Hebatalla I. Ahmed

Effects of indole-3-carbinol on clonidine-induced neurotoxicity in rats: Impact on oxidative stress, inflammation, apoptosis and monoamine levels.

The relationship between inflammation, oxidative stress and the incidence of depression had been well studied. Indole-3-carbinol (I3C), a natural active compound found in cruciferous vegetables, was shown to have anti-oxidant and anti-inflammatory activities. Therefore, the aim of this study was to investigate the potential protective effects of I3C against clonidine-induced depression-like behaviors in rats. Also, the possible mechanisms underlying this neuroprotection; anti-oxidant, anti-inflammatory as well as the modulatory effect on monoamine levels in brain tissues were investigated. I3C was given orally (50mg/kg) daily over 2 weeks starting 7 days before giving clonidine (0.8mg/kg i.p.). Fluoxetine was used as a standard anti-depressant. Open-field test and forced swimming test were carried out to assess exploratory activity and despair behavior, respectively. I3C showed a significant improvement in the behavioral changes induced by clonidine. As indicators of oxidative stress, clonidine induced a significant reduction in GSH and SOD levels as well as an increase lipid peroxidation level. Tissue levels of pro-inflammatory and apoptotic markers were significantly increased in clonidine group. In addition, monoamine levels; noradrenaline and serotonin, showed a drastic decrease in clonidine group. Also, neuron specific enolase (NSE) was significantly elevated in clonidine group. In contrast, I3C pre-treatment significantly attenuated clonidine-induced oxidative stress, inflammation, apoptosis, decreased NSE expression and increased levels of monoamines. Fluoxetine was used as a standard. In conclusion, the findings of this study suggest that I3C protects against clonidine-induced depression. This neuroprotective effect is partially mediated by its anti-oxidant, anti-inflammatory and anti-apoptotic activities as well as elevating monoamines levels.

Protective Effect of Boswellic Acids against Doxorubicin-Induced Hepatotoxicity: Impact on Nrf2/HO-1 Defense Pathway

The current study aimed to investigate the potential protective role of boswellic acids (BAs) against doxorubicin- (DOX-) induced hepatotoxicity. Also, the possible mechanisms underlying this protection; antioxidant, as well as the modulatory effect on the Nrf2 transcription factor/hem oxygenase-1 (Nrf2/HO-1) pathway in liver tissues, was investigated. Animals were allocated to five groups: group 1: the saline control, group 2: the DOX group, animals received DOX (6 mg/kg, i.p.) weekly for a period of three weeks, and groups 3–5: animals received DOX (6 mg/kg, i.p.) weekly and received protective doses of BAs (125, 250, and 500 mg/kg/day). Treatment with BAs significantly improved the altered liver enzyme activities and oxidative stress markers. This was coupled with significant improvement in liver histopathological features. BAs increased the Nrf2 and HO-1 expression, which provided protection against DOX-induced oxidative insult. The present results demonstrated that BAs appear to scavenge ROS and inhibit lipid peroxidation and DNA damage of DOX-induced hepatotoxicity. The antioxidant efficacy of BAs might arise from its modulation of the Nrf2/HO-1 pathway and thereby protected liver from DOX-induced oxidative injury.

Protective effect of vinpocetine against neurotoxicity of manganese in adult male rats

Manganese (Mn) is required for many essential biological processes as well as in the development and functioning of the brain. Extensive accumulation of Mn in the brain may cause central nervous system dysfunction known as manganism, a motor disorder associated with cognitive and neuropsychiatric deficits similar to parkinsonism. Vinpocetine, a synthetic derivative of the alkaloid vincamine, is used to improve the cognitive function in cerebrovascular diseases. It possesses antioxidant and antiinflammatory properties. The present work was designed to explore the potential neuroprotective mechanisms exerted by vinpocetine in the Mn-induced neurotoxicity in rats. Rats were allocated into four groups. First group was given saline. The other three groups were given MnCl2; two of them were treated with either l-dopa, the gold standard antiparkinsonian drug, or vinpocetine. Rats receiving MnCl2 exhibited lengthened catalepsy duration in the grid and bar tests, motor impairment in the open-field test and short-term memory deficit in the Y-maze test. Additionally, histological examination revealed structural alterations and degeneration in different brain regions. Besides, striatal monoamines and mitochondrial complex I contents were declined, apoptotic biomarker caspase-3 expression and acetylcholinesterase activity were elevated. Moreover, oxidative stress and inflammation were detected in the striata. l-dopa or vinpocetine exerted protective effects against MnCl2-induced neurotoxicity. It could be hypothesized that modulation of monoamines, upregulation of mitochondrial complex I, antioxidant, antiinflammatory, and antiapoptotic activities are significant mechanisms underlying the neuroprotective effect of vinpocetine in the Mn-induced neurotoxicity model in rats.

