Phosphodiesterase (PDE) III inhibitor, Cilostazol, improved memory impairment in aluminum chloride-treated rats: modulation of cAMP/CREB pathway.

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 and biochemical examinations of the hippocampal region were carried out. Aluminum chloride-treated rats showed histological, biochemical, and behavioral changes similar to Alzheimer's disease. Cilostazol improved rats' behavioral and histological conditions, raised neprilysin level while reduced levels of amyloid-beta protein and phosphorylated tau protein. It also decreased the hippocampal levels of tumor necrosis factor-alpha, nuclear factor-kappa B, FAS ligand, acetylcholinesterase content, and malondialdehyde. These outcomes demonstrate the protective activity of cilostazol versus aluminum-induced memory impairment.

Neuroprotective effect of liraglutide in an experimental mouse model of multiple sclerosis: role of AMPK/SIRT1 signaling and NLRP3 inflammasome.

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 nerve fiber percentage. Liraglutide elevated the protein content of p-AMPK and SIRT1, in addition to the autophagy proteins Beclin-1 and LC3B. Liraglutide halted cellular damage as manifested by reduced HMGB1 protein and consequently TLR-4 downregulation, coupled with a decrease in NF-κB. Liraglutide also suppressed NLRP3 transcription. Dorsomorphin pre-administration indicated a possible interplay between AMPK/SIRT1 and NLRP3 inflammasome activation as it partially reversed liraglutide's effects. Immunohistochemical examination of Iba+ microglia emphasized these findings. In conclusion, liraglutide exerts neuroprotection against cuprizone-induced demyelination via anti-inflammatory, autophagic flux activation, NLRP3 inflammasome suppression, and anti-apoptotic mechanisms, possibly mediated, at least in part, via AMPK/SIRT1, autophagy, TLR-4/ NF-κB/NLRP3 signaling. The potential mechanistic insight of Lira in alleviating Cup-induced neurotoxicity via: (1) AMPK/SIRT1 pathways activation resulting in the stimulation of brain autophagy flux (confirmed by lowering Beclin-1 and LC3-B protein expression). (2) Inhibition of NLRP3 inflammasome activation, as evidenced by reduced HMGB1, TLR-4, NF-κB and NLRP3 protein expression, alongside diminishing the activation of its downstream cascade as reflected by reduced levels of caspase-1 and IL-1ß protein expression. (3) A possible modulating interplay between the previously mentioned two pathways.

Modulation of PTZ-induced convulsions in rats using topiramate alone or combined with low dose gamma irradiation: involving AKT/m-TOR pathway.

The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate against pentylenetetrazole (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (75 mg/kg i.p.). The other three groups were pretreated with single low dose radiation (0.5 Gy), topiramate (50 mg/kg, p.o., seven days) and TPM with LDR respectively before PTZ injection. Racine' score, latency, and duration of the convulsions were assessed. Glutamate and GABA were measured. AKT/m-TOR signaling pathway including AKT (protein kinase B), mammalian target of rapamycin (m-TOR), protein S6, and caspase 3 were also assessed. Measurements of markers of oxidative stress including malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) were carried out. Histological examinations of hippocampi were done. PTZ produced behavioral changes (high Racine score, short latency, and long duration). It elevated MDA and NO contents, while reduced GSH content. TPM treatment alone or combined with LDR ameliorated the PTZ-induced convulsions and caused significant improvement in behavioral changes, brain mediators, m-TOR pathway, oxidative stress, and histological pictures in hippocampal regions. Histopathological examinations of the normal group showed normal structure with intact cells, while PTZ-treated rats exhibited necrosis, pyknosis, and atrophy of pyramidal cells. The histological findings corroborated with the amendment of biochemical parameters. The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signaling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.

Developmental toxicity of lead in rats after gestational exposure and the protective role of taurine.

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.

Metformin and trimetazidine ameliorate diabetes-induced cognitive impediment in status epileptic rats.

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-1ß (IL-1ß) 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.

Combination of pomegranate extract and curcumin ameliorates thioacetamide-induced liver fibrosis in rats: impact on TGF-ß/Smad3 and NF-κB signaling pathways.

