Sourdough bread as nutritional intervention tool for improvement of cognitive dysfunction in diabetic rats.

BACKGROUND: The current research targeted to study the impact of nutritional intervention by two sourdough breads in improvement of cognitive dysfunction in diabetic rats. METHODS: Type-2 diabetes was induced in rats by Streptozotocin-Nicotinamide (STZ-NC). Diabetic rats were fed on balanced diet or balanced diet containing 20% of sourdough bread I or II for a month. Lipid profile, oxidative stress, inflammatory markers and cognitive functions were assessed in all rats. Gene expression of brain-derived neurotrophic factor (BDNF) and nuclear respiratory factor 2 (NRF-2) were assessed in hippocampal tissue, while expression of phosphoenol pyruvate carboxy kinase (PEPCK), and glucose transporter 2 (GLUT2) genes were evaluated in hepatic tissue. Chemical composition and fatty acids profile were evaluated in the prepared sourdough bread. RESULTS: Sourdough bread II showed higher content of phenolic compounds, fat, fiber and carbohydrates. Fatty acids profile revealed that sourdough bread I was higher in saturated fatty acids (16.08%), while sourdough bread sample II was higher in unsaturated fatty acids (79.33%). Sourdough bread I or II feeding rats' showed significant improvement in hyperglycemia, oxidative stress markers, inflammatory markers, lipid profile, liver and kidney functions in association with improvement in cognitive function. Gene expression of BDNF and NRF2 in hippocampal tissue were increased significantly, while hepatic GLUT2 and PEPCK gene expression were down-regulated in diabetic given sourdough bread I or II. CONCLUSION: Sourdough bread II was superior in all the studied parameters. The anti-diabetic effect and protection from cognitive dysfunction of sourdough bread samples may be ascribed to the occurrence of dietary fibers, phenolic compounds, and polyunsaturated fatty acids.

Evaluation of the biological efficiency of Terminalia chebula fruit extract against neurochemical changes induced in brain of diabetic rats: an epigenetic study.

Diabetes mellitus (DM) is a chronic and progressive metabolic disorder that can stimulate neuroinflammation and increase oxidative stress in the brain. Therefore, the present study was aimed to assess the efficacy of ethanolic Terminalia chebula extract against the neurochemical and histopathological changes induced in the brains of diabetic rats. The study clarified the reduction in oxidative stress induced in the brains of diabetic rats by the significant (P ≤ 0.05) increase in levels of the antioxidants with decreasing the peroxidation products via ethanolic T. chebula extract at both doses (400 and 600 mg/kg). Moreover, T. chebula extract improved the brain integrity by lowering levels of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), ß-amyloid (Aß) content, monocyte chemoattractant protein-1 (MCP-1) and acetylcholine esterase (ACHE) significantly (P ≤ 0.05) in a dose dependent manner compared to brain of diabetic rats. Severe nuclear pyknosis and degeneration were noticed in neurons of the cerebral cortex, hippocampus and striatum in brains of diabetic rats. The severity of these alterations decreased with T. chebula extract at a dose of 600 mg/kg compared to the other treated groups. The different electrophoretic protein and isoenzyme assays revealed that the lowest similarity index (SI%) values exist in the brains of diabetic rats compared to the control group. The quantity of the most native proteins and isoenzyme types increased significantly (P ≤ 0.05) in the brains of diabetic rats, and these electrophoretic variations were completely diminished by T. chebula extract. The study concluded that T. chebula extract ameliorated the biochemical, histopathological and electrophoretic abnormalities induced in the brains of diabetic rats when administered at a dose of 600 mg/kg.

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson's disease in rats.

