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Mansour, R. M., N. S. El Sayed, M. A. E. Ahmed, and A. E. El-Sahar, "Addressing Peroxisome Proliferator-Activated Receptor-gamma in 3-Nitropropionic Acid-Induced Striatal Neurotoxicity in Rats.", Molecular neurobiology, vol. 59, issue 7, pp. 4368-4383, 2022. Abstract

Telmisartan (TEL) is an angiotensin II type 1 receptor blocker and a partial activator of peroxisome proliferator-activated receptor-gamma (PPARγ), which regulates inflammatory and apoptotic pathways. Increasing evidence has demonstrated the PPARγ agonistic property of TEL in several brain disorders. This study aims to explore the neuroprotective impact of TEL in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats. The PPARγ effect of TEL was affirmed by using the PPARγ agonist pioglitazone (PIO), and the antagonist GW9662. 3-NP led to a significant reduction in body weight alongside motor and cognitive functioning. The striata of the 3-NP-treated rats showed energy-deficit, microglia-mediated inflammatory reactions, apoptotic damage as well as histopathological lesions. PIO and TEL improved motor and cognitive perturbations induced by 3-NP, as confirmed by striatal histopathological examination, energy restoration, and neuronal preservation. Both drugs improved mitochondrial biogenesis evidenced by elevated mRNA expression of PPARγ, PGC-1α, and TFAM, alongside increased striatal ATP and SDH. The mitochondrial effect of TEL was beyond PPARγ activation. As well, their anti-inflammatory effect was attributed to suppression of microglial activation, and protein expression of pS536 p65 NF-κB with marked attenuation of striatal inflammatory mediator's release. Anti-inflammatory cytokine IL-10 expression was concurrently increased. TEL effectively participated in neuronal survival as it promoted phosphorylation of Akt/GSK-3β, further increased Bcl-2 expression, and inhibited cleavage of caspase-3. Interestingly, co-treatment with GW9662 partially revoked the beneficial effects of TEL. These findings recommend that TEL improves motor and cognitive performance, while reducing neuronal inflammation and apoptosis in 3-NP-induced neurotoxicity via a PPARγ-dependent mechanism.

El-Safty, H., A. Ismail, R. M. Abdelsalam, A. E. El-Sahar, and M. A. Saad, "Dapagliflozin diminishes memory and cognition impairment in Streptozotocin induced diabetes through its effect on Wnt/β-Catenin and CREB pathway.", Brain research bulletin, vol. 181, pp. 109-120, 2022. Abstract

Diabetic neuropathy is a chronic condition that affects a significant number of individuals with diabetes. Streptozotocin injection intraperitoneally to rodents produces pancreatic islet β-cell destruction causing hyperglycemia, which affect the brain leading to memory and cognition impairment. Dapagliflozin may be able to reverse beta-cell injury and alleviate this impairment. This effect may be via neuroprotective effect or possible involvement of the antioxidant, and anti-apoptotic properties. Forty rats were divided into four groups as follows: The normal control group, STZ-induced diabetes group, STZ-induced diabetic rats followed by treatment with oral dapagliflozin group and normal rats treated with oral dapagliflozin. Behavioral tests (Object location memory task and Morris water maze) were performed. Serum biomarkers (blood glucose and insulin) were measured and then the homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. In the hippocampus the followings were determined; calmodulin, ca-calmodulin kinase Ⅳ (CaMKIV), protein kinase A (PKA) and cAMP-responsive element-binding protein to determine the transcription factor CREB and its signaling pathway also Wnt signaling pathway and related parameters (WnT, B-catenin, lymphoid enhancer binding factor LEF, glycogen synthase kinase 3β). Moreover, nuclear receptor-related protein-1, acetylcholine and its hydrolyzing enzyme acetylcholine esterase, oxidative stress parameter malondialdehyde (MDA) and apoptotic parameter caspase-3 were determined. STZ was able to cause destruction to pancreatic β-cells which was reflected on glucose levels causing diabetes. Diabetic neuropathy was clear in the rats performing the behavioral tests. Memory and cognition parameters in the hippocampus were negatively affected. Oxidative stress and apoptotic parameter were elevated while the electrical activity was declined. Dapagliflozin was able to reverse the previously mentioned parameters and behavior. Thus, to say dapagliflozin significantly showed neuroprotective action along with antioxidant, and anti-apoptotic properties.