Protection against liver injury and its consequences is considered an essential issue to minimize the number of annual deaths caused by liver diseases. The present study was designed to evaluate the potential role of pomegranate extract (PE) and/or curcumin in the regression of thioacetamide (TAA)-induced liver fibrosis, focusing on their modulatory effects on Nrf2/HO-1, NF-κB, and TGF-ß/Smad3 signaling pathways. Liver fibrosis was induced in male Wistar rats by intraperitoneal injection of TAA (100 mg/kg) three times a week, for 8 weeks. To assess the protective effects of PE and/or curcumin against TAA-induced liver fibrosis, rats were treated on a daily basis with oral doses of PE (200 mg/kg) and/or curcumin (200 mg/kg) for 8 weeks. The results indicated that PE and/or curcumin attenuated TAA-induced liver fibrogenesis, as evidenced by a significant improvement in the liver function tests (AST, ALT, ALP, and albumin), oxidative stress biomarkers (MDA, SOD, and GSH), and inflammatory biomarkers (NF-ĸB, TNF-α, IL-1ß, iNOS, TGF-ß, and MPO), compared to TAA group. Moreover, treatment with PE and/or curcumin exerted a significant upregulation of Nrf2/HO-1 gene expressions along with significant downregulation of NF-ĸB, TGF-ß, and phospho-Smad3 protein expressions, as well as α-SMA and collagen-1 gene expressions. The histopathological examination has corroborated these findings. In conclusion, hepatoprotective activities of PE and/or curcumin could be linked to their abilities to modulate Nrf2/HO-1, NF-κB, and TGF-ß/Smad3 signaling pathways. It is worth noting that the combination of PE and curcumin exerted superior hepatoprotective effects against TAA-induced liver fibrosis, as compared to monotherapy.

Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFκB and Nrf2-antioxidant signaling pathways.

Gliptins have been recently shown to conquer neuronal degeneration in cell cultures via modulating glucagon-like peptide (GLP)-1. This peptide produced in the gut not only crosses the blood-brain barrier but is also synthesized in the brain and acts on GLP-1R exerting central anti-inflammatory and antiapoptotic effects, thus impeding neuronal damage. This study investigated the antiparkinsonian effect of vildagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor in a rat rotenone model targeting mainly the RAGE-NFκB/Nrf2-signaling pathways, to judge the potential anti-inflammatory/antioxidant effects of the drug. Vildagliptin markedly improved the motor performance in the open field and rotarod tests, effects that were emphasized by the accompanied reduction in striatal dopamine content. It modified the striatal energy level (ADP/ATP) associated with partial antagonism of body weight reduction. This incretin enhancer suppressed nuclear factor (NF)κB and, consequently, the downstream inflammatory mediator tumor necrosis factor-α. Normalization of receptor for advanced glycated end product (RAGE) is a main finding which justifies the anti-inflammatory effects of vildagliptin, together with hampering striatal inducible nitric oxide synthase, intracellular adhesion molecule-1 as well as myeloperoxidase. The antioxidant potential of vildagliptin was depicted as entailing reduction in thiobarbituric acid-reactive substances and the transcriptional factor Nrf-2 level. Vildagliptin guarded against neuronal demise through an antiapoptotic effect as reflected by the reduction in the mitochondrial matrix component cytochrome c and the key downstream executioner caspase-3. In conclusion, vildagliptin is endowed with various neuroprotective effects and thus can be a promising candidate for the management of Parkinson's disease. In the rat rotenone model of Parkinson's disease (PD), striatal RAGE/NFκB signaling was up-regulated associated with elevated levels of inflammatory, oxidative stress, and apoptotic mediators resulting in dopaminergic neurons death and hence motor impairment. Vildagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, blocked the RAGE/NFκB cascade exerting a potential antiparkinsonian effect. RAGE, receptor for advanced glycation end product; NFκB, nuclear factor κB; TNFα, tumor necrosis factor alpha; ICAM, intracellular adhesion molecule; iNOS, inducible nitric oxide synthase; MPO, myeloperoxidase.

Bone Marrow and Adipose-Derived Mesenchymal Stem Cells Alleviate Methotrexate-Induced Pulmonary Fibrosis in Rat: Comparison with Dexamethasone.

