Marwa Safar - Academia.edu (original) (raw)

Papers by Marwa Safar

Molecular Neurobiology

Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. ... more Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. Cilostazol (CLZ) has pleiotropic effects including neuroprotection in several ravaging central disorders; nonetheless, its potential role in transient central ischemic-induced allodynia and hyperalgesia has not been asserted before. Rats were allocated into 4 groups; sham, sham + CLZ, and 45 min-bilateral carotid occlusion followed by a 48 h-reperfusion period either with or without CLZ (50 mg/kg; p.o) post-treatment. CLZ prolonged latency of hindlimb withdrawal following von Frey filaments, 4 °C cold, and noxious mechanical stimulations. Histopathological alterations and the immunoexpression of glial fibrillary acidic protein induced by I/R were reduced by CLZ in the anterior cingulate cortex (ACC) area, while, CLZ enhanced intact neuronal count. Meanwhile, CLZ modulated cerebral cortical glutamate, dopamine neurotransmission, and transient receptor potential ankyrin 1 (TRPA1). CLZ anti...

Fundamental & Clinical Pharmacology

Great attention was recently given to the importance of RAS in controlling inflammatory bone dise... more Great attention was recently given to the importance of RAS in controlling inflammatory bone diseases, following the discovery of its local existence in skeletal tissues. Local RAS was found to be expressed on osteoblastic and osteoclastic cells and to exert its action via angiotensin II (AngII) receptors, including angiotensin II type 1 receptor (AT1 R) and angiotensin II type 2 receptors. Telmisartan (TLM), an AT1 R blocker (ARBs), was investigated in the present study for its therapeutic effect on bone health in osteoporotic rats. D-galactose, a reducing sugar at a dose of 200 mg/kg/day/i.p. was used to induce osteoporosis in male rats. TLM, at a dose of 5 mg/kg/day, was orally introduced in the osteoporotic rats for four consecutive weeks. Tibia and femur bone densitometry were estimated, bone formation and bone resorption biomarkers serum levels were measured, mineral content in blood was also valued, and finally the extracellular regulated kinase (ERK) expression in bone was determined. TLM considerably improved the deleterious effect of D-galactose on bone mineral density. It blunted serum bone specific alkaline phosphatase and osteocalcin while elevating serum osteoprotegrin (OPG). On the other hand, TLM turned off the pronounced elevation in serum receptor activator of nuclear factor-κβ ligand (RANKL), tartrate-resistant acid phosphatase and cathepsin-k. Furthermore, it significantly hindered the bone expression of ERK which hampered osteoclastogenesis. AT1 R inhibition abolished the rise in serum calcium and phosphorus and normalized serum superoxide dismutase and catalase. These TLM protective effects in D-galactose-treated rats were confirmed by the histopathological examination. The results all together denote the potential therapeutic value of ARBs therapy in osteoporosis.

Egyptian Journal of Radiation Sciences and Applications, 2022

G ROWING evidence suggests that nicotine, the addictive component of cigarettes, plays a direct r... more G ROWING evidence suggests that nicotine, the addictive component of cigarettes, plays a direct role in testicular injury and infertility. The present study was intended to investigate the therapeutic effect of epigallocatechin-3-gallate (EGCG) and rutin (RUT), either alone or in combination with a low-dose radiation (LDR), against testicular injury evoked by nicotine in rats. For the induction of testicular injury, nicotine (1mg/kg) was administered orally for 30 days. Following that, rats were administered EGCG (100 mg/ kg), RUT (30 mg/kg) orally, either alone or in combination with LDR (2 x 0.25 Gy) for an additional 14 days. Rats were sacrificed on day 45, the testes were then dissected for histopathological analysis, and several biochemical parameters in serum and testicular tissue were also evaluated. The results showed that nicotine administration significantly increased the testicular thiobarbituric acid reactive substances and decreased the reduced glutathione contents. Besides, the activities of testicular androgenic enzymes (3 beta-hydroxysteroid dehydrogenases and 17 beta-hydroxysteroid dehydrogenases) were reduced, whereas serum lactate dehydrogenase activity was considerably raised. In addition, the follicle-stimulating hormone, luteinizing hormone, and testosterone serum levels were reduced, indicating hormonal alterations. The testicular seminiferous tubules structure was also deformed after histological examination. On the other hand, treatment with LDR combined with either EGCG or RUT dramatically reduced the deleterious effects of nicotine compared to their individual effects, as evidenced by biochemical and histological findings. Accordingly, exposure to LDR combined with natural antioxidants, either EGCG or RUT, may be a promising candidate for treating testicular injury caused by nicotine.