El-Shamarka, M. E. - S., A. E. El-Sahar, M. A. Saad, N. A. G. L. A. A. ASSAF, and R. H. Sayed, "Inosine attenuates 3-nitropropionic acid-induced Huntington's disease-like symptoms in rats via the activation of the A2AR/BDNF/TrKB/ERK/CREB signaling pathway.", Life sciences, vol. 300, pp. 120569, 2022. Abstract

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by involuntary bizarre movements, psychiatric symptoms, dementia, and early death. Several studies suggested neuroprotective activities of inosine; however its role in HD is yet to be elucidated. The current study aimed to demonstrate the neuroprotective effect of inosine in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats while investigating possible underlying mechanisms. Rats were randomly divided into five groups; group 1 received i.p. injections of 1% DMSO, whereas groups 2, 3, 4, and 5 received 3-NP (10 mg/kg, i.p.) for 14 days, concomitantly with inosine (200 mg/kg., i.p.) in groups 3, 4, and 5, SCH58261, a selective adenosine 2A receptor (A2AR) antagonist, (0.05 mg/kg, i.p.) in group 4, and PD98059, an extracellular signal-regulated kinase (ERK) inhibitor, (0.3 mg/kg, i.p.) in group 5. Treatment with inosine mitigated 3-NP-induced motor abnormalities and body weight loss. Moreover, inosine boosted the striatal brain-derived neurotrophic factor (BDNF) level, p-tropomyosin receptor kinase B (TrKB), p-ERK, and p-cAMP response element-binding protein (CREB) expression, which subsequently suppressed oxidative stress biomarkers (malondialdehyde and nitric oxide) and pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-1β) and replenished the glutathione content. Similarly, histopathological analyses revealed decreased striatal injury score, the expression of the glial fibrillary acidic protein, and neuronal loss after inosine treatment. These effects were attenuated by the pre-administration of SCH58261 or PD98059. In conclusion, inosine attenuated 3-NP-induced HD-like symptoms in rats, at least in part, via the activation of the A2AR/BDNF/TrKB/ERK/CREB signaling pathway.

El-Saiy, K. A., R. H. Sayed, A. E. El-Sahar, and E. S. R. A. A. A. KANDIL, "Modulation of histone deacetylase, the ubiquitin proteasome system, and autophagy underlies the neuroprotective effects of venlafaxine in a rotenone-induced Parkinson's disease model in rats.", Chemico-biological interactions, vol. 354, pp. 109841, 2022. Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms. Impairment of the ubiquitin proteasome system (UPS) and autophagy has been suggested to contribute to α-synuclein accumulation, which is identified as the pathological hallmark of PD. Recently, alteration in histone-3 acetylation has also been found to be correlated to PD. Interestingly, the histone deacetylase 6 (HDAC6) enzyme, which regulates the acetylation of histone-3, was shown to be involved in autophagy. Venlafaxine is an antidepressant that was proposed to inhibit HDAC expression in depressive rats' hippocampi. In this study, we aimed to examine the ability of venlafaxine to inhibit striatal HDAC6 and to enhance α-synuclein clearance through the activation of the UPS and autophagy, in addition to treating depression, which is the most debilitating non-motor symptom, in a rotenone model of PD. Venlafaxine administration was noted to decrease α-synuclein accumulation and preserve dopaminergic neurons along with restoration of striatal dopamine levels and motor recovery. Its administration augmented the UPS and autophagic markers (beclin-1, p62, and LC3) with consequent modulation of apoptotic indicators (Bax/Bcl-2 ratio, cytochrome c, and caspase-3). Additionally, venlafaxine inhibited HDAC6 with further enhancement of autophagy and restoration of histone-3 acetylation with subsequent increases in survival gene expressions (Bcl-2 and brain-derived neurotrophic factor). Chloroquine (autophagy inhibitor) was used to indicate the proposed pathway. Moreover, venlafaxine hampered depressive symptoms and improved hippocampal noradrenaline and serotonin levels. Collectively, venlafaxine is suggested to display neuroprotective effects with improvement of motor and non-motor PD symptoms.

El-Sahar, A. E., N. A. Shiha, N. S. El Sayed, and L. A. Ahmed, "Alogliptin Attenuates Lipopolysaccharide-Induced Neuroinflammation in Mice Through Modulation of TLR4/MYD88/NF-κB and miRNA-155/SOCS-1 Signaling Pathways.", The international journal of neuropsychopharmacology, vol. 24, issue 2, pp. 158-169, 2021. Abstract

BACKGROUND: Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer's disease models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects.

METHODS: Mice were treated with alogliptin (20 mg/kg/d; p.o.) for 14 days, starting 1 day prior to intracerebroventricular LPS injection (8 μg/μL in 3 μL).

RESULTS: Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 and myeloid differentiation primary response 88 protein expression, nuclear factor-κB p65 content, and microRNA-155 gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein expression in the brain.

CONCLUSION: The present study sheds light on the potential neuroprotective effects of alogliptin against intracerebroventricular LPS-induced neuroinflammation and its associated memory impairment via inhibition of toll-like receptor 4/ myeloid differentiation primary response 88/ nuclear factor-κB signaling, modulation of microRNA-155/suppressor of cytokine signaling-1 expression, and enhancement of cAMP/phosphorylated cAMP response element binding protein signaling.

