Mona A. El-Ghazaly

Possible role of vitamin E, coenzyme Q10 and rutin in protection against cerebral ischemia/reperfusion injury in irradiated rats

Purpose:u2003To investigate the possible role of vitamin E, coenzyme Q10 and rutin in ameliorating the biochemical changes in brain and serum induced by cerebral ischemia/reperfusion (I/R) in whole body γ-irradiated rats. Materials and methods:u2003Cerebral ischemia was induced in male Wistar rats (either irradiated or non-irradiated) followed by reperfusion. Results:u2003I/R increased brain content of malondialdehyde (MDA) and depleted its glutathione (GSH) content with a compensatory elevation in cytosolic activities of glutathione peroxidase (GPx) and glutathione reductase (GR) enzymes. It also raised brain cytosolic lactate dehydrogenase (LDH) activity and calcium (Ca2+) level. Furthermore, I/R provoked an inflammatory response reflected by an increment in serum levels of the proinflammatory cytokines tumour necrosis factor-α (TNF-α) and interlukin-1β (IL-1β). Moreover, induction of I/R in irradiated rats resulted in a further increase in brain oxidative stress and cytosolic LDH activity, disturbed brain Ca2+ homeostasis and exaggerated the inflammatory reaction. During irradiation, administration of each of vitamin E, coenzyme Q10 (CoQ10) and rutin to irradiated rats before induction of I/R, alleviated the brain oxidative stress. Moreover, these antioxidants caused attenuation of the rise of the cytosolic activities of GPx and GR. A lowering effect of the cytosolic LDH activity and Ca2+ level were caused by treatment with antioxidants. Each of vitamin E and rutin revealed an anti-inflammatory action of these antioxidants, while CoQ10 had no effect on serum levels of TNF-α and IL-1β. Conclusion:u2003These findings indicate that supplementation with either vitamin E, CoQ10 or rutin ameliorated most of the biochemical changes induced by I/R in irradiated rat brain and serum.

Effect of selective COX-2 inhibitor, celecoxib on adjuvant-induced arthritis model in irradiated rats

Purpose:u2003The potential value of celecoxib was compared to a standard non-steroidal anti-inflammatory drug (NSAID), diclofenac in the adjuvant-induced arthritis (AIA) model in rats as a model of chronic inflammation under the influence of ionising radiation. Material and methods:u2003Various inflammatory mediators and biochemical parameters were measured in the arthritic rats under the influence of ionising radiation. Results:u2003Exposure of the animals to a radiation dose of 2u2009Gy before inoculation of the adjuvant led to a marked increase in the paw volume reaching ca. 70% more than that in non-irradiated ones as well as a significant increase in the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) as an index of cyclooxygenase-2 (COX-2) activity, thromboxane B2 (TXB2) as an index of cyclooxygenase-1 (COX-1) activity and plasma level of malondialdehyde (MDA). The blood glutathione (GSH) level was not affected by the dose of irradiation used while superoxidedismutase (SOD) activity was reduced. Treatment with celecoxib in a dose of 5u2009mg/kg was effective in decreasing the elevated levels of IL-6, IL-1β, TNF-α, PGE2 whereas it lacked any effect on TXB2 level since it had hardly any effect on COX-1 enzyme. Both drugs at the selected dose levels showed no effect on level of MDA, GSH and SOD activity. Conclusion:u2003Irradiation of animals caused a marked change in the inflammatory response in AIA model of inflammation. Both celecoxib and diclofenac were nearly equipotent in suppressing the inflammatory response in both normal and irradiated rats. Accordingly, since the inhibition of COX-1 by traditional NSAID is thought to have undesirable side-effects on proliferating tissues, it would seem preferable to use selective COX-2 inhibitors to limit such deleterious effect.

Activation of Poly(ADP-Ribose) Polymerase-1 Delays Wound Healing by Regulating Keratinocyte Migration and Production of Inflammatory Mediators

Poly(ADP-ribosyl)ation (PARylation) is a protein modification reaction regulating various diverse cellular functions ranging from metabolism, DNA repair and transcription to cell death. We set out to investigate the role of PARylation in wound healing, a highly complex process involving various cellular and humoral factors. We found that topically applied poly(ADP-ribose) polymerase (PARP) inhibitors 3-aminobenzamide and PJ-34 accelerated wound closure in a mouse model of excision wounding. Moreover, wounds also closed faster in PARP-1 knockout mice as compared with wild-type littermates. Immunofluorescent staining for poly(ADP-ribose) (PAR) indicated increased PAR synthesis in scattered cells of the wound bed. Expression of interleukin (IL)-6, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase and matrix metalloproteinase-9 was lower in the wounds of PARP-1 knockout mice as compared with control, and expression of IL-1 β, cyclooxygenase-2, TIMP-1 and -2 also were affected. The level of nitrotyrosine (a marker of nitrating stress) was lower in the wounds of PARP-1 knockout animals as compared with controls. In vitro scratch assays revealed significantly faster migration of keratinocytes treated with 3-aminobenzamide or PJ34 as compared with control cells. These data suggest that PARylation by PARP-1 slows down the wound healing process by increasing the production of inflammatory mediators and nitrating stress and by slowing the migration of keratinocytes.