The present study examined the therapeutic effects of bone marrow mesenchymal stem cells (BM-MSCs) and adipose-derived mesenchymal stem cells (AD-MSCs) in methotrexate (MTX)-induced pulmonary fibrosis in rats as compared with dexamethasone (Dex). MTX (14 mg/kg, as a single dose/week for 2 weeks, p.o.) induced lung fibrosis as marked by elevation of relative lung weight, malondialdehyde, nitrite/nitrate, interleukin-4, transforming growth factor-ß1, deposited collagen, as well as increased expression of Bax along with the reduction of reduced glutathione content and superoxide dismutase activity. These deleterious effects were antagonized after treatment either with BM-MSCs or AD-MSCs (2 × 10(6) cells/rat) 2 weeks after MTX to even a better extent than Dex (0.5 mg/kg/ for 7 days, p.o.). In conclusion, BM-MSC and AD-MSCs possessed antioxidant, antiapoptotic, as well as antifibrotic effects, which will probably introduce them as remarkable candidates for the treatment of pulmonary fibrosis.

Red yeast rice and coenzyme Q10 as safe alternatives to surmount atorvastatin-induced myopathy in hyperlipidemic rats.

Statins are the first line treatment for the management of hyperlipidemia. However, the primary adverse effect limiting their use is myopathy. This study examines the efficacy and safety of red yeast rice (RYR), a source of natural statins, as compared with atorvastatin, which is the most widely used synthetic statin. Statin interference with the endogenous synthesis of coenzyme Q10 (CoQ10) prompted the hypothesis that its deficiency may be implicated in the pathogenesis of statin-associated myopathy. Hence, the effects of combination of CoQ10 with either statin have been evaluated. Rats were rendered hyperlipidemic through feeding them a high-fat diet for 90 days, during the last 30 days of the diet they were treated daily with either atorvastatin, RYR, CoQ10, or combined regimens. Lipid profile, liver function tests, and creatine kinase were monitored after 15 and 30 days of drug treatments. Heart contents of CoQ9 and CoQ10 were assessed and histopathological examination of the liver and aortic wall was performed. RYR and CoQ10 had the advantage over atorvastatin in that they lower cholesterol without elevating creatine kinase, a hallmark of myopathy. RYR maintained normal levels of heart ubiquinones, which are essential components for energy production in muscles. In conclusion, RYR and CoQ10 may offer alternatives to overcome atorvastatin-associated myopathy.

Design, synthesis, molecular docking, and molecular dynamic studies of novel quinazoline derivatives as phosphodiesterase 7 inhibitors.

Introduction: Phosphodiesterase 7 (PDE7) is a high-affinity cyclic AMP (cAMP)-specific PDE that is expressed in immune and proinflammatory cells. In this work, we explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases. Methods: A series of novel substituted 4-hydrazinoquinazoline derivatives and fused triazoloquinazolines were designed, synthesized, and evaluated in vitro for their PDE7A inhibition activities, in comparison with Theophylline, a non-selective PDE inhibitor, and BRL50481, a selective PDE7A inhibitor. This series of novel quinazoline derivatives were synthesized via multi-step reactions. The reaction sequence began with selective monohydrazinolysis of compounds 2a,b to give 3a,b. Schiff bases 4a-h were synthesized by the reaction of the quinazolylhydrazines 3a,b with various substituted aromatic aldehydes. The reaction of 4a-h with bromine in acetic acid, in turn, gave fused triazoloquinazolines 5a-h. These compounds were characterized by satisfied spectrum analyses mainly including 1HNMR, 13CNMR, and MS together with elemental analyses. Results and discussion: The results of in vitro PDE7A inhibition activity clearly indicated that compounds 4b, 4g, 5c, and 5f exhibited good potency. Molecular docking and molecular dynamic simulation studies further supported our findings and provided the basis of interaction in terms of conventional hydrogen bonds and π-π stacking patterns. The present results lay the groundwork for developing lead compounds with improved phosphodiesterase seven inhibitory activities.