Candesartan and epigallocatechin-3-gallate ameliorate gentamicin-induced renal damage in rats through p38-MAPK and NF-κB pathways: AHMED and MOHAMED

This study pointed to estimate the possible protective impacts of candesartan and/or epigallocatechin‐3‐gallate (EGCG) against gentamicin‐induced nephrotoxicity. The current work revealed that gentamicin significantly elevated relative kidney weight and the serum level of creatinine and urea. Also, renal level of malondialdehyde was significantly increased with a concurrent decrease in renal glutathione‐S‐transferase and superoxide dismutase activities. Moreover, renal levels of nuclear factor‐kappa B (NF‐κB) and p38 mitogen‐activated protein kinase (p38‐MAPK) were increased together with the elevation of tumor necrosis factor‐alpha and interleukin‐1 beta levels after gentamicin treatment. In addition, caspase‐3 expression was elevated, and histological examination revealed extreme alterations enlightening inflammation, degeneration, and necrosis. Pretreatments with candesartan and/or EGCG attenuated gentamicin‐induced nephrotoxicity. Importantly, the altered expression of p38‐MAPK and NF‐κB may play a significant role in the protective mechanisms exerted by candesartan and EGCG. Coadministration of candesartan and EGCG exhibited more profound response compared with the monotherapy.

Protective effect of irbesartan against doxorubicin-induced nephrotoxicity in rats: implication of AMPK, PI3K/Akt, and mTOR signaling pathways

Nephrotoxicity is one of the serious undesirable effects related to doxorubicin (DOX). Herein, we have investigated the potential protective effect of irbesartan (IRB) against chronic nephrotoxicity induced by DOX, and the implication of different mechanistic pathways underlying these effects. Rats were treated with either DOX (2.5 mg/kg i.p., 3 times/week) for 2 weeks, and (or) IRB (40 mg/kg, daily) for 3 weeks. IRB prohibited nephrotoxicity induced by DOX, which was evident by the increase in blood urea nitrogen and creatinine levels and histopathological changes. IRB improved DOX-induced alterations in oxidative status by diminishing lipid peroxidation and upregulating the antioxidant enzymes. Also, upon DOX treatment, the renal expression of tumor necrosis factor-α, interleukin-6, and caspase-3 were significantly increased; IRB diminished DOX-induced alterations in these parameters. Moreover, DOX significantly decreased the expression level of AMP-activated protein kinase (AMPK). Meanwhile, DOX induced activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt/PKB) and mammalian target of rapamycin (mTOR) pathways that cross talked with AMPK. On the contrary, IRB successfully counterbalanced all these effects. Collectively, these outcomes suggest that the modulation of AMPK, PI3K, Akt, and mTOR pathways plays a critical role in conferring the protective effects of IRB against DOX nephrotoxicity.

Protective Effect of Zinc against Postnatal Lead-Induced Alterations in the Neurobehavioral Development of Normally-Fed and Protein MalnourishedRats

Background: The most critical effects of lead (Pb) toxicity occur among children exposed during fetal development, postnatal development or both. Malnutrition is a common problem worldwide and occurs in both developing and developed countries. Zinc is an essential mineral and a fundamental component of the endogenous enzymatic antioxidant system. Objective: To evaluate the possible protective effects of zinc against postnatal Pb-induced alterations in the physical and neurobehavioral development in both normally-fed (NF) and protein malnourished (PM) rats. Methods: Protein sufficient diet (20% casein) for NF groups and protein deficient one (8% casein) for PM groups were utilized. Both NF and PM groups were subdivided to 3 groups 6 dams/each and received daily from parturition until weaning (together with diet); saline for control, 1 ml lead acetate (12 mg/ml) and zinc sulphate (32 mg/kg) with Pb. Pups were evaluated for physical and neurobehavioral development as well as for performance in Neonatal T-maze and Open-field test (OFT). Results: Postnatal Pb exposure inhibited most physical and neurobehavioral development of both NF and PM pups. It also reduced number of correct choices as well as ambulation and rearing frequencies in both pups, the effect was more pronounced in PM pups. However, Zinc increased these parameters in NF and PM pups but increased body weight, ambulation and rearing frequencies while decreased time of appearance of eye opening and grooming time in NF pups only. Conclusion: Postnatal Pb exposure caused alteration in some aspect of physical and neurobehavioral development as well as in some behavioral functions as learning, emotionality as well as locomotor and exploratory activities. The alterations were much greater under the condition of protein malnutrition. Zinc was shown to protect against these lead-induced alterations in both NF and PM rat pups. However the protective effect of Zinc sometimes declined under concomitant protein malnutrition.