Egyptian Journal of Chemistry, 2019

Inflammopharmacology

The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable... more The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable. Existing treatments for Alzheimer's disease, such as acetylcholinesterase inhibitors, are only effective for symptom relief. Disease-modifying medications for Alzheimer's disease are desperately required, given the enormous burdens that the disease places on individuals and communities. Phosphodiesterase (PDE) inhibitors are gaining a lot of attention in the research community because of their potential in treating age-related cognitive decline. Cilostazol is a selective PDE III inhibitor used as antiplatelet agent through cAMP response element-binding (CREB) protein phosphorylation pathway (cAMP/CREB). The neuroprotective effect of cilostazol in AD-like cognitive decline in rats was investigated in this study. After 2 months of intraperitoneal administration of 10 mg/kg aluminum chloride, Morris water maze and Y-maze (behavioral tests) were performed. After that, histological ...

Inflammopharmacology

The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable... more The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable. Existing treatments for Alzheimer's disease, such as acetylcholinesterase inhibitors, are only effective for symptom relief. Disease-modifying medications for Alzheimer's disease are desperately required, given the enormous burdens that the disease places on individuals and communities. Phosphodiesterase (PDE) inhibitors are gaining a lot of attention in the research community because of their potential in treating age-related cognitive decline. Cilostazol is a selective PDE III inhibitor used as antiplatelet agent through cAMP response element-binding (CREB) protein phosphorylation pathway (cAMP/CREB). The neuroprotective effect of cilostazol in AD-like cognitive decline in rats was investigated in this study. After 2 months of intraperitoneal administration of 10 mg/kg aluminum chloride, Morris water maze and Y-maze (behavioral tests) were performed. After that, histological ...

Inflammopharmacology, 2022

The heterogeneous nature of multiple sclerosis (MS) and the unavailability of treatments addressi... more The heterogeneous nature of multiple sclerosis (MS) and the unavailability of treatments addressing its intricate network and reversing the disease state is yet an area that needs to be elucidated. Liraglutide, a glucagon-like peptide-1 analogue, recently exhibited intriguing potential neuroprotective effects. The currents study investigated its potential effect against mouse model of MS and the possible underlying mechanisms. Demyelination was induced in C57Bl/6 mice by cuprizone (400 mg/kg/day p.o.) for 5 weeks. Animals received either liraglutide (25 nmol/kg/day i.p.) or dorsomorphin, an AMPK inhibitor, (2.5 mg/Kg i.p.) 30 min before the liraglutide dose, for 4 weeks (starting from the second week). Liraglutide improved the behavioral profile in cuprizone-treated mice. Furthermore, it induced the re-myelination process through stimulating oligodendrocyte progenitor cells differentiation via Olig2 transcription activation, reflected by increased myelin basic protein and myelinated...

Estrogen deficiency in postmenopausal women resulted in increased production of several osteoclas... more Estrogen deficiency in postmenopausal women resulted in increased production of several osteoclastogenic cytokines as IL-1, IL-6 and TNF-α. Poly unsaturated fatty acids (PUFAs) are thought to have an effect on estrogen deficiency-induced osteoporosis through their anti-inflammatory activity. This study evaluated the effect of linseed oil (LO), fish oil (FO) compared to alendronate sodium on bone mineral density and serum bone turn over markers in ovariectomized rats. Rats were rendered osteoporotic by bilateral ovariectomy and maintained on modified diet for 12 weeks. Linseed oil (90, 180 mg/kg po), fish oil (90, 180 mg/kg po) and alendronate sodium (3 mg/kg po) were administered to osteoporotic female rats for 8 weeks. Dual-energy X-ray absorptiometry (DEXA) measurements for femur bone mineral density showed that all the administered drugs resulted in significantly lower bone loss among ovariectomized rats after 8 weeks of treatment. Also serum biomarkers revealed that all the give...

Nanotechnology, Science and Applications, 2020

Toxicology Mechanisms and Methods, 2021

CONCLUSIONS The positive effects of LDR could offer a possible contributor in management of convu... more CONCLUSIONS The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signalling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.HighlightsMale Wistar rats were treated with topiramate 50 mg/kg p.o. for 7 days.on the 6th day of topiramate treatment, rats were exposed to a single low dose whole body gamma radiation (0.5 Gy).on the 7th day of topiramate treatment, rats were injected with pentylenetetrazole 75 mg/kg i.p. 2h after the 7th dose of TOP to illustrate the protective effects of TOP against acute convulsions induced by PTZ.Low dose whole body gamma irradiation purveyed novel anticonvulsant activity which could offer a possible contributor in the basic management of convulsions to avoid side effects of traditional anticonvulsant drugs such as liver and kidney impairments.