Parkinson's disease (PD) is the second most common progressive age-related neurodegenerative disorder. Paramount evidence shed light on the role of PI3K/AKT signaling activation in the treatment of neurodegenerative disorders. PI3K/AKT signaling can be activated via cAMP-dependent pathways achieved by phosphodiesterase 4 (PDE4) inhibition. Roflumilast is a well-known PDE4 inhibitor that is currently used in the treatment of chronic obstructive pulmonary disease. Furthermore, roflumilast has been proposed as a favorable candidate for the treatment of neurological disorders. The current study aimed to unravel the neuroprotective role of roflumilast in the rotenone model of PD in rats. Ninety male rats were allocated into six groups as follows: control, rotenone (1.5 mg/kg/48 h, s.c.), L-dopa (22.5 mg/kg, p.o), and roflumilast (0.2, 0.4 or 0.8 mg/kg, p.o). All treatments were administrated for 21 days 1 h after rotenone injection. Rats treated with roflumilast showed an improvement in motor activity and coordination as well as preservation of dopaminergic neurons in the striatum. Moreover, roflumilast increased cAMP level and activated the PI3K/AKT axis via stimulation of CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling cascades. Roflumilast also caused an upsurge in mTOR and Nrf2, halted GSK-3ß and NF-ĸB, and suppressed FoxO1 and caspase-3. Our study revealed that roflumilast exerted neuroprotective effects in rotenone-induced neurotoxicity in rats. These neuroprotective effects were mediated via the crosstalk between CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling pathways which activates PI3K/AKT trajectory. Therefore, PDE4 inhibition is likely to offer a reliable persuasive avenue in curing PD via PI3K/AKT signaling activation.

Natural Polyphenols-Resveratrol, Quercetin, Magnolol, and ß-Catechin-Block Certain Aspects of Heroin Addiction and Modulate Striatal IL-6 and TNF-α.

We have examined the effects of four different polyphenols in attenuating heroin addiction using a conditioned place preference (CPP) paradigm. Adult male Sprague Dawley rats received heroin (alternating with saline) in escalating doses starting from 10 mg/kg, i.p. up to 80 mg/kg/d for 14 consecutive days. The rats were treated with distilled water (1 mL), quercetin (50 mg/kg/d), ß-catechin (100 mg/kg/d), resveratrol (30 mg/kg/d), or magnolol (50 mg/kg/d) through oral gavage for 7 consecutive days, 30 min before heroin administration, starting on day 8. Heroin withdrawal manifestations were assessed 24 h post last heroin administration following the administration of naloxone (1 mg/kg i.p). Heroin CPP reinstatement was tested following a single dose of heroin (10 mg/kg i.p.) administration. Striatal interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) were quantified (ELISA) after naloxone-precipitated heroin withdrawal. Compared to the vehicle, the heroin-administered rats spent significantly more time in the heroin-paired chamber (p < 0.0001). Concomitant administration of resveratrol and quercetin prevented the acquisition of heroin CPP, while resveratrol, quercetin, and magnolol blocked heroin-triggered reinstatement. Magnolol, quercetin, and ß-catechin blocked naloxone-precipitated heroin withdrawal and increased striatal IL-6 concentration (p < 0.01). Resveratrol administration was associated with significantly higher withdrawal scores compared to those of the control animals (p < 0.0001). The results of this study show that different polyphenols target specific behavioral domains of heroin addiction in a CPP model and modulate the increase in striatal inflammatory cytokines TNF-α and IL-6 observed during naloxone-precipitated heroin withdrawal. Further research is needed to study the clinical utility of polyphenols and to investigate the intriguing finding that resveratrol enhances, rather than attenuates naloxone-precipitated heroin withdrawal.

Protective effect of hot peppers against amyloid ß peptide and brain injury in AlCl3-induced Alzheimer's disease in rats.