El-Sayed, S. S., M. F. El-Yamany, H. A. Salem, and A. E. El-Sahar, "New insights into the effects of vinpocetine against neurobehavioral comorbidities in a rat model of temporal lobe epilepsy via the downregulation of the hippocampal PI3K/mTOR signalling pathway.", The Journal of pharmacy and pharmacology, vol. 73, issue 5, pp. 626-640, 2021. Abstract

OBJECTIVES: As one of the most frequent worldwide neurological disorders, epilepsy is an alteration of the central nervous system (CNS) characterized by abnormal increases in neuronal electrical activity. The mammalian target of rapamycin (mTOR) signalling pathway has been investigated as an interesting objective in epilepsy research. Vinpocetine (VNP), a synthesized derivative of the apovincamine alkaloid, has been used in different cerebrovascular disorders. This study aimed to examine the modulatory effects of VNP on neurobehavioral comorbidities via the mTOR signalling pathway in a lithium-pilocarpine (Li-Pil) rat model of seizures.

METHODS: In male Wistar rats, seizures were induced with a single administration of pilocarpine (60 mg/kg; i.p.) 20 hours after the delivery of a single dose of lithium (3 mEq/kg; i.p.). VNP (10 mg/kg; i.p.) was administered daily for 14 consecutive days before Li-Pil administration.

KEY FINDINGS: VNP had a protective effect against Li-Pil-induced seizures. VNP improved both the locomotor and cognitive abilities, moreover, VNP exerted a neuroprotective action, as verified histologically and by its inhibitory effects on hippocampal glutamate excitotoxicity, mTOR pathway, and inflammatory and apoptotic parameters.

CONCLUSIONS: VNP is a valuable candidate for epilepsy therapy via its modulation of the mechanisms underlying epileptogenesis with emphasis on its modulatory effect on mTOR signalling pathway.

Fouad, M. R., R. M. Salama, H. F. Zaki, and A. E. El-Sahar, "Vildagliptin attenuates acetic acid-induced colitis in rats via targeting PI3K/Akt/NFκB, Nrf2 and CREB signaling pathways and the expression of lncRNA IFNG-AS1 and miR-146a.", International immunopharmacology, vol. 92, pp. 107354, 2021. Abstract

Inflammatory processes, including ulcerative colitis (UC), are associated with the increase in synthesis and release of pro-inflammatory cytokines. The release of these cytokines is regulated by phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor-kappa B (NFκB) and cAMP response element-binding protein (CREB) signaling pathways as well as over expression of microRNA 146a (miR-146a) and long non-coding RNA interferon gamma antisense 1 (lncRNA IFNG-AS1). Vildagliptin (Vilda), a dipeptidyl peptidase IV (DPP-IV) inhibitor, has an anti-inflammatory, antioxidant and anti-apoptotic effects which were established in various models. However, its possible protective effect in UC has not been clarified. Hence, the current study aimed to explore the possible prophylactic effect of different doses of Vilda against acetic acid (AA)-induced colitis in rats. Forty-eight adult Wistar rats were divided into six groups: control, Vilda (10 mg/kg/day; p.o.), AA, AA + Vilda (5 mg/kg/day; p.o.), AA + Vilda (10 mg/kg/day; p.o.) and AA + sulfasalazine (Sulfa) (100 mg/kg/day; p.o.).Low- and high-dose Vilda showed significant improvement in the disease activity index (DAI) and macroscopic assessment markers. Vilda has markedly inhibited the expression of lncRNA IFNG-AS1 and miR-146a, as well as PI3K/Akt/NFκB pathway, while activated CREB and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, and this was reflected in alleviated oxidative stress, inflammation and apoptosis. Such outcomes were more prominent with the high-dose Vilda versus low-dose Vilda and Sulfa. Moreover, the histological examination showed almost intact histological features in Vilda-treated groups when compared to AA group treated with saline. In conclusion, Vilda can be regarded as a new promising therapeutic alternative against UC.

Helmy, H. T. S., M. A. Senousy, A. E. El-Sahar, R. H. Sayed, M. A. Saad, and E. M. Elbaz, "Aberrations of miR-126-3p, miR-181a and sirtuin1 network mediate Di-(2-ethylhexyl) phthalate-induced testicular damage in rats: The protective role of hesperidin.", Toxicology, vol. 433-434, pp. 152406, 2020. Abstract