MitoQ alleviates hippocampal damage after cerebral ischemia: The potential role of SIRT6 in regulating mitochondrial dysfunction and neuroinflammation.

AIMS: Mitochondrial perturbations are the major culprit of the inflammatory response during the initial phase of cerebral ischemia. The present study explored the neuroprotective effect of the mitochondrial-targeted antioxidant, Mitoquinol (MitoQ), against hippocampal neuronal loss in an experimental model of brain ischemia/reperfusion (I/R) injury. MAIN METHODS: Rats were subjected to common carotid artery occlusion for 45 min, followed by reperfusion for 24 h. MitoQ (2 mg/kg; i.p daily) was administered for 7 successive days prior to the induction of brain ischemia. KEY FINDINGS: I/R rats exhibited hippocampal damage evidenced by aggravated mitochondrial oxidative stress, thereby enhancing mtROS and oxidized mtDNA, together with inhibiting mtGSH. Mitochondrial biogenesis and function were also affected, as reflected by the reduction of PGC-1α, TFAM, and NRF-1 levels, as well as loss of mitochondrial membrane potential (△Ψm (. These changes were associated with neuroinflammation, apoptosis, impairment of cognitive function as well as hippocampal neurodegenerative changes in histopathological examination. Notably, SIRT6 was suppressed. Pretreatment with MitoQ markedly potentiated SIRT6, modulated mitochondrial oxidative status and restored mitochondrial biogenesis and function. In addition, MitoQ alleviated the inflammatory mediators, TNF-α, IL-18, and IL-1ß and dampened GFAB immunoexpression along with downregulation of cleaved caspase-3 expression. Reversal of hippocampal function by MitoQ was accompanied by improved cognitive function and hippocampal morphological aberrations. SIGNIFICANCE: This study suggests that MitoQ preserved rats' hippocampi from I/R insults via maintenance of mitochondrial redox status, biogenesis, and activity along with mitigation of neuroinflammation and apoptosis, thereby regulating SIRT6.

Telmisartan: An angiotensin receptor blocker regulates osteoclastogenesis via inhibition of the ERK triggering in osteoporotic male rats.

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 was 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-κß 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.

Cilostazol Alleviates NLRP3 Inflammasome-Induced Allodynia/Hyperalgesia in Murine Cerebral Cortex Following Transient Ischemia: Focus on TRPA1/Glutamate and Akt/Dopamine/BDNF/Nrf2 Trajectories.

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-inflammatory potential was mediated by the downregulated p65 NF-κB and sirtuin-1 enhancement to reduce nucleotide-binding domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), active caspase-1, and interleukin-1ß, indicative of inflammasome deactivation. It also revealed an antioxidant capacity via boosting nuclear factor E2-related factor (Nrf2) enhancing glutathione through forkhead box protein O3a (FOXO3a) reduction. Additionally, CLZ triggered neuronal survival by promoting the p-content of Akt, TrkB, and CREB as well as BDNF content. A novel approach of CLZ in hindering global cerebral I/R-mediated neuropathy is firstly documented herein to forward its adjunct action via deactivating the NLRP3 inflammasome, besides enhancing Nrf2 axis, neuronal survival, and dopamine neurotransmission as well as inhibiting TRPA1 and excitotoxicity.

Targeting ROS-Dependent AKT/GSK-3ß/NF-κB and DJ-1/Nrf2 Pathways by Dapagliflozin Attenuates Neuronal Injury and Motor Dysfunction in Rotenone-Induced Parkinson's Disease Rat Model.

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-3ß (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.

Novel mechanistic insights towards the repositioning of alogliptin in Parkinson's disease.

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.

Ameliorative effect of fractionated low-dose gamma radiation in combination with ellagic acid on nicotine-induced hormonal changes and testicular toxicity in rats.