Objectives: This study investigated the therapeutic effect of red hot pepper (Capsicum annuum) methanolic extract in induced Alzheimer's disease using AlCl3 in male rats. Materials and Methods: Rats were injected with AlCl3 intraperitoneally (IP) daily for two months. Starting from the 2nd month of AlCl3, rats received, in addition, IP treatments with Capsicum extract (25 and 50 mg/kg) or saline. Other groups received only saline or Capsicum extract at 50 mg/kg for two months. Brain levels of reduced glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) were determined. Additionally, paraoxonase-1 (PON-1) activity, interleukin-6 (IL-6), Aß-peptide, and acetylcholinesterase (AChE) concentrations in the brain were measured. Behavioral testing included wire-hanging tests for neuromuscular strength and memory tests such as Y-maze and Morris water maze. Histopathology of the brain was also done. Results: Compared with saline-treated rats, AlCl3 caused significant elevation of brain oxidative stress as GSH level and PON-1 activity were depleted along with MDA and NO level elevation in the brain. There were also significant increases in brain Aß-peptide, IL-6, and AChE levels. Behavioral testing indicated that AlCl3 decreased neuromuscular strength and impaired memory performance. Capsicum extract given to AlCl3-treated rats significantly alleviated oxidative stress and decreased Aß-peptide and IL-6 in the brain. It also improved grip strength and memory functioning and prevented neuronal degeneration in the cerebral cortex, hippocampus, and substantia nigra of AlCl3-treated rats. Conclusion: Short-term administration of ASA (50 mg/kg) has adverse effects on male reproductive function in mice. Co-administration of melatonin protects against ASA-induced impairment of male reproductive function by preventing the reduction in serum TAC and testosterone levels seen with ASA treatment alone.

In vivo assessment of inflammatory cytokines induced oxidative stress signalling, and troponin I gene dysregulation in cardiac tissue associated with chronic administration of boldenone and tramadol, alone or in combination.

INTRODUCTION: The risk of cardiotoxicity is associated with the use of anabolic-androgenic steroids and analgesics, several deaths were attributed to such medications. OBJECTIVES: This study investigates the effects of boldenone (BOLD) and tramadol (TRAM) alone or in combination on the heart. MATERIAL AND METHODS: Forty adult male rats were divided into four groups. Normal control group, BOLD (5 mg/kg, i.m.) per week, tramadol Hcl (TRAM) (20 mg/kg, i.p.) daily and a combination of BOLD (5 mg/kg) and TRAM (20 mg/kg), respectively for two months. Serum and cardiac tissue were extracted for determination of serum, aspartate aminotransferase (AST), creatine phosphokinase (CPK) and lipid profiles, tissue malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), nitric oxide (NO), tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and histopathological examination. Troponin I gene expression was quantified in cardiac tissue using real-time polymerase chain reaction technique. RESULTS: Groups received BOLD and TRAM alone and in combination showed elevated serum biochemical parameters (AST, CPK) and deviations in lipid profiles, elevation in oxidative and inflammatory parameters (MDA, NO, TNF-α and IL-6), and decrease in GSH and SOD, up-regulated cardiac troponin I as well as distorted cardiac histopathological pictures. CONCLUSION: The current study elucidated the risk of administration of these drugs for sustained periods as well as the marked detrimental effects of using these drugs in combination.

Curcumin modulation of L-dopa and rasagiline-induced neuroprotection in rotenone model of Parkinson's disease.

