International journal of molecular sciences, vol. 22, issue 7, 2021. Abstract

BACKGROUND: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated (marker of cell damage) and (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects.

OBJECTIVES: To test the hypothesis that Nourin-associated and are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats".

METHODS: 25 male Wistar rats (180-220 g) were used: ISO/saline ( = 6), ISO/CCrP (0.8 g/kg/day) ( = 5), control/saline ( = 5), and control/CCrP (0.8 g/kg/day) ( = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day ( = 3) and a higher dose of 1.2 g/kg/day ( = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of and were measured in serum samples using quantitative real-time PCR (qPCR).

RESULTS: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of and by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function.

CONCLUSIONS: Results suggest a role of Nourin-associated and in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.

Sayed, N. H., N. Fathy, M. A. Kortam, M. A. Rabie, A. F. Mohamed, and A. S. Kamel, "Vildagliptin Attenuates Huntington's Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model.", Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2019. Abstract

Vildagliptin (Vilda), a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been highlighted as a promising therapeutic agent for neurodegenerative diseases as Alzheimer's and Parkinson's diseases. Vilda's effect is mostly linked to PI3K/Akt signaling in CNS. Moreover, PI3K/Akt activation reportedly enhanced survival and dampened progression of Huntington's disease (HD). However, Vilda's role in HD is yet to be elucidated. Thus, the aim of the study is to uncover the potentiality of Vilda in HD and unfold its link with PI3K/Akt pathway in 3-nitropropionic acid (3NP) rat model. Rats were randomly assigned into 4 groups; group 1 received saline, whereas, groups 2, 3 and 4 received 3NP (10 mg/kg/day; i.p.) for 14 days, concomitantly with Vilda (5 mg/kg/day; p.o.) in groups 3 and 4, and wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) in group 4. Vilda improved cognitive and motor perturbations induced by 3NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. The molecular signaling of Vilda was estimated by elevation of GLP-1 level and protein expressions of survival proteins; p85/p55 (pY458/199)-PI3K, pS473-Akt. Together, it boosted striatal neurotrophic factors and receptor; pS133-CREB, BDNF, pY515-TrKB, which subsequently maintained mitochondrial integrity, as indicated by enhancing both SDH and COX activities, and the redox modulators; Sirt1, Nrf2. Such neuroprotection restored imbalance of neurotransmitters through increasing GABA and suppressing glutamate as well PDE10A. These effects were reversed by WM pre-administration. In conclusion, Vilda purveyed significant anti-Huntington effect which may be mediated, at least in part, via activation of GLP-1/PI3K/Akt pathway in 3NP rat model.

Rabie, M. A., M. A. Abd El Fattah, N. N. Nassar, D. M. Abdallah, and H. S. El-Abhar, "Correlation between angiotensin 1-7-mediated Mas receptor expression with motor improvement, activated STAT3/SOCS3 cascade, and suppressed HMGB-1/RAGE/NF-κB signaling in 6-hydroxydopamine hemiparkinsonian rats.", Biochemical pharmacology, pp. 113681, 2019. Abstract

In the current investigation, a Parkinson's disease (PD) model was established by a single direct right intrastriatal injection of the 6-hydroxydopamine (OHDA) in male Wistar rats followed by 7 daily unilateral injection of angiotensin (Ang) 1-7 in the striatum. To confirm the putative role of Mas receptor (MasR), the selective antagonist A779 was also injected intrastriatally prior to Ang 1-7 injections and a correlation analysis was performed between MasR expression and the assessed parameters. Ang 1-7 upregulated MasR expression to correlate strongly with the improved rotarod (r=0.95, p=0.003) and spontaneous activity task (r=0.99, p<0.0001). This correlation extends to involve other effects of Ang 1-7, such as the increased striatal dopamine content (r=0.98, p=0.0005), substantia nigra pars compacta tyrosine hydroxylase immune-reactivity (r=0.97, p=0.001), active pY705-STAT3 (r=0.99, p<0.0001) and SOCS3 (r=0.99, p<0.0001). Conversely, Ang 1-7 inhibited inflammatory markers to correlate negatively with NF-κBp65 (r= - 0.99, p<0.0003) and its downstream targets, high mobility group box-1 (HMGB-1; r= -0.97, p=0.002), receptor for advanced glycation end products (RAGE; r= -0.98, p=0.0004), and TNF-α (r=-0.99, p<0.0003), besides poly-ADP-ribose polymerase-1 (r=-0.99, p=0.0002). In confirmation, the pre-administration of the selective MasR antagonist, A779, partially attenuated Ang 1-7-induced alterations towards 6-OHDA neurodegeneration. Collectively, our findings support a novel role for the anti-inflammatory capacity of the MasR axis to prove potential therapeutic relevance in PD via the upregulation/activation of MasR-dependent STAT3/SOCS3 cascade to negatively control the HMGB-1/RAGE/NF-κB axis hindering PD associated neuro-inflammation along with DA depletion and motor deficits.