Recently, oxidative stress was implicated in the environmental contaminant Di-(2-ethylhexyl) phthalate (DEHP)-induced testicular toxicity, however the mechanism is unclear. We investigated the role of oxidative stress-responsive microRNAs in DEHP-induced aberrations and the protective effect of the citrus flavonoid, hesperidin (HSP). Male Wistar rats were randomly allocated into four groups as vehicle-treated control, DEHP-alone group (500 mg/kg/day) for 30 days, and HSP (25 or 50 mg/kg) for 60 days; testicular damage was triggered by oral administration of DEHP (500 mg/kg/day) after thirty days of oral administration of HSP (25 or 50 mg/kg). DEHP administration reduced testis weight coefficient, serum testosterone, testicular 3β-hydroxysteroid dehydrogenase and antioxidant enzyme activities, and elevated serum fatty acid-binding protein-9, testicular malondialdehyde, and Bax/Bcl2 ratio. Aberrant testicular miR-126-3p and miR-181a expression was observed, along with decreased expression of sirtuin1 (SIRT1) and its targets; nuclear factor-erythroid 2-related factor2, haeme oxygenase-1, and superoxide dismutase2. HSP administration significantly ameliorated these changes and restored testicular function in a dose-dependent manner. We highlight a novel role of oxidative stress-miR-126/miR-181a-SIRT1 network in mediating DEHP-induced changes which were reversed by the antioxidant HSP.

El-Sahar, A. E., A. A. Rastanawi, M. F. El-Yamany, and M. A. Saad, "Dapagliflozin improves behavioral dysfunction of Huntington's disease in rats via inhibiting apoptosis-related glycolysis.", Life sciences, vol. 257, pp. 118076, 2020. Abstract

AIMS: Huntington's disease is a rare neurodegenerative disorder which is associated with defected glucose metabolism with consequent behavioral disturbance including memory and locomotion. 3-nitropropionic acid (3-NP) can cause, in high single dose, an acute striatal injury/Huntington's disease. Dapagliflozin, which is one of the longest duration of action of SGLTIs family, may be able to diminish that injury and its resultant behavioral disturbances.

MATERIAL AND METHODS: Forty rats were divided into four groups (n = 10 in each group): normal control group (CTRL), dapagliflozin (CTRL + DAPA) group, 3-nitropropionic acid (3-NP) group, and dapagliflozin plus 3-nitropropionic acid (DAPA + 3-NP) group. Behavioral tests (beam walking test, hanging wire test, limb withdrawal test, Y-maze spontaneous alteration, elevated plus maze) were performed with evaluating neurological scoring. In striatum, neurotransmitters (glutamate, aspartate, GABA, ACh and AChE activity) were measured. In addition, apoptosis and glycolysis markers (NF-κB, Cyt-c, lactate, HK-II activity, P53, calpain, PEA15 and TIGAR) were determined. Inflammation (IL-1β, IL-6, IL-8 and TNF-α) and autophagy (beclin-1, LC3 and DRAM) indicators were measured. Additionally, histopathological screening was conducted.

KEY FINDINGS: 3-Nitropropionic acid had the ability to perturb the neurotransmission which was reflected in impaired behavioral outcome. All of glycolysis, apoptosis and inflammation markers were elevated after 3-NP acute intoxication but autophagy parameters, except DRAM, were reduced. However, DAPA markedly reversed the abovementioned parameters.

SIGNIFICANCE: Dapagliflozin demonstrated anti-glycolytic, anti-apoptotic, anti-inflammatory and autophagic effects on 3-NP-damaged striatal cells and promoted the behavioral outcome.

Shaaban, M. A., A. M. Kamal, S. I. Faggal, N. A. Farag, N. M. Aborehab, A. E. Elsahar, and K. O. Mohamed, "Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors.", Archiv der Pharmazie, pp. e2000027, 2020. Abstract

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through H nuclear magnetic resonance (NMR), C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC  = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.

Arab, H. H., M. A. Saad, A. E. El-Sahar, and M. Y. Al-Shorbagy, "Mechanistic perspective of morin protection against ketoprofen-induced gastric mucosal injury: Targeting HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways.", Archives of biochemistry and biophysics, vol. 693, pp. 108552, 2020. Abstract

Ketoprofen is a widely used NSAID which incurs gastric mucosal damage. The high mobility group Box 1 (HMGB1) protein is a DNA-binding protein which exerts robust inflammatory actions, however, its role in ketoprofen-induced gastric damage has not been explored. Additionally, no previous studies have linked HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways in ketoprofen-induced gastropathy. The current work aimed to explore the potential of morin, a flavonoid with marked antioxidant/anti-inflammatory actions, to protect against ketoprofen-evoked gastric damage. Moreover, the underlying mechanisms, including the impact of morin on HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways were addressed. Immunoblotting and ELISA were used to examine the expression of target signals. Morin (50 mg/kg, p. o.) attenuated the severity of gastric injury via lowering of ulceration/hemorrhage and macroscopic damage scores. Meanwhile, it attenuated the histopathologic aberrations/damage scores. In the context of inflammation, morin suppressed TNF-α and myeloperoxidase levels and enhanced IL-10. Furthermore, it inhibited HMGB1/RAGE/NF-κB pathway through downregulating HMGB1, RAGE and phospho-NF-κBp65 protein expression. Morin successfully inhibited gastric mucosal oxidative stress through lowering of lipid peroxides and boosting of reduced glutathione, glutathione peroxidase and total antioxidant capacity. It also boosted DJ-1/Nrf2/HO-1 pathway via upregulating DJ-1, Nrf2 and HO-1 protein expression. Additionally, morin counteracted the apoptotic events by downregulating the proapoptotic Bax and Bax/Bcl-2 ratio and augmenting the PI3K/mTOR pathway through upregulating PI3Kp110α and phospho-mTOR protein expression. In conclusion, the current study demonstrates, for the first time, that morin shows a promise for the management of ketoprofen-induced mucosal insult through targeting of HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways.