Objectives: Parkinson's disease (PD) is one of the most incurable, chronic, and progressive neurodegenerative disorders Worldwide. Curcumin, a natural polyphenolic anti-oxidant compound, has a long history in traditional medicine. We investigate the effect of curcumin on brain oxidative stress, DNA fragmentation, and motor changes in rotenone-induced PD in mice. The possible modulation of the anti-parkinsonian action of drugs L-dopa and rasagiline by curcumin was also studied. Materials and Methods: Mice received rotenone 1.5 mg/kg and were treated with curcumin (150 mg/kg), L-dopa (25 mg/kg), rasagiline (1 mg/kg), L-dopa+curcumin, or rasagiline+curcumin. Striatal malondialdehyde, reduced glutathione, nitric oxide, tyrosine hydroxylase, and brain DNA fragmentations were measured. Histopathological examination of brain tissues was done. Motor coordination and behavioral tests such as wire-hanging, stair, and wood-waking tests were included. Results: Rotenone caused elevation in brain malondialdehyde and nitric oxide contents, depletion of reduced glutathione accompanied by a reduction in rearing behavior, and impairment of motor activity in wire-hanging, stair, and wood-waking tests. Also, severe DNA fragmentation in the striatum, marked decrease of substantia nigra pigmented neurons, neuronal degeneration in the cerebral cortex and hippocampus, decreased glial fibrillary acidic protein reaction (GFAP) and glial cell size in the cerebral cortex were caused by rotenone. In rotenone-treated mice, brain oxidative stress was decreased by curcumin, L-dopa, rasagiline, curcumin+L-dopa, and curcumin+rasagiline. These treatments also prevented DNA fragmentation and markedly improved the motor and behavioral impairment caused by rotenone. Rotenone-induced histopathological changes were ameliorated by curcumin which had an additive effect to that of l-dopa or rasagiline. Conclusion: These data indicate that curcumin showed additive neuroprotective effects to L-dopa or rasagiline and ameliorated neurodegeneration, DNA fragmentation, and motor defects caused by rotenone in mice.

The Behavioral and Neurochemical Changes Induced by Boldenone and/or Tramadol in Adult Male Rats.

Boldenone and tramadol are abused among large sectors of adolescents. Therefore, the behavioral changes concerned with memory and cognitive functions and neurochemical variations were investigated in the cortex of rats treated with boldenone and/or tramadol. Rats were divided into control and rats treated with boldenone, tramadol, or both drugs. At the end of the treatment period, the memory and cognitive functions were evaluated by the Y-maze test (YMT) and elevated plus maze test (EPMT) and the motor activity was determined by the open field test (OFT). The cortex was dissected to carry out the neurochemical analyses. Rats treated with boldenone and/or tramadol showed impaired memory and cognitive functions and reduced motor activity. A significant increase in lipid peroxidation (MDA), nitric oxide (NO), and a significant decrease in reduced glutathione (GSH) were observed in the cortex of rats treated with boldenone and/or tramadol. The levels of acetylcholinesterase (AChE) and monoamine oxidase (MAO) decreased significantly. Western blot data showed a significant decrease in Bcl2 and a significant increase in caspase-3 and inducible nitric oxide synthase (iNOS) in rats treated with boldenone and/or tramadol. These changes were associated with neuronal death as indicated from the histopathological examination.The present findings indicate that boldenone and/or tramadol induced impairment in memory and cognitive functions. These changes could be mediated by the increase in oxidative stress, neuroinflammation, reduced AChE level, and reduced number of survived neurons in the cortex as indicated from the decreased Bcl2 level and the histological examination.

Apigenin attenuates LPS-induced neurotoxicity and cognitive impairment in mice via promoting mitochondrial fusion/mitophagy: role of SIRT3/PINK1/Parkin pathway.

RATIONALE: Alteration of the NAD+ metabolic pathway is proposed to be implicated in lipopolysaccharide (LPS)-induced neurotoxicity and mitochondrial dysfunction in neurodegenerative diseases. Apigenin, a naturally-occurring flavonoid, has been reported to maintain NAD+ levels and to preserve various metabolic functions. OBJECTIVES: This study aimed to explore the effect of apigenin on mitochondrial SIRT3 activity as a mediator through which it could modulate mitochondrial quality control and to protect against intracerebrovascular ICV/LPS-induced neurotoxicity. METHODS: Mice received apigenin (40 mg/kg; p.o) for 7 consecutive days. One hour after the last dose, LPS (12 µg/kg, icv) was administered. RESULTS: Apigenin robustly guarded against neuronal degenerative changes and maintained a normal count of intact neurons in mice hippocampi. Consequently, it inhibited the deleterious effect of LPS on cognitive functions. Apigenin was effective in preserving the NAD+/NADH ratio to boost mitochondrial sirtuin-3 (SIRT3), activity, and ATP production. It conserved normal mitochondrial features via induction of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α), along with mitochondrial transcription factor A (TFAM) and the fusion proteins, mitofusin 2 (MFN2), and optic atrophy-1 (OPA1). Furthermore, it increased phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and parkin expression as well as the microtubule-associated protein 1 light chain 3 II/I ratio (LC3II/I) to induce degradation of unhealthy mitochondria via mitophagy. CONCLUSIONS: These observations reveal the marked neuroprotective potential of apigenin against LPS-induced neurotoxicity through inhibition of NAD+ depletion and activation of SIRT3 to maintain adequate mitochondrial homeostasis and function.