Comparative Study on the Influence of Epigallocatechin-3-gallat e and/or Coenzyme Q10 against Alzheimer's disease Induced by Aluminiumin Normally-Fed and Protein Malnourished Rats

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder greatly influenced by oxidative stress and mitochondrial dysfunction which may lead to deposition of β-amyloid (Aβ) peptides. Protein malnutrition increases oxidative damage in cortex, hippocampus and cerebellum. Epigallocatechin-3-gallate (EGCG) has health-promoting effects in CNS, while Coenzyme Q10 (CoQ10) is intracellular antioxidant and mitochondrial membrane stabilizer. Objective: To investigate the possible protective effect of EGCG and/or CoQ10 against aluminium-induced neurotoxicity presenting symptoms that mimic AD in both normally-fed (NF) and protein malnourished (PM) rats. Methods: Ten groups of rats were used; five for NF (20% casein) and the same for PM (10% casein). Both NF and PM groups received daily for four weeks; either saline for control or AlCl3 (70 mg/kg, I.P) for AD induction groups, treated groups received together with AlCl3 either EGCG (10 mg/kg, I.P), CoQ10 (200 mg/kg, P.O) or combination of both. Histopathological changes in the brain and biochemical changes in Aβ, Acetyl cholinesterase (ACHE) as well as oxidative parameters (MDA, SOD, TAC) were evaluated for all groups. Results: The study revealed that, brain neurological damage characterizing induction of AD as indicated by histopathological changes in the brain and the increase in Aβ, ACHE and MDA as well as the decrease in SOD and TAC was more pronounced in PM rats. Administration of EGCG and/or CoQ10 during induction of AD showed protective effect in both NF and PM rats as indicated by the decreased Aβ, ACHE, MDA together with the increased SOD, TAC and confirmed by histo pathological examinations in different brain regions. However, the effect of combined treatment was more pronounced in both NF and PM rats. Conclusion: PM is a risk factor in induction of AD, EGCG and CoQ10 combined therapy has marked protective effects during induction of AD in both NF and PM rats rather than each individual treatment.

The Potential Effect of Caffeine and Nicotine Co-administration againstAluminum-induced Alzheimer's disease in Rats

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized clinically by cognitive decline and memory loss. Caffeine and nicotine are the most commonly co-used psycho stimulants. Caffeine is one of the major contributors to the dietary antioxidants which prevent oxidative damage and may reduce the risk of chronic neurodegenerative diseases. Nicotine has the ability to decrease level of reactive oxygen species (ROS) in the hippocampus and suggested to attenuate the impairment of memory associated with AD. The study aimed to evaluate the influence of caffeine and nicotine co-administration against aluminium-induced neurotoxicity that mimics AD in rats. Five groups of rats were used and received daily for five weeks: Saline for control, aluminium chloride (AlCl3) (70 mg/kg, IP) for AD mimic group, while treated groups received together with AlCl3, either Caffeine (5mg/kg, IP), Nicotine (1 mg/kg, SC) or their combination. Three behavioral experiments were performed: Forced Swimming Test (FST), Morris Water Maze (MWM) task and Conditioned-Avoidance and Learning (CAL) test. Histo pathological changes in the brain and biochemical changes in Acetyl cholinesterase (AchE) as well as oxidative parameters; malon dialdehyde (MDA), superoxide dismutase (SOD), total anti oxidane capacity (TAC) were also evaluated for all groups. Results of the behavioral tests showed that caffeine and nicotine co-administration had more pronounced protecting effect from learning and memory impairment induced by AlCl3 than each one alone. Caffeine and nicotine co-administration also prevent neuronal degeneration in the hippocampus and the eosinophilic plagues in the striatum induced by AlCl3 while nicotine alone still showed mild gliosis in striatum. The marked protection of caffeine and nicotine co-administration confirmed also by the significant increase in TAC and SOD and decrease in MDA and AchE in brain tissue. In conclusion, co-administration of caffeine and nicotine can reduce the risk of neuronal degeneration in the hippocampus and attenuate the impairment of learning and memory associated with AD.