Yossef, R. R., M. F. Al-Yamany, M. A. Saad, and A. E. El-Sahar, "Neuroprotective effects of vildagliptin on drug induced Alzheimer's disease in rats with metabolic syndrome: Role of hippocampal klotho and AKT signaling pathways.", European journal of pharmacology, vol. 889, pp. 173612, 2020. Abstract

Growing evidences suggest the presence of several similarities in the molecular mechanisms underlying the neurodegenerative diseases and metabolic abnormalities. Adults who develop Metabolic Syndrome (MS) are at a higher risk of developing Alzheimer's disease (AD). Pharmacological agents, like dipeptidyl peptidase-4 (DPP-4) inhibitors that increase the levels of glucagon like peptide 1 (GLP-1) and ameliorate symptoms of MS, have become an auspicious candidate as disease modifying agents in the treatment of AD. The present study investigates the beneficial effects of Vildagliptin, a DPP-4 inhibitor in counteracting cognitive decline in different models of dementia targeting the AKT, JAK/STAT signaling pathways and hippocampal Klotho expression, to judge the neuroprotective, anti-apoptotic and anti-inflammatory effects of the drug. Cognitive decline was induced by either administration of high fat high sugar (HFHS) diet for 45 days alone, or with oral administration of AlCl (100 mg/kg/day) for 60 days. Rats were orally administered Vildagliptin (10 mg/kg) for 60 days along with AlCl administration. Vildagliptin treatment improved spatial memory and activities in morris water maze (MWM) test and open field test respectively. Results revealed an increase of both hippocampal klotho and Bcl-2 expressions along with an increase in both AKT and ERK1/2 phosphorylation. In contrast, Vildagliptin treatment decreased hippocampal contents of inflammatory, apoptotic and oxidative stress biomarkers as TNF-α, caspase-3 and FOXO1 along with restoring metabolic abnormalities. A significant decrease in BAX expressions with JAK2/STAT3 inhibition was observed. These findings demonstrate that the neuroprotective role of vildagliptin is possibly via modulating Klotho protein together with AKT pathway.

Shabaan, M. A., A. M. Kamal, S. I. Faggal, A. E. Elsahar, and K. O. Mohamed, "Synthesis and biological evaluation of pyrazolone analogues as potential anti-inflammatory agents targeting cyclooxygenases and 5-lipoxygenase.", Archiv der Pharmazie, vol. 353, issue 4, pp. e1900308, 2020. Abstract

New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX) and their selectivity indices were calculated. The results showed that compounds 3f, 3h, 3l, and 3p have an excellent COX-2 selectivity index. Moreover, they showed potent 5-LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti-inflammatory activity using the carrageenan-induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX-2 and 5-LOX active sites was performed to rationalize their anti-inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual-acting COX-2/5-LOX inhibitors to be used as potent and safe anti-inflammatory agents.

Elbaz, E. M., H. T. S. Helmy, A. E. El-Sahar, M. A. Saad, and R. H. Sayed, "Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington's disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/β-catenin signalling pathways.", Neurochemistry international, vol. 131, pp. 104548, 2019. Abstract

3-Nitropropionic acid (3-NP) induces a spectrum of Huntington's disease (HD)-like neuropathologies in the rat striatum. The present study aimed to demonstrate the neuroprotective effect of lercanidipine (LER) in rats with 3-NP-induced neurotoxicity, address the possible additional protective effect of combined treatment with bone marrow-derived mesenchymal stem cells (BM-MSCs) and LER, and investigate the possible involvement of the Ca/calcineurin (CaN)/nuclear factor of activated T cells c4 (NFATc4) and Wnt/β-catenin signalling pathways. Rats were injected with 3-NP (10 mg/kg/day, i.p.) for two weeks and were divided into four subgroups; the first served as the control HD group, the second received a daily dose of LER (0.5 mg/kg, i.p.), the third received a single injection of BM-MSCs (1 x 106/rat, i.v.) and the last received a combination of both BM-MSCs and LER. The combined therapy improved motor and behaviour performance. Meanwhile, this treatment led to a marked reduction in striatal cytosolic Ca CaN, tumour necrosis factor-alpha, and NFATc4 expression and the Bax/Bcl2 ratio. Combined therapy also increased striatal brain-derived neurotrophic factor, FOXP3, Wnt, and β-catenin protein expression. Furthermore, haematoxylin-eosin and Nissl staining revealed an amelioration of striatum tissue injury with the combined treatment. In conclusion, the current study provides evidence for a neuroprotective effect of LER and/or BM-MSCs in 3-NP-induced neurotoxicity in rats. Interestingly, combined LER/BM-MSC therapy was superior to cell therapy alone in inhibiting 3-NP-induced neurological insults via modulation of the Ca/CaN/NFATc4 and Wnt/β-catenin signalling pathways. LER/BM-MSC combined therapy may represent a feasible approach for improving the beneficial effects of stem cell therapy in HD.