Cross-talk between down-regulation of steroidogenic genes expression and oxidative and apoptotic biomarkers in testes induced by administration of tramadol and boldenone and their combination in male albino rats.

Objectives: The testis is the male reproductive gland or gonad having two vital functions: to produce both sperm and androgens, primarily testosterone. The study aimed to investigate the effect of tramadol and boldenone injected alone or in combination for 2 months in rats on testicular function. Materials and Methods: Group 1, normal control; Group 2, tramadol HCl (TRAM) (20 mg/kg bwt.) (IP); Group 3, boldenone undecylenate (BOLD) (5 mg/kg bwt) (i.m); Group 4, combination of TRAM (20 mg/kg bwt.) and BOLD (5 mg/kg); respectively for 2 months. Results: TRAM and BOLD alone and in combination showed deteriorated testicular functions, lowered serum steroid levels (FSH, LH, and testosterone), elevation in oxidative biomarkers (MDA & NO) and reduction in GSH and SOD, down-regulation of StaR and HSD17B3 as well as histopathological testicular assessment using H&E staining revealing massive degenerative changes in the seminiferous epithelium and vacuolar changes of most of the spermatogenic stages in both TRAM and BOLD groups. PAS stain showed an intensive reaction in the interstitial tissue between the tubules in the TRAM group. Masson trichrome stain showed abundant collagen fiber deposits in the tunica albuginea with congested BV in the TRAM group. Conclusion: The study illuminated the hazard of administration of these drugs for a long period as well as the prominent deleterious effects reported on concurrent use of both drugs.

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.

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-1ß) 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.

Inhibition of boldenone-induced aggression in rats by curcumin: Targeting TLR4/MyD88/TRAF-6/NF-κB pathway.

The illicit abuse of anabolic steroids is associated with brutal aggression, which represents a serious health hazard and social threat. Boldenone is commonly used for doping by athletes and adolescents for esthetic purposes and to enhance performance and endurance during competitions. However, the mechanistic pathways underlying boldenone-induced behavioral deviations and neuronal toxicity have not yet been elucidated. On the other hand, the natural polyphenol curcumin is appreciated for its relative safety, potent antioxidant activity, and anti-inflammatory properties. Therefore, the present study was initiated to explore the signaling pathways underlying boldenone-induced anxiety and aggression in rats, and the protective effects of curcumin. To achieve this aim, male Wistar albino rats were randomly distributed into control, curcumin (100 mg/kg in sesame oil, p.o., once daily), boldenone (5 mg/kg, intramuscular, once weekly), and combination groups. Rats were challenged across the open field, irritability, defensive aggression, and resident-intruder tests. The prefrontal cortex was used to assess serotonin level, oxidative stress markers, and mRNA expression of myeloid differentiation primary response gene (MyD88), TNFR-associated factor 6 (TRAF-6), tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), protein expression of toll-like receptor 4 (TLR4), and phosphorylated nuclear factor-κB transcription factor (NF-κB p65). Unprecedented, the current results showed that boldenone elicited aggression in rats accompanied by depleted serotonin, enhanced oxidative stress, and exaggerated inflammatory response via upregulation of TLR4/MyD88/TRAF-6/NF-κB pathway. Interestingly, curcumin mitigated boldenone-induced neurobehavioral disturbances in rats, normalized the oxidant/antioxidant balance, and suppressed TLR4/MyD88/TRAF-6/NF-κB pathway and its downstream proinflammatory signaling molecules TNF-α and IL-1ß.