ACS Chemical Neuroscience, 2021

Dapagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has emerged as a pr... more Dapagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has emerged as a promising neuroprotective agent in murine models of epilepsy and obesity-induced cognitive impairment through its marked antioxidant/antiapoptotic features. However, the impact of dapagliflozin on the pathogenesis of Parkinson's disease (PD) is lacking. Hence, the present study aimed at exploring the potential neuroprotective effects of dapagliflozin against PD-associated neurodegenerative aberrations/motor dysfunction in rotenone-induced PD rat model. Rotenone (1.5 mg/kg) was subcutaneously administered every other day for 3 weeks. The expression of target signals was investigated using qPCR, Western blotting, ELISA, and immunohistochemistry. Dapagliflozin (1 (mg/kg)/day, by gavage for 3 weeks) attenuated PD motor dysfunction and improved motor coordination in the open-field and rotarod tests without triggering hypoglycemia. It also diminished the histopathologic alterations and α-synuclein expression and augmented tyrosine hydroxylase and dopamine levels. Dapagliflozin markedly alleviated neuronal oxidative stress via lowering lipid peroxides with consequent restoration of the disturbed DJ-1/Nrf2 pathway. Moreover, dapagliflozin counteracted ROS-dependent neuronal apoptosis and upregulated GDNF and its downstream PI3K/AKT/GSK-3β (Ser9) pathway. Meanwhile, it suppressed neuroinflammation via curbing the activation of NF-κB pathway and TNF-α levels. Together, these pleiotropic neuroprotective effects highlight the promising role of dapagliflozin in the management of PD.

Stroke and diabetes mellitus are two separate conditions which share multiple common threads. Ato... more Stroke and diabetes mellitus are two separate conditions which share multiple common threads. Atorvastatin plays an important role in the maintenance of hyperlipidemia especially in diabetic patients. Debate continues about the best strategies for manageme nt of diabetic stroke. Thus, interest was raised to investigate the neuroprotective effects of atorvastatin against transient ischemia/reperfusion (I/R) injury in diabetic rats targeting mainly the oxidative -inflammatoryapoptotic cascade which has been previously addressed as co-conspirators in this insult. Forebrain ischemia was induced in streptozotocin -diabetic rats by bicommon carotid occlusion for 15 min followed by 1h reperfusion. Atorvastatin (15 mg/kg; p.o) was administered daily for 2 weeks prior to I/R injury. The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa NF-κB, and consequently the downstream inflammatory cytokines tumor necrosis factor -α and i...

Life Sciences, 2021

Parkinson's disease (PD) is a progressive neurodegenerative disease that impairs people's... more Parkinson's disease (PD) is a progressive neurodegenerative disease that impairs people's lives tremendously. The development of innovative treatment modalities for PD is a significant unmet medical need. The critical function of glucagon-like peptide-1 (GLP-1) in neurodegenerative diseases has raised impetus in investigating the repositioning of a dipeptidyl peptidase IV inhibitor, alogliptin (ALO), as an effective treatment for PD. As a result, the focus of this research was to assess the effect of ALO in a rat rotenone (ROT) model of PD. For 21 days, ROT (1.5 mg/kg) was delivered subcutaneously every other day. ALO (30 mg/kg/day), delivered by gavage for 21 days, recovered motor performance and improved motor coordination in the open-field and rotarod testing. These impacts were highlighted by restoring striatal dopamine content and correcting histological changes that occurred concurrently. The ALO molecular signaling was determined by increasing the quantity of GLP-1 and the protein expression of its downstream signaling pathway, pT172-AMPK/SIRT1/PGC-1α. Furthermore, it curbed neuroinflammation via hampering HMGB1/TLR4/NLRP3 inflammasome activation and conquered striatal microglia activation. Pre-administration of dorsomorphin reversed the neuroprotective effects. In conclusion, the promising neuroprotective effect of ALO highlights the repositioning of ALO as a prospective revolutionary candidate for combating PD.