Nicotine is an active pharmacological ingredient in cigarette smoke, which may negatively influence the male reproductive system and fertility. This study aims to investigate the effect of fractionated low-dose radiation (fractionated-LDR) and/or ellagic acid (EA) on nicotine-induced hormonal changes and testicular toxicity in rats. Nicotine was administrated orally (1 mg/kg) for 30 days, afterward, rats were treated with LDR (2 × 0.25 Gy/1-week interval), EA (10 mg/kg, 14 consecutive days p.o.), or a combination of both fractionated-LDR and EA. Rats were sacrificed 24 h after the last dose of treatment, then testes were dissected for histopathology examination, along with some biochemical parameters in serum and testicular tissue were evaluated. Nicotine-induced oxidative stress was evidenced by an increase in testicular thiobarbituric acid reactive substances (TBARS) and a decrease in reduced glutathione (GSH) content. Additionally, the activities of testicular androgenic enzymes were decreased, and the activity of serum lactate dehydrogenase (LDH) was significantly increased. The hormonal changes were verified by a noticeable reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone serum levels. Histological evaluation revealed that the testicular seminiferous tubules structure was distorted. On the contrary, fractionated-LDR plus EA attenuated the negative changes caused by nicotine observed through biochemical and histological findings. Accordingly, the exposure to fractionated-LDR combined with EA may be a promising candidate for treating hormonal changes and testicular toxicity caused by nicotine.

Chloroquine ameliorates bone loss induced by d-galactose in male rats via inhibition of ERK associated osteoclastogenesis and antioxidant effect.

Chloroquine (CQ); a lysosomotropic agent used for decade ago as anti-malarial, was tested against aging induced osteoporosis. Osteoporosis in male rats was induced using d-galactose (D-gal) as a reducing sugar at a dose of 200 mg/kg/day; i.p. Osteoporotic rats were orally treated with CQ (10 mg/kg/day) for four successive weeks. Bone densitometry of tibia and femur were evaluated. Bone formation biomarkers; osteoprotegrin (OPG), bone specific alkaline phosphatse (BALP), and osteocalcin (OCN), and bone resorption biomarker; receptor activator of nuclear factor kappa-B ligand (RANKL), cathepsin-k (CTSK), tartrate-resistant acid phosphatase (TRAP) were estimated. Moreover, the expression of extracellular regulated kinase (ERK) in bone was determined. CQ ameliorated the bone detrimental changes induced by d-galactose. It enhanced bone health as revealed by measurement of bone densitometry, halted the activation of receptor activator of nuclear factor kappa-B ligand (RANKL) and reduced bone manifestation of ERK. Furthermore, CQ treatment abated serum cathepsin-k (CTSK) and serum tartrate-resistant acid phosphatase (TRAP) thus inhibited osteoclastogenesis and consequently restored the RANKL/OPG ratio. CQ demonstrated an antioxidant effect in bone where it increased both Catalase (CAT) and Superoxide dismutase (SOD). These CQ preserving effect in rats treated with d-galactose were confirmed by the histopathological examination. The present study points to the potential therapeutic effect of CQ as anti-osteoporotic agent possibly through its antioxidant effects and suppression of ERK associated osteoclastogenesis.

Suppression of BACE1 and amyloidogenic/RAGE axis by sitagliptin ameliorates PTZ kindling-induced cognitive deficits in rats.

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 ß-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3ß (GSK-3ß). It also opposed the boosted 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 ß-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-3ß/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.

Telmisartan Protects Against Aluminum-Induced Alzheimer-like Pathological Changes in Rats.

Currently, there is no effective mean for treatment or prevention of Alzheimer's disease (AD). Commonly used AD drugs have a moderate effect and treat only the associated symptoms, therefore there is a strong need to search for more effective agents. Our goal is to examine telmisartan neuroprotective effect in aluminum-induced cognitive impairment in rats. Aluminum chloride (10 mg/kg, i.p) was administered for 2 months then behavioral tests (Y-maze and Morris water maze) were done. Hippocampal biochemical and histological analysis were then carried out. AD-like histological, biochemical, and behavioral alterations appeared in aluminum-treated rats. Telmisartan improved rats' condition on behavioral and histological levels. It reversed the increase in hippocampal amyloid beta protein, phosphorylated tau protein contents together with augmentation of neprilysin level, it also diminished levels of nuclear factor kappa-B, FAS ligand, tumor necrosis factor-alpha, malondialdehyde, and acetylcholinesterase content.These findings show the protective action of telmisartan against AD-like pathological alterations.