Saad, M. A., A. E. El-Sahhar, H. H. Arab, and M. Y. Al-Shorbagy, "Nicorandil abates arthritic perturbations induced by complete Freund's adjuvant in rats via conquering TLR4-MyD88-TRAF6 signaling pathway.", Life sciences, vol. 218, pp. 284-291, 2019. Abstractnicorandil_paper.pdf

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease which poses a need to explore effective yet safe pharmacotherapeutic options. The current work aimed to study the therapeutic role of nicorandil in controlling RA.

EXPERIMENTAL APPROACH: Complete Freund's adjuvant (CFA)-induced arthritis model was applied by injecting 400 μL of CFA in the right hind paw at day 0 and day 7. Four groups of rats were used as follows: normal-control (CTRL), CFA-induced arthritis (ART), CFA-induced arthritis treated with diclofenac (DIC) and CFA-induced arthritis treated with nicorandil (NIC). Both NIC and DIC were administered at day 14 for two weeks. Paw volume, knee joint diameter, pain behavior assessment as well as body weight were all periodically recorded throughout the experimental period. Following the sacrifice of animals at day 28, gene expressions of TLR-4, MyD88 and TRAF6 as well as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), nuclear factor Kappa B (NF-κB) were quantified in hind paws tissue. Finally, the serum levels of the inflammatory biomarkers (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) together with the histopathological examination of sections in the rat hind paw were recorded.

RESULTS: Both NIC and DIC proved promising anti-arthritic potential mediated, at least in part through switching off TLR4-MyD88-TRAF6 axis as well as downstream TRAF6 dependent activated MAP kinases and NF-κB.

CONCLUSION AND IMPLICATIONS: Nicorandil, via interfering with TLR4 signaling, sheds light on a potential clinical role of the drug in pursuit for safe and effective regimens for RA.

Mohamed, L. W., M. A. Shaaban, A. S. H. R. A. F. F. ZAHER, S. M. Alhamaky, and A. M. Elsahar, "Synthesis of new pyrazoles and pyrozolo [3,4-b] pyridines as anti-inflammatory agents by inhibition of COX-2 enzyme.", Bioorganic chemistry, vol. 83, pp. 47-54, 2019. Abstract

New pyrazoles and pyrazolo[3,4-b] pyridines were synthesized and their structure was confirmed by elemental analyses as well as IR, H NMR, C NMR, and mass spectral data. All the newly synthesized derivatives were evaluated in vitro for inhibitory activity against COX-1 and COX-2 enzymes and their IC values were calculated, most of the derivatives showed good inhibitory activity with derivatives IVb, IVh and IVJ showing inhibitory activity better than celecoxib. Moreover, the eight most potent derivatives IVa, IVb, IVc, IVd, IVe, IVh, IVJ, and IVL were selected for in vivo assay to measure their effect on paw edema in rates and their ulcerogenic effect. Compounds IVa, IVb and IVc were found to be the most active and selective as COX-2 inhibitors and most effective in protection from edema, they were also found to have lowest ulcerogenic effect among all derivatives.

Saad, M. A., A. E. El-Sahar, R. H. Sayed, E. M. Elbaz, H. T. S. Helmy, and M. A. Senousy, "Venlafaxine Mitigates Depressive-Like Behavior in Ovariectomized Rats by Activating the EPO/EPOR/JAK2 Signaling Pathway and Increasing the Serum Estradiol Level.", Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2018 Oct 25. Abstract