Environmental Science and Pollution Research, 2021

Journal of Biochemical and Molecular Toxicology, 2021

The present study was conducted to investigate the potential adverse effect of Pb on pregnant Spr... more The present study was conducted to investigate the potential adverse effect of Pb on pregnant Sprague–Dawley rats and their fetuses after maternal exposure, on gestational days (GD) 7–16. The possible protective role of taurine (TA), administered throughout the gestation period (GD 1–20) against Pb toxicity, was also evaluated. Pregnant rats were divided into four groups: Group 1 (control) was given distilled water; Group 2 was exposed to Pb (250 ppm) in drinking water (GD 7–16), whereas Group 3 received TA (50 mg/kg/day) by oral gavage (GD 1–20); Group 4 was exposed to Pb (GD 7–16), whereas pretreated with TA from GD 1 till the end of the gestation period. After termination on GD 20, maternal and embryo‐fetal outcomes were evaluated. Blood samples were collected for hematological and biochemical parameters assessment. The results showed that, Pb induced a significant reduction in the maternal body weight, weight gain, uterine and placental weight, in addition to a high incidence of abortion and fetal resorption. Meanwhile, fetuses demonstrated decreased body weight and length, with a high rate of mortality as well as external and skeletal abnormalities. Additionally, Pb induced severe hematological and biochemical alterations in both dams and fetuses. The toxicity of Pb was further emphasized by placental histopathological examination and hepatic DNA fragmentation. Pretreatment with TA greatly attenuated the impact of Pb on both maternal and fetal parameters. Moreover, TA alleviated the incidence of placental damage and hepatic DNA fragmentation. The results highlight the potential prophylaxis role of TA against maternal and developmental Pb toxicity.

Journal of Herbs, Spices & Medicinal Plants, 2021

ABSTRACT Despite rutin, extracted from black mulberry, has several pharmacological activities, it... more ABSTRACT Despite rutin, extracted from black mulberry, has several pharmacological activities, its exact effect against hepatic fibrosis remains incompletely identified. Accordingly, this study investigates whether rutin is a promising candidate for treating hepatic fibrosis and to clarify its underlying antifibrotic mechanisms in vitro and in vivo. In vitro studies were performed on hepatic stellate cell line (HSC-T6) whereas liver fibrosis was established in rats via chronic thioacetamide (TAA)-intoxication. Rats were divided into (i) normal, (ii) TAA-intoxicated rats; TAA-intoxicated rats treated with (iii) silymarin or (iv) rutin. Levels of ALT, AST, platelet-derived growth factor-BB (PDGF-BB), tissue inhibitor metalloproteinases type-1 (TIMP-1), hydroxyproline and expression of proliferating cellular nuclear antigen (PCNA) together with histological changes were examined. Activities of rutin on TGF-β1, α-smooth muscle actin (α-SMA) and caspase-3 were measured in vitro and in vivo. Rutin exhibited no marked HSC-T6 cell death (IC50 = 460 µg.ml−1), however, it showed reduction in HSCs activation (low TGF-β1 level and α-SMA positive cells) and induced apoptosis (high caspase-3 positive cells). Rutin also ameliorated liver functions, reduced hepatic levels of PDGF-BB, TGF-β1, TIMP-1, hydroxyproline and restored PCNA, together with attenuation in fibrosis score (S1 vs S4). Rutin could be a promising candidate for treating hepatic fibrosis through down-regulation of HSCs activation and induction of apoptosis.

Toxicology Mechanisms and Methods, 2020

Chemico-Biological Interactions, 2020

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional... more The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and β-amyloid proteins. SITA also opposed the boosted glycogen synthase kinase-3β (GSK-3β), matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both β-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3β/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.

Epilepsy & Behavior, 2020

Patients with diabetes and epilepsy are more prone to cognitive impairment, dementia, and even Al... more Patients with diabetes and epilepsy are more prone to cognitive impairment, dementia, and even Alzheimer's disease. Diabetes-induced inflammatory process is one of the main contributing factors; however, the impact on seizure is not clear. The current study is aimed to examine the role of metformin and trimetazidine in the reduction of neuronal damage caused by inflammatory mediators and apoptotic factors in diabetic epileptic rodent model. Diabetic epileptic rats received orally either metformin (100 mg/kg) or trimetazidine (10 mg/kg) for 3 weeks exhibited reduced cognitive function and ameliorated the disturbed brain neurotransmission. Besides, they improved both the inflammatory status and the histopathologic alterations. Administration of metformin or trimetazidine ameliorated the deterioration in cognitive function in Morris water maze (MWM) and reduced seizure score. Furthermore, brain neurotransmitters glutamate and γ-aminobutyric acid (GABA) were reverted back to their normal values. Both treatments reduced the rise in inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), apoptotic markers nuclear factor-κB (NF-κB) and caspase-3, and improved the pathological photomicrograph of the hippocampus of diabetic epileptic rats. Such effects were closely correlated to the observed increase in the adenosine triphosphate and adenosine diphosphate (ATP/ADP) ratio and reduction of death-associated protein (DAP) and mammalian target of rapamycin (mTOR). In conclusion, the current study shed light on the potential neuroprotective role of metformin and trimetazidine in the amelioration of cognitive function via hindering inflammatory processes in diabetic epileptic rats.