Rabie, M. A., H. F. Zaki, and H. M. Sayed, "Telluric acid ameliorates hepatic ischemia reperfusion-induced injury in rats: Involvement of TLR4, Nrf2, and PI3K/Akt signaling pathways.", Biochemical pharmacology, vol. 168, pp. 404-411, 2019. Abstract

In past tellurium-based compounds had limited use, however, their therapeutic potential have been target of interest recently due to antioxidant and anti-inflammatory capabilities in experimental endotoxemia. Nevertheless, their potential hepatoprotective effect against ischemia reperfusion (IR) injury is still obscure. This study examined the possible hepatoprotective effect of telluric acid (TELL), one of tellurium-based compound, against the deteriorating effect hepatic IR injury in rats through directing toll like receptor-4 (TLR4) cascade, phosphoinositide 3-kinase(PI3K)/Akt axis, and nuclear erythroid-related factor-2 (Nrf-2) pathway as possible mechanisms contributed to TELL's effect. Indeed, male Wistar rats were randomized into 3 groups: sham-operated, control IR and TELL (50 µg/kg). TELL was administrated once daily for seven consecutive days prior to the IR induction. Pretreatment with TELL attenuated hepatic IR injury as manifested by hampered plasma aminotransaminases and lactate dehydrogenase activities. Also, TELL opposed IR induced elevation in tissue expression/activity of high-mobility group box protein-1 (HMGB1), TLR4, myeloid differentiation primary-response protein 88 (MyD88), phospho-nuclear factor-kappa B p65 (p-NF-κB p65), phospho-mitogen activated protein kinasep38 (p-MAPKp38) and tumor necrosis factor-alpha (TNF-α). Moreover, TELL reduced the elevated thiobarbituric acid reactive substances along with increased both Nrf-2 and endothelial nitric oxide synthase (eNOS) protein expression, beside replenishment of hepatic reduced glutathione. In addition, TELL induced obvious upregulation of p-PI3K and p-Akt protein expressions together with restoration of histopathological changes in IR injury. In conclusion, TELL purveyed conceivable novel hepatoprotective mechanisms and attenuated events associated with acute hepatic injury via inhibition of TLR4 downstream axis and activation of Nrf-2 and PI3K/Akt signaling cascades. Thus, TELL may provide a novel therapeutic potential for complications of hepatic IR injury.

Rabie, M. A., M. A. E. A. Fattah, N. N. Nassar, D. M. Abdallah, and H. S. El-Abhar, "The Mas Receptor as a Future Perspective in Parkinson’s Disease", journal of neurology and neuromedicine, vol. 3, issue 2572-942X, pp. 65-68, 2018.
Rabie, M. A., M. A. Abd El Fattah, N. N. Nassar, H. S. El-Abhar, and D. M. Abdallah, "Angiotensin 1-7 ameliorates 6-hydroxydopamine lesions in hemiparkinsonian rats through activation of MAS receptor/PI3K/Akt/BDNF pathway and inhibition of angiotensin II type-1 receptor/NF-κB axis.", Biochemical pharmacology, vol. 151, pp. 126-134, 2018 05. Abstract

MAS receptor (MASR), expressed in several brain areas, conferred neuroprotection against neurodegenerative disorders when activated by angiotensin (Ang) 1-7; however, its role in Parkinson's disease (PD) remains elusive. Intra-striatal post-administration of Ang1-7, using a 6-hydroxydopamine (OHDA) PD model, improved motor performance and muscle coordination. On the molecular level, Ang1-7 upregulated the striatal expression of MASR and caused upsurge in its downstream targets (p-PI3K/p-Akt/p-CREB/BDNF) to phosphorylate TrKB, which in a positive feedback upregulates MASR. Moreover, Ang1-7 increased substantia nigral tyrosine hydroxylase (TH) expression and striatal dopamine (DA) content to indicate the preservation of the dopaminergic neuronal signal. This effect extended to inhibit the striatal expression of Ang II type-1 receptor (AT-1R) to hold the neurodegenerative effect and to boost Ang1-7 anti-inflammatory/antioxidant effects by abating NADPH oxidase, along with lipid peroxidation. Indeed, Ang1-7 was able to decrease p-MAPK p38/NF-κB p65 to level the inflammatory and oxidative stress events off. The Ang1-7-mediated activation of MASR cue and the suppression of the AT-1R cascade were partially reversed by the intrastartial injection of A-779, a MASR antagonist. The current data suggests a novel therapeutic potential for the Ang1-7 against neurotoxicity associated motor impairment related to PD. The anti-parkinsonian effect of Ang1-7, is in part, mediated by its binding to MASR and the initiation of PI3K/Akt/CREB/BDNF/TrKB cue to increase DA synthesis, besides the downregulation/inhibition of AT-1R/MAPK p38/NF-κB p65/NADPH oxidase pathway.

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