Reduced estradiol levels are associated with depression in women during the transition to and after menopause. A considerable number of studies focusing on the theme of treating depression through the activation of erythropoietin (EPO)-induced signaling pathways have been published. Venlafaxine is an approved antidepressant drug that inhibits both serotonin and norepinephrine transporters. The aim of the present study was to investigate the effects of venlafaxine on the depressive-like behaviors and serum estradiol levels in female rats following ovariectomy (OVX) and the possible roles of EPO-induced signaling pathways. Venlafaxine (10 mg/kg/day) was orally administered to OVX rats over a period of 4 weeks using two different treatment regimens: either starting 24 h or 2 weeks after OVX. Venlafaxine showed a superior efficacy in inducing antidepressant-like effects after an acute treatment (24 h post-OVX) than after the delayed treatment (2 weeks post-OVX) and was characterized by a decreased immobility time in the forced swimming test. In parallel, venlafaxine induced EPO and EPO receptor mRNA expression and increased levels of phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 5, and phospho-extracellular signal-regulated kinase 1/2 in the hippocampus of OVX rats. Meanwhile, rats exhibited a marked reduction in the hippocampal Bax/Bcl2 ratio, caspase-3 activity, and tumor necrosis factor alpha levels after venlafaxine treatment. Venlafaxine also increased the hippocampal brain-derived neurotrophic factor and serum estradiol levels. Based on these findings, venlafaxine exerts a neuroprotective effect on OVX rats that is at least partially attributed to the activation of EPO/EPOR/JAK2 signaling pathways, anti-apoptotic activities, anti-inflammatory activities, and neurotrophic activities, as well as an increase in serum estradiol level. Graphical Abstract ᅟ.

Mansour, R. M., M. A. E. Ahmed, A. E. El-Sahar, and N. S. El Sayed, "Montelukast attenuates rotenone-induced microglial activation/p38 MAPK expression in rats: Possible role of its antioxidant, anti-inflammatory and antiapoptotic effects.", Toxicology and applied pharmacology, vol. 358, pp. 76-85, 2018 Nov 01. Abstract1-s2.0-s0041008x18304186-main.pdf

Montelukast (MK),a cysteinyl leukotriene (CysLT1) receptor antagonist, latterly exhibited a remarkable neuroprotective activity in various neurodegenerative disorders. This study aims to elucidate the neuroprotective effect of MK in rotenone-induced Parkinson's disease(PD) model in rats. Ninety six male rats were split into four groups: vehicle control (0.2 ml/kg/48 h, sc), MK (10 mg/kg/day, ip), rotenone (1.5 mg/kg/48 h, sc.) and rotenone pretreated with MK. Rotenone treatment led to significant reduction in motor functioning and elevation in oxidative stress markers. Additionally, upregulation of p38 mitogen-activated protein kinase (p38 MAPK) and CysLT1 receptor expressions were anchored with enhanced striatal microglial activation generating a severe neuro-inflammatory milieu. Furthermore, an augmentation in p53 expression and cleaved caspases-3 activity increased apoptotic neurodegeneration synchronized with reduction of striatal tyrosine hydroxylase (TH) content. Changes in neuronal morphology was also noted. MK administration significantly mitigated motor impairment and rise in oxidative stress mediators. As well, the anti-inflammatory activity of MK was manifested by hindering the principal controller of inflammatory pathway, nuclear factor-kappa B, followed by its downstream pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta), by attenuating striatal microglial activation and hampering the expression of both p38 MAPK and CysLT1. Moreover, MK revealed a decline in p53 expression with its downstream cleaved caspases-3 which resulted in preservation of striatal TH terminals as verified by increased striatal TH content and improvement in the histopathological changes incited by rotenone. In conclusion, MK endowed neuroprotective effects in rotenone-induced PD animal model via attenuation of microglial cell activation and p38 MAPK expression.

Helmy, H. S., A. E. El-Sahar, R. H. Sayed, R. N. Shamma, A. H. Salama, and E. M. Elbaz, "Therapeutic effects of lornoxicam-loaded nanomicellar formula in experimental models of rheumatoid arthritis.", International journal of nanomedicine, vol. 12, pp. 7015-7023, 2017. Abstractf_ijn-147738-the-therapeutic-effects-of-lornoxicam-loaded-nanomicellar-fo_092217_38524.pdf

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease treated by nonsteroidal anti-inflammatory drugs (NSAIDs) including lornoxicam (LX). Nanocarriers have been used to increase the efficacy and reduce the side effects of various drugs. The objective of the present study was to compare the therapeutic efficacy of systemic administration of lornoxicam-loaded nanomicellar formula (LX-NM) with that of free LX.

MATERIALS AND METHODS: The LX-loaded mixed polymeric nanomicellar formula was prepared by direct equilibrium technique. Two rat models were used in the study: carrageenan-induced acute edema and Freund's complete adjuvant (FCA)-induced chronic arthritis.

RESULTS: The inhibitory effect of LX-NM on carrageenan-induced edema was higher than free LX for the same dose (1.3 mg/kg, i.p.). LX-NM (0.325 mg/kg, i.p.) produced effects comparable to that of diclofenac, which served as a standard. In the FCA model, daily treatment with LX-NM (0.325 mg/kg, i.p.) starting on day 14 significantly reduced the percentage of edema and increased weight growth. However, the same dose of LX failed to confer any significant change. Additionally, LX-NM significantly attenuated the rise of tumor necrosis factor-α (TNF-α), interleukin-1β, prostaglandin E2, nuclear factor-κβ, malondialdehyde and nitric oxide serum levels. In contrast, LX failed to show any significant reduction in elevated serum biomarkers except for TNF-α.