Molecular Neurobiology

Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. ... more Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. Cilostazol (CLZ) has pleiotropic effects including neuroprotection in several ravaging central disorders; nonetheless, its potential role in transient central ischemic-induced allodynia and hyperalgesia has not been asserted before. Rats were allocated into 4 groups; sham, sham + CLZ, and 45 min-bilateral carotid occlusion followed by a 48 h-reperfusion period either with or without CLZ (50 mg/kg; p.o) post-treatment. CLZ prolonged latency of hindlimb withdrawal following von Frey filaments, 4 °C cold, and noxious mechanical stimulations. Histopathological alterations and the immunoexpression of glial fibrillary acidic protein induced by I/R were reduced by CLZ in the anterior cingulate cortex (ACC) area, while, CLZ enhanced intact neuronal count. Meanwhile, CLZ modulated cerebral cortical glutamate, dopamine neurotransmission, and transient receptor potential ankyrin 1 (TRPA1). CLZ anti...

Fundamental & Clinical Pharmacology

Great attention was recently given to the importance of RAS in controlling inflammatory bone dise... more Great attention was recently given to the importance of RAS in controlling inflammatory bone diseases, following the discovery of its local existence in skeletal tissues. Local RAS was found to be expressed on osteoblastic and osteoclastic cells and to exert its action via angiotensin II (AngII) receptors, including angiotensin II type 1 receptor (AT1 R) and angiotensin II type 2 receptors. Telmisartan (TLM), an AT1 R blocker (ARBs), was investigated in the present study for its therapeutic effect on bone health in osteoporotic rats. D-galactose, a reducing sugar at a dose of 200 mg/kg/day/i.p. was used to induce osteoporosis in male rats. TLM, at a dose of 5 mg/kg/day, was orally introduced in the osteoporotic rats for four consecutive weeks. Tibia and femur bone densitometry were estimated, bone formation and bone resorption biomarkers serum levels were measured, mineral content in blood was also valued, and finally the extracellular regulated kinase (ERK) expression in bone was determined. TLM considerably improved the deleterious effect of D-galactose on bone mineral density. It blunted serum bone specific alkaline phosphatase and osteocalcin while elevating serum osteoprotegrin (OPG). On the other hand, TLM turned off the pronounced elevation in serum receptor activator of nuclear factor-κβ ligand (RANKL), tartrate-resistant acid phosphatase and cathepsin-k. Furthermore, it significantly hindered the bone expression of ERK which hampered osteoclastogenesis. AT1 R inhibition abolished the rise in serum calcium and phosphorus and normalized serum superoxide dismutase and catalase. These TLM protective effects in D-galactose-treated rats were confirmed by the histopathological examination. The results all together denote the potential therapeutic value of ARBs therapy in osteoporosis.

Egyptian Journal of Radiation Sciences and Applications, 2022

G ROWING evidence suggests that nicotine, the addictive component of cigarettes, plays a direct r... more G ROWING evidence suggests that nicotine, the addictive component of cigarettes, plays a direct role in testicular injury and infertility. The present study was intended to investigate the therapeutic effect of epigallocatechin-3-gallate (EGCG) and rutin (RUT), either alone or in combination with a low-dose radiation (LDR), against testicular injury evoked by nicotine in rats. For the induction of testicular injury, nicotine (1mg/kg) was administered orally for 30 days. Following that, rats were administered EGCG (100 mg/ kg), RUT (30 mg/kg) orally, either alone or in combination with LDR (2 x 0.25 Gy) for an additional 14 days. Rats were sacrificed on day 45, the testes were then dissected for histopathological analysis, and several biochemical parameters in serum and testicular tissue were also evaluated. The results showed that nicotine administration significantly increased the testicular thiobarbituric acid reactive substances and decreased the reduced glutathione contents. Besides, the activities of testicular androgenic enzymes (3 beta-hydroxysteroid dehydrogenases and 17 beta-hydroxysteroid dehydrogenases) were reduced, whereas serum lactate dehydrogenase activity was considerably raised. In addition, the follicle-stimulating hormone, luteinizing hormone, and testosterone serum levels were reduced, indicating hormonal alterations. The testicular seminiferous tubules structure was also deformed after histological examination. On the other hand, treatment with LDR combined with either EGCG or RUT dramatically reduced the deleterious effects of nicotine compared to their individual effects, as evidenced by biochemical and histological findings. Accordingly, exposure to LDR combined with natural antioxidants, either EGCG or RUT, may be a promising candidate for treating testicular injury caused by nicotine.