Inhibition of aluminum chloride-induced amyloid Aß peptide accumulation and brain neurodegeneration by Bougainvillea spectabilis flower decoction.

OBJECTIVES: To investigate the potential therapeutic effect of Bougainvillea spectabilis flower decoction on aluminum chloride (AlCl3)-induced neurotoxicity. MATERIALS AND METHODS: Rats received daily intraperitoneal injections of AlCl3 at 10 mg/kg for two months and were treated with B. spectabilis decoction at 50 or 100 mg/kg or saline during the 2nd month of the study. The control group received saline. Brain malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), acetylcholinesterase (AChE), amyloid Aß peptide, and interleukin-6 (IL-6) concentrations and paraoxonase-1 (PON-1) activity were determined and brain histology was done. Behavioral and neurological testing included Morris water maze (WMZ), Y maze, and wire hanging. RESULTS: Compared with saline controls, AlCl3 significantly increased brain MDA and NO along with decreased GSH and PON-1 activity. It also increased AChE, IL-6, and amyloid Aß concentrations. AlCl3 impaired motor strength and memory performance and caused brain neurodegeneration. B. spectabilis decoction given at 50 or 100 mg/kg protected against the biochemical and histopathological alterations evoked by AlCl3 by alleviating the increase in MDA and NO, and decrease in GSH and PON-1 activity. B. spectabilis decoction showed no significant effect on AChE but markedly decreased IL-6 and amyloid Aß in the brain of AlCl3-treated rats. It also restored memory performance and motor strength, and protected against AlCl3-induced neurodegeneration. CONCLUSION: These results suggest that B. spectabilis flower decoction might prove of value in the treatment of Alzheimer's disease.

The protective effect of inosine against rotenone-induced Parkinson's disease in mice; role of oxido-nitrosative stress, ERK phosphorylation, and A2AR expression.

Parkinson's disease (PD) is a severe disabling syndrome in which neuroinflammation and various signaling pathways are believed to mediate dopaminergic neurodegeneration. Here, the possible disease-modifying effects of the purine nucleoside inosine were examined against rotenone-induced PD. Mice were allocated into six groups, namely, a normal control group receiving dimethylsulfoxide, a PD control group receiving rotenone, a standard treatment group receiving L-dopa/carbidopa together with rotenone, and three treatment groups receiving inosine in low, medium, and high doses together with rotenone. At the end of the experimental protocol, three behavioral tests were performed to assess PD motor manifestations, namely, wire-hanging test, wood-walking test, and stair test. After performing the behavioral study, mice striata were isolated for the colorimetric assay of hypoxanthine, the enzyme-linked immunosorbent assay of dopamine, tumor necrosis factor-α, interleukin-6 and nitrite, the Western blot estimation of total and phosphorylated extracellular signal-regulated kinase (tERK and pERK), the polymerase chain reaction estimation of adenosine A2A receptor (A2AR) expression, as well as the histopathological examination of substantia nigra and striatal tissue. Inosine protected against PD progression in a dose-dependent manner, with the effect comparable to the standard treatment L-dopa/carbidopa, evidenced by behavioral, biochemical, and histologic findings. The beneficial antiparkinsonian effect of inosine could be attributed to the ability of the drug to ameliorate neuroinflammation and oxido-nitrosative stress, together with suppression of ERK phosphorylation and down-regulation of A2AR expression. Inosine could therefore be considered as a disease-modifying agent against PD, but further studies are claimed to confirm such effects clinically.

Neuroprotective effect of PPAR alpha and gamma agonists in a mouse model of amyloidogenesis through modulation of the Wnt/beta catenin pathway via targeting alpha- and beta-secretases.