CONCLUSION: LX-NM is an alternative delivery system that is simply prepared at low costs. It showed a superior therapeutic efficacy against RA compared to free LX. Thus, LX-NM can be considered as a promising candidate for treatment of RA and similar inflammatory disorders.

Sayed, R. H., M. A. Saad, and A. E. El-Sahar, "Dapoxetine attenuates testosterone-induced prostatic hyperplasia in rats by the regulation of inflammatory and apoptotic proteins.", Toxicology and applied pharmacology, vol. 311, pp. 52-60, 2016 Nov 15. Abstract

Serotonin level plays a role in suppressing the pathological findings of benign prostatic hyperplasia (BPH). Thus a new selective serotonin reuptake inhibitor, dapoxetine was used to test its ability to ameliorate the pathological changes in the rat prostate. A dose response curve was constructed between the dose of dapoxetine and prostate weight as well as relative prostate weight, then a 5mg/kg dose was used as a representative dose for dapoxetine administration. Rats were divided into four groups; the control group that received the vehicle; the BPH-induced group received daily s.c injection of 3mg/kg testosterone propionate dissolved in olive oil for four weeks; BPH-induced group treated with finasteride 5mg/kg/day p.o and BPH-induced group treated with dapoxetine 5mg/kg/day p.o. Injection of testosterone increased prostate weight and relative prostate weight which were both returned back to the normal value after treatment with dapoxetine as well as finasteride. Testosterone also upregulated androgen receptor (AR) and proliferating cell nuclear antigen gene expression. Furthermore, testosterone injection elevated cyclooxygenase-II (COX II), inducible nitric oxide synthase (iNOS), B-cell lymphoma-2 (Bcl2) expression and tumor necrosis factor alpha content and reduced caspase-3 activity, Bcl-2-associated X protein (Bax) expression and Bax/Bcl2 ratio. Dapoxetine and finasteride administration reverted most of the changes made by testosterone injection. In conclusion, the current study provides an evidence for the protective effects of dapoxetine against testosterone-induced BPH in rats. This can be attributed, at least in part, to decreasing AR expression, and the anti-proliferative, anti-inflammatory and pro-apoptotic activities of dapoxetine in BPH.

Sayed, R. H., M. A. Saad, and A. E. El-Sahar, "Dapoxetine attenuates testosterone-induced prostatic hyperplasia in rats by the regulation of inflammatory and apoptotic proteins.", Toxicology and applied pharmacology, vol. 311, pp. 52-60, 2016 Nov 15. Abstract

Serotonin level plays a role in suppressing the pathological findings of benign prostatic hyperplasia (BPH). Thus a new selective serotonin reuptake inhibitor, dapoxetine was used to test its ability to ameliorate the pathological changes in the rat prostate. A dose response curve was constructed between the dose of dapoxetine and prostate weight as well as relative prostate weight, then a 5mg/kg dose was used as a representative dose for dapoxetine administration. Rats were divided into four groups; the control group that received the vehicle; the BPH-induced group received daily s.c injection of 3mg/kg testosterone propionate dissolved in olive oil for four weeks; BPH-induced group treated with finasteride 5mg/kg/day p.o and BPH-induced group treated with dapoxetine 5mg/kg/day p.o. Injection of testosterone increased prostate weight and relative prostate weight which were both returned back to the normal value after treatment with dapoxetine as well as finasteride. Testosterone also upregulated androgen receptor (AR) and proliferating cell nuclear antigen gene expression. Furthermore, testosterone injection elevated cyclooxygenase-II (COX II), inducible nitric oxide synthase (iNOS), B-cell lymphoma-2 (Bcl2) expression and tumor necrosis factor alpha content and reduced caspase-3 activity, Bcl-2-associated X protein (Bax) expression and Bax/Bcl2 ratio. Dapoxetine and finasteride administration reverted most of the changes made by testosterone injection. In conclusion, the current study provides an evidence for the protective effects of dapoxetine against testosterone-induced BPH in rats. This can be attributed, at least in part, to decreasing AR expression, and the anti-proliferative, anti-inflammatory and pro-apoptotic activities of dapoxetine in BPH.

T.Khayyal, M., A. M.Agha, H. F.Zaki, A. El-Sahar, and H. Abdel-Aziz, "Mechanisms Involved in the Anti-inflammatory and Vascular Effect of Iberis amara Extract", Planta medica, vol. 81, issue 12, pp. 1097-1102, 2015. khayyal_et_al._2015_planta_med_iberis.pdf
M.Safar, M., H. F. Zaki, A. S.Attia, and A. A. Shoka, "Pioglitazone Attenuates Cerebral Ischemia-Reperfusion Injury In Streptozotocin-Induced Diabetic Rats", 5th international scientific conference of faculty of pharmacy Cairo university., Cairo university, 24 April, 2014.