Egyptian Journal of Chemistry, 2019

Inflammopharmacology

The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable... more The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable. Existing treatments for Alzheimer's disease, such as acetylcholinesterase inhibitors, are only effective for symptom relief. Disease-modifying medications for Alzheimer's disease are desperately required, given the enormous burdens that the disease places on individuals and communities. Phosphodiesterase (PDE) inhibitors are gaining a lot of attention in the research community because of their potential in treating age-related cognitive decline. Cilostazol is a selective PDE III inhibitor used as antiplatelet agent through cAMP response element-binding (CREB) protein phosphorylation pathway (cAMP/CREB). The neuroprotective effect of cilostazol in AD-like cognitive decline in rats was investigated in this study. After 2 months of intraperitoneal administration of 10 mg/kg aluminum chloride, Morris water maze and Y-maze (behavioral tests) were performed. After that, histological ...

Inflammopharmacology

The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable... more The most prevalent type of dementia is Alzheimer's disease (AD), which is currently incurable. Existing treatments for Alzheimer's disease, such as acetylcholinesterase inhibitors, are only effective for symptom relief. Disease-modifying medications for Alzheimer's disease are desperately required, given the enormous burdens that the disease places on individuals and communities. Phosphodiesterase (PDE) inhibitors are gaining a lot of attention in the research community because of their potential in treating age-related cognitive decline. Cilostazol is a selective PDE III inhibitor used as antiplatelet agent through cAMP response element-binding (CREB) protein phosphorylation pathway (cAMP/CREB). The neuroprotective effect of cilostazol in AD-like cognitive decline in rats was investigated in this study. After 2 months of intraperitoneal administration of 10 mg/kg aluminum chloride, Morris water maze and Y-maze (behavioral tests) were performed. After that, histological ...

Inflammopharmacology, 2022

The heterogeneous nature of multiple sclerosis (MS) and the unavailability of treatments addressi... more The heterogeneous nature of multiple sclerosis (MS) and the unavailability of treatments addressing its intricate network and reversing the disease state is yet an area that needs to be elucidated. Liraglutide, a glucagon-like peptide-1 analogue, recently exhibited intriguing potential neuroprotective effects. The currents study investigated its potential effect against mouse model of MS and the possible underlying mechanisms. Demyelination was induced in C57Bl/6 mice by cuprizone (400 mg/kg/day p.o.) for 5 weeks. Animals received either liraglutide (25 nmol/kg/day i.p.) or dorsomorphin, an AMPK inhibitor, (2.5 mg/Kg i.p.) 30 min before the liraglutide dose, for 4 weeks (starting from the second week). Liraglutide improved the behavioral profile in cuprizone-treated mice. Furthermore, it induced the re-myelination process through stimulating oligodendrocyte progenitor cells differentiation via Olig2 transcription activation, reflected by increased myelin basic protein and myelinated...

Estrogen deficiency in postmenopausal women resulted in increased production of several osteoclas... more Estrogen deficiency in postmenopausal women resulted in increased production of several osteoclastogenic cytokines as IL-1, IL-6 and TNF-α. Poly unsaturated fatty acids (PUFAs) are thought to have an effect on estrogen deficiency-induced osteoporosis through their anti-inflammatory activity. This study evaluated the effect of linseed oil (LO), fish oil (FO) compared to alendronate sodium on bone mineral density and serum bone turn over markers in ovariectomized rats. Rats were rendered osteoporotic by bilateral ovariectomy and maintained on modified diet for 12 weeks. Linseed oil (90, 180 mg/kg po), fish oil (90, 180 mg/kg po) and alendronate sodium (3 mg/kg po) were administered to osteoporotic female rats for 8 weeks. Dual-energy X-ray absorptiometry (DEXA) measurements for femur bone mineral density showed that all the administered drugs resulted in significantly lower bone loss among ovariectomized rats after 8 weeks of treatment. Also serum biomarkers revealed that all the give...

Nanotechnology, Science and Applications, 2020

Toxicology Mechanisms and Methods, 2021

CONCLUSIONS The positive effects of LDR could offer a possible contributor in management of convu... more CONCLUSIONS The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signalling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.HighlightsMale Wistar rats were treated with topiramate 50 mg/kg p.o. for 7 days.on the 6th day of topiramate treatment, rats were exposed to a single low dose whole body gamma radiation (0.5 Gy).on the 7th day of topiramate treatment, rats were injected with pentylenetetrazole 75 mg/kg i.p. 2h after the 7th dose of TOP to illustrate the protective effects of TOP against acute convulsions induced by PTZ.Low dose whole body gamma irradiation purveyed novel anticonvulsant activity which could offer a possible contributor in the basic management of convulsions to avoid side effects of traditional anticonvulsant drugs such as liver and kidney impairments.