The present study was conducted to evaluate the efficacy of fenofibrate and pioglitazone in a mouse model of amyloidogenesis induced by amyloidß (ßA) peptide. Mice were injected intracerebroventricularly with ßA1-40 (400 pmol/mouse) once, followed by treatment with fenofibrate (300 mg/kg), pioglitazone (30 mg/kg),or both. After 21 days of daily treatment, memory impairment and cognitive function were evaluated by Morris water maze (MWM), Y-maze and object recognition tests. On the 22nd day, mice were sacrificed, and their hippocampi were dissected to determine the levels of α- and ß-secretase, peroxisome proliferator-activated receptor (PPARα and ß), Wnt and ß-catenin. Significant memory impairment and cognitive dysfunction were observed in the mouse model group. This finding was associated with a significant increase in α- and ß-secretase levels and a significant decrease in Wnt, ß-catenin, and PPARα and ß levels. Neuronal damage was also evident after histopathological examination. Treatment with fenofibrate, pioglitazone and their combination resulted in a significant improvement in the behavioural and neurochemical changes induced by ßA injection. The present findings indicate that the combined administration of fenofibrate and pioglitazone was more effective than monotherapy in ameliorating the behavioural, neurochemical and histopathological changes in amyloidogenesis model mice and provide a promising therapeutic approach in the management of Alzheimer's disease complicated by diabetes and hypercholesterolemia.

Combined neurotoxic effects of cannabis and nandrolone decanoate in adolescent male rats.

Polydrug use among adolescence is a widespread phenomenon and has increased in the last few years. In particular, most nandrolone decanoate (Nan) abusers combine its use with cannabis (Can); thus, studying the consequences of this combination in adolescent subjects is important because potentiation of their effects may increase their neurotoxicity. The present study was designed to study the neurotoxic effects of Nan and Can, alone and in combination, in adolescent male rats by studying the behavioural, biochemical, and histopathological effects. Nan (15 mg/kg, s.c.) and Can (20 mg/kg, s.c.) were given alone or in combination to rats once daily for one month. The combined administration of Can and Nan induced learning and spatial memory deficits, hypo-locomotion, anxiety and aggression in adolescent rats as evidenced by the Morris water maze, open field, elevated plus maze, and defensive aggression tests. In parallel, rats treated with the combination showed severe deleterious effects in the hippocampal and prefrontal cortex (PFC) neural architecture along with a decrease in brain-derived neurotropic factor. Furthermore, combined administration of Can and Nan increased oxidative stress (significantly increased malondialdehyde and nitric oxide levels and reduced glutathione content), elevated brain pro-inflammatory cytokines (tumour necrosis factor alpha and interleukin 1 beta), and upregulated caspase-3, caspase-8, and caspase-9 mRNA expression and cytochrome c levels. In conclusion, abuse of both Can and Nan conferred greater neurotoxic effects than either drug alone that were at least partially attributed to oxidative stress, inflammation, and intrinsic and extrinsic apoptosis in the hippocampus and PFC of rats.

New prospects of mesenchymal stem cells for ameliorating temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is present in 30% of epileptic patients and does not respond to conventional treatments. Bone marrow derived mesenchymal stem cells (BMSCs) induce endogenous neural stem cells, inhibit neurodegeneration, and promote brain self-repair mechanisms. The present study addresses the feasibility of BMSCs transplantation against pilocarpine-induced TLE experimentally. BMSCs were injected either intravenously (IV) or in hippocampus bilaterally (IC). Increased cell count of BMSCs was achieved via IC route. BMSCs treatment ameliorated the pilocarpine-induced neurochemical and histological changes, retained amino acid neurotransmitters to the normal level, downregulated the immunoreactivity to insulin growth factor-1 receptor, synaptophysin, and caspase-3 and reduced oxidative insult and inflammatory markers detected in epileptic model. It is worth noting that BMSCs IC-administered showed more pronounced effects than those administered via IV route. BMSCs transplantation presents a promise for TLE treatment that has to be elucidated clinically.