Influence of L-arginine on Cisplatin-Induced Hepatotoxicity in both normally Fed and Protein Malnourished Rats

Liver has great capacity to detoxify toxic substances and synthesized useful principles. Therefore, damage to the liver inflicted by hepatotoxic agents is of grave consequences. Protein malnutrition produces profound effects on biochemistry and physiology of the body as well as growth failure of most body organs. Cisplatin is a member of anticancer drugs that elicits many hepatotoxicity. The study was carried out to investigate the possible hepato-curative and hepato-protective effect of l-arginine either alone or in combination with silymarin against hepatotoxicity resulted from cisplatin (7.5 mg/kg i.p.) treatment in normally fed and protein malnourished male albino rats. All treatments were administered for 5 consecutive days (l-arginine, 200 mg/kg i.p.) and (silymarin, 100 mg/kg i.p.) after and before cisplatin injection. In the cisplatin group, the results revealed significant decrease in the body weight and increase in alanine aminotransferase and aspartate aminotransferase, as well as liver body weight ratio. Antioxidant status was suppressed as manifested by significant decline in reduced glutathione content and total protein level along with decreased enzymatic activity of super oxide dismutase and increased lipid peroxidation, nitric oxide, an effect that was enhanced by combination with protein malnutrition. Administration of l-arginine was effective in decreasing cisplatin hepatotoxicity that restore of anti-oxidant machinery and blunting of mounted malondialdehyde levels. Moreover, histological examination demonstrated that l-arginine significantly reduced cellular infiltration, congestion blood vessels, degenerative changes in hepatocytes and fatty changes. It is concluded that the combined administration of l-arginine with silymarin represents a promising strategy to restrain the cisplatin hepatotoxicity.

STRESS AS A RISK FACTOR IN INDUCTION AND PROGRESSION OF ALZHEIMER’S DISEASE: IMPACT ON THE POSSIBLE PROTECTION USING EPIGALLOCATECHIN-3-GALLATE AND/OR DIAZEPAM

Background/Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Stress is implicated in the development of AD since oxidative stress has been linked to cognitive impairment. Epigallocatechin-3-Gallate (EGCG) is the most abundant catechin in green tea and has antioxidant, anti-inflammatory and anti-atherogenic effects, while Diazepam is an anxiolytic with promising neuroprotective properties. The study aimed to evaluate the impact of stress on behavioral, biochemical and histopathological changes accompanied induction and progression of AD as well as the possible protection using EGCG and/or Diazepam. Methods: Seven groups (8 rats/group) were daily IP injected for six week either with saline for control (2 groups) or with 70 mg/kg AlCl3 for AD-induced model (5 groups). Stress was induced for all groups except one control and one AlCl3 group by exposing rats 6 times during six weeks to Stress-induced box paradigm (one time/week for 30 minute). Three groups of AD-induced model were also daily received either EGCG (10 mg/kg, IP), Diazepam (0.1 mg/kg, IP) or their combination. All rats were examined in two behavioral experiments; Morris water maze task and Conditioned-avoidance test. Histological examination was achieved in different brain regions and biochemical measurements as brain cholinergic markers (AChE); oxidative stress markers (SOD, GPx, MDA, TAC) and inflammatory mediators (TNF-α, IL-1β) were also assayed for all groups. Results: Rats exposed to AlCl3 together with stress showed marked decline in learning and memory abilities. Stress also induced significant elevation in hippocampus TNF-α, IL-1β and MDA level as well as in AChE activity accompanied by reduction in GPx, TAC and SOD activities. Marked histopathological brain degenerations were also shown in AD-model group exposed to stress. EGCG showed more marked protective effect than Diazepam from stress-potentiated the deleterious effect of AlCl3 on the brain, however Co-administration of both resulted in more pronounced protection as regarding all measured parameters. Conclusions: Exposure to stress represents a risk factor in induction and progression of AD. The deleterious effect of stress on the brain and hippocampus can be counteracted by Co-administration of both EGCG and Diazepam.