ACS Chemical Neuroscience, 2021

Dapagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has emerged as a pr... more Dapagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has emerged as a promising neuroprotective agent in murine models of epilepsy and obesity-induced cognitive impairment through its marked antioxidant/antiapoptotic features. However, the impact of dapagliflozin on the pathogenesis of Parkinson's disease (PD) is lacking. Hence, the present study aimed at exploring the potential neuroprotective effects of dapagliflozin against PD-associated neurodegenerative aberrations/motor dysfunction in rotenone-induced PD rat model. Rotenone (1.5 mg/kg) was subcutaneously administered every other day for 3 weeks. The expression of target signals was investigated using qPCR, Western blotting, ELISA, and immunohistochemistry. Dapagliflozin (1 (mg/kg)/day, by gavage for 3 weeks) attenuated PD motor dysfunction and improved motor coordination in the open-field and rotarod tests without triggering hypoglycemia. It also diminished the histopathologic alterations and α-synuclein expression and augmented tyrosine hydroxylase and dopamine levels. Dapagliflozin markedly alleviated neuronal oxidative stress via lowering lipid peroxides with consequent restoration of the disturbed DJ-1/Nrf2 pathway. Moreover, dapagliflozin counteracted ROS-dependent neuronal apoptosis and upregulated GDNF and its downstream PI3K/AKT/GSK-3β (Ser9) pathway. Meanwhile, it suppressed neuroinflammation via curbing the activation of NF-κB pathway and TNF-α levels. Together, these pleiotropic neuroprotective effects highlight the promising role of dapagliflozin in the management of PD.

Stroke and diabetes mellitus are two separate conditions which share multiple common threads. Ato... more Stroke and diabetes mellitus are two separate conditions which share multiple common threads. Atorvastatin plays an important role in the maintenance of hyperlipidemia especially in diabetic patients. Debate continues about the best strategies for manageme nt of diabetic stroke. Thus, interest was raised to investigate the neuroprotective effects of atorvastatin against transient ischemia/reperfusion (I/R) injury in diabetic rats targeting mainly the oxidative -inflammatoryapoptotic cascade which has been previously addressed as co-conspirators in this insult. Forebrain ischemia was induced in streptozotocin -diabetic rats by bicommon carotid occlusion for 15 min followed by 1h reperfusion. Atorvastatin (15 mg/kg; p.o) was administered daily for 2 weeks prior to I/R injury. The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa NF-κB, and consequently the downstream inflammatory cytokines tumor necrosis factor -α and i...

Life Sciences, 2021

Parkinson's disease (PD) is a progressive neurodegenerative disease that impairs people's... more Parkinson's disease (PD) is a progressive neurodegenerative disease that impairs people's lives tremendously. The development of innovative treatment modalities for PD is a significant unmet medical need. The critical function of glucagon-like peptide-1 (GLP-1) in neurodegenerative diseases has raised impetus in investigating the repositioning of a dipeptidyl peptidase IV inhibitor, alogliptin (ALO), as an effective treatment for PD. As a result, the focus of this research was to assess the effect of ALO in a rat rotenone (ROT) model of PD. For 21 days, ROT (1.5 mg/kg) was delivered subcutaneously every other day. ALO (30 mg/kg/day), delivered by gavage for 21 days, recovered motor performance and improved motor coordination in the open-field and rotarod testing. These impacts were highlighted by restoring striatal dopamine content and correcting histological changes that occurred concurrently. The ALO molecular signaling was determined by increasing the quantity of GLP-1 and the protein expression of its downstream signaling pathway, pT172-AMPK/SIRT1/PGC-1α. Furthermore, it curbed neuroinflammation via hampering HMGB1/TLR4/NLRP3 inflammasome activation and conquered striatal microglia activation. Pre-administration of dorsomorphin reversed the neuroprotective effects. In conclusion, the promising neuroprotective effect of ALO highlights the repositioning of ALO as a prospective revolutionary candidate for combating PD.