Silver oxide nanoparticles alleviate indomethacin-induced gastric injury: a novel antiulcer agent.

Silver and silver oxides are gaining interest in medical applications for their prominent antibacterial and antimicrobial potentials. Recent studies suggest that nanosilver oxide has remarkable anti-inflammatory effects and enhances wound healing. Nevertheless, its effect on gastric ulcer has not yet been illustrated. Thus the current study aimed to explore the prospect protective effect of nanosilver oxide against indomethacin-induced gastric ulcer. A new approach has been followed to synthesize nanosilver oxide. X-ray diffraction, UV-Vis spectroscopy and transition electron microscope techniques have been successfully used to characterize the synthesized nanoparticles. Treatment of ulcerated rats with different doses of nanosilver oxide especially (175 and 350 ppm/p.o.) alleviated adverse effects of indomethacin-induced gastric injury as demonstrated by decreasing ulcer index and elevating % of ulcer inhibition. These positive effects excelled those exerted by the reference antiulcer drug omeprazole. Nanosilver oxide suppressed gastric inflammation by reducing myeloperoxidase, tumor necrosis alpha, interleukin 1beta and interferon gamma. Moreover, nanosilver oxide halted gastric oxidative stress via inhibiting lipid  peroxidation and enhancing glutathione and paraoxonase-1. Regarding gastric apoptosis, nanosilver oxide down regulated the expression of caspase 9, tumor protein 53, and nuclear factor kappa B and allograft inflammatory factor-1 genes. These findings emphasize the antiulcerogenic potential of nanosilver oxide against indomethacin-induced gastric ulcers which are multi-factorial including anti-inflammatory, antioxidant and antiapoptotic effects.

Cannabis-induced impairment of learning and memory: effect of different nootropic drugs.

Cannabis sativa preparations are the most commonly used illicit drugs worldwide. The present study aimed to investigate the effect of Cannabis sativa extract in the working memory version of the Morris water maze (MWM; Morris, 1984[43]) test and determine the effect of standard memory enhancing drugs. Cannabis sativa was given at doses of 5, 10 or 20 mg/kg (expressed as Δ(9)-tetrahydrocannabinol) alone or co-administered with donepezil (1 mg/kg), piracetam (150 mg/ kg), vinpocetine (1.5 mg/kg) or ginkgo biloba (25 mg/kg) once daily subcutaneously (s.c.) for one month. Mice were examined three times weekly for their ability to locate a submerged platform. Mice were euthanized 30 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, glucose and brain monoamines were determined. Cannabis resulted in a significant increase in the time taken to locate the platform and enhanced the memory impairment produced by scopolamine. This effect of cannabis decreased by memory enhancing drugs with piracetam resulting in the most-shorter latency compared with the cannabis. Biochemically, cannabis altered the oxidative status of the brain with decreased MDA, increased GSH, but decreased nitric oxide and glucose. In cannabis-treated rats, the level of GSH in brain was increased after vinpocetine and donepezil and was markedly elevated after Ginkgo biloba. Piracetam restored the decrease in glucose and nitric oxide by cannabis. Cannabis caused dose-dependent increases of brain serotonin, noradrenaline and dopamine. After cannabis treatment, noradrenaline is restored to its normal value by donepezil, vinpocetine or Ginkgo biloba, but increased by piracetam. The level of dopamine was significantly reduced by piracetam, vinpocetine or Ginkgo biloba. These data indicate that cannabis administration is associated with impaired memory performance which is likely to involve decreased brain glucose availability as well as alterations in brain monoamine neurotransmitter levels. Piracetam is more effective in ameliorating the cognitive impairments than other nootropics by alleviating the alterations in glucose, nitric oxide and dopamine in brain.