Environmental Science and Pollution Research, 2021

Journal of Biochemical and Molecular Toxicology, 2021

The present study was conducted to investigate the potential adverse effect of Pb on pregnant Spr... more The present study was conducted to investigate the potential adverse effect of Pb on pregnant Sprague–Dawley rats and their fetuses after maternal exposure, on gestational days (GD) 7–16. The possible protective role of taurine (TA), administered throughout the gestation period (GD 1–20) against Pb toxicity, was also evaluated. Pregnant rats were divided into four groups: Group 1 (control) was given distilled water; Group 2 was exposed to Pb (250 ppm) in drinking water (GD 7–16), whereas Group 3 received TA (50 mg/kg/day) by oral gavage (GD 1–20); Group 4 was exposed to Pb (GD 7–16), whereas pretreated with TA from GD 1 till the end of the gestation period. After termination on GD 20, maternal and embryo‐fetal outcomes were evaluated. Blood samples were collected for hematological and biochemical parameters assessment. The results showed that, Pb induced a significant reduction in the maternal body weight, weight gain, uterine and placental weight, in addition to a high incidence of abortion and fetal resorption. Meanwhile, fetuses demonstrated decreased body weight and length, with a high rate of mortality as well as external and skeletal abnormalities. Additionally, Pb induced severe hematological and biochemical alterations in both dams and fetuses. The toxicity of Pb was further emphasized by placental histopathological examination and hepatic DNA fragmentation. Pretreatment with TA greatly attenuated the impact of Pb on both maternal and fetal parameters. Moreover, TA alleviated the incidence of placental damage and hepatic DNA fragmentation. The results highlight the potential prophylaxis role of TA against maternal and developmental Pb toxicity.

Journal of Herbs, Spices & Medicinal Plants, 2021

ABSTRACT Despite rutin, extracted from black mulberry, has several pharmacological activities, it... more ABSTRACT Despite rutin, extracted from black mulberry, has several pharmacological activities, its exact effect against hepatic fibrosis remains incompletely identified. Accordingly, this study investigates whether rutin is a promising candidate for treating hepatic fibrosis and to clarify its underlying antifibrotic mechanisms in vitro and in vivo. In vitro studies were performed on hepatic stellate cell line (HSC-T6) whereas liver fibrosis was established in rats via chronic thioacetamide (TAA)-intoxication. Rats were divided into (i) normal, (ii) TAA-intoxicated rats; TAA-intoxicated rats treated with (iii) silymarin or (iv) rutin. Levels of ALT, AST, platelet-derived growth factor-BB (PDGF-BB), tissue inhibitor metalloproteinases type-1 (TIMP-1), hydroxyproline and expression of proliferating cellular nuclear antigen (PCNA) together with histological changes were examined. Activities of rutin on TGF-β1, α-smooth muscle actin (α-SMA) and caspase-3 were measured in vitro and in vivo. Rutin exhibited no marked HSC-T6 cell death (IC50 = 460 µg.ml−1), however, it showed reduction in HSCs activation (low TGF-β1 level and α-SMA positive cells) and induced apoptosis (high caspase-3 positive cells). Rutin also ameliorated liver functions, reduced hepatic levels of PDGF-BB, TGF-β1, TIMP-1, hydroxyproline and restored PCNA, together with attenuation in fibrosis score (S1 vs S4). Rutin could be a promising candidate for treating hepatic fibrosis through down-regulation of HSCs activation and induction of apoptosis.

Toxicology Mechanisms and Methods, 2020

Chemico-Biological Interactions, 2020

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional... more The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and β-amyloid proteins. SITA also opposed the boosted glycogen synthase kinase-3β (GSK-3β), matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both β-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3β/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.

Epilepsy & Behavior, 2020

Patients with diabetes and epilepsy are more prone to cognitive impairment, dementia, and even Al... more Patients with diabetes and epilepsy are more prone to cognitive impairment, dementia, and even Alzheimer's disease. Diabetes-induced inflammatory process is one of the main contributing factors; however, the impact on seizure is not clear. The current study is aimed to examine the role of metformin and trimetazidine in the reduction of neuronal damage caused by inflammatory mediators and apoptotic factors in diabetic epileptic rodent model. Diabetic epileptic rats received orally either metformin (100 mg/kg) or trimetazidine (10 mg/kg) for 3 weeks exhibited reduced cognitive function and ameliorated the disturbed brain neurotransmission. Besides, they improved both the inflammatory status and the histopathologic alterations. Administration of metformin or trimetazidine ameliorated the deterioration in cognitive function in Morris water maze (MWM) and reduced seizure score. Furthermore, brain neurotransmitters glutamate and γ-aminobutyric acid (GABA) were reverted back to their normal values. Both treatments reduced the rise in inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), apoptotic markers nuclear factor-κB (NF-κB) and caspase-3, and improved the pathological photomicrograph of the hippocampus of diabetic epileptic rats. Such effects were closely correlated to the observed increase in the adenosine triphosphate and adenosine diphosphate (ATP/ADP) ratio and reduction of death-associated protein (DAP) and mammalian target of rapamycin (mTOR). In conclusion, the current study shed light on the potential neuroprotective role of metformin and trimetazidine in the amelioration of cognitive function via hindering inflammatory processes in diabetic epileptic rats.