Neuroprotective effect of EGb761® and low-dose whole-body γ-irradiation in a rat model of Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. The present study was undertaken to investigate the pretreatment effects of standardized Ginkgo biloba extract (EGb761®) and low-dose whole-body γ-irradiation on the neurological dysfunction in the reserpine model of PD. Male Wistar rats were pretreated orally with EGb761 or fractionated low-dose whole-body γ-irradiation or their combination, then subjected to intraperitoneal injection of reserpine (5 mg/kg body weight) 24 h after the final dose of EGb761 or radiation. Reserpine injection resulted in the depletion of striatal dopamine (DA) level, increased catalepsy score, increased oxidative stress indicated via depletion of glutathione (GSH), increased malondialdehyde (MDA) and iron levels, decreased DA metabolites metabolizing enzymes; indicated by inhibition by glutathione-S-transferase, and nicotinamide adenine dinucleotide phosphate (NADPH)-quinone oxidoreductase (NQO) activities, mitochondrial dysfunction; indicated by declined complex I activity, and adenosine triphosphate (ATP) level and increased apoptosis; indicated by decreased mitochondrial B cell lymphoma-2 (Bcl-2) protein level and by transmission electron microscope. EGb761 and low-dose γ-radiation ameliorated the reserpine-induced state of oxidative stress, mitochondrial dysfunction, and apoptosis in brain. It can be concluded that EGb761, a widely used herbal medicine and low dose of γ-irradiation have protective effects for combating Parkinsonism possibly via replenishment of GSH levels.

Potential efficacy of dopamine loaded-PVP/PAA nanogel in experimental models of Parkinsonism: Possible disease modifying activity

This study aimed to investigate the ability of dopamine (DA)-loaded polyvinylpyrrolidone-poly(acrylic acid) (PVP/PAAc) nanogel [synthesized by gamma (γ) radiation-induced template polymerization] [Nano-DA] to deliver DA across the blood brain barrier, and to evaluate the efficacy and safety of the acute and subchronic administration of Nano-DA in modulating motor activity and/or the biochemical changes in rat brain; induced by different models of Parkinsonism. In this respect, (PVP/PAAc) nanogel was synthesized by gamma radiation-induced polymerization of acrylic acid (AAc) in an aqueous solution of PVP as a template polymer, and then, it was used as a nano-drug carrier for DA. The PVP/PAAc and (PVP/PAAc loaded-DA nanogel particles were characterized by dynamic light scattering, infrared spectroscopy, and field emission-scanning electron microscopy. The loaded gel was administered in different doses and dosing regimens to Parkinsonian rats, and the catalepsy score and striatal DA levels were assessed. Then, the potential disease-modifying activity of this form of DA was investigated, through the assessment of the improvement in mitochondrial function, following the subchronic administration of Nano-DA to Parkinsonian rats. Significant disease-modifying effects were observed upon the administration of Nano-DA; in addition to normalization in their motor activity.

Protective effect of the herbal preparation, STW 5, against intestinal damage induced by gamma radiation in rats

Abstract Purpose: STW 5 (marketed as Iberogast®, Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany) is a herbal preparation reported to possess anti-inflammatory properties and antioxidant activity. We investigated the effect of STW 5 against intestinal injury induced after whole body exposure to ionizing radiation (IR). Materials and methods: Intestinal mucositis was induced in rats by irradiation at a level of 6 Gy. STW 5 (5 ml/kg) was delivered orally for 5 days before irradiation and 2 days after. Rats were sacrificed, jejunum homogenates were tested to assess biochemical parameters indicating intestinal injury and jejunum segments were exposed to semi-quantitative histological examination. Results: IR led to an increase in overall damage severity (ODS) score associated with a significant rise in tumor necrosis factor (TNF-α) and thiobarbituric acid reactive substances (TBARS) by 46% and 50% (p ≤ 0.05), respectively, whereas the reduced glutathione (GSH), sucrase and alkaline phosphatase enzyme activities were significantly decreased by 68%, 76% and 25% (p ≤ 0.05), respectively, in intestinal homogenates. IR led to a reduction of plasma citrulline. Pre-treatment with STW 5 guarded against the changes in ODS score and in all parameters measured. Conclusion: Pre-treatment with STW 5 has the potential to decrease the severity of radiation-induced mucositis.

A multi-component herbal preparation, STW 5, shows anti-apoptotic effects in radiation induced intestinal mucositis in rats

PURPOSEnIntestinal mucositis is a common adverse effect in patients undergoing radiotherapy and constitutes a treatment-limiting condition. Since no agents are yet known that can adequately guard against its development, the search continues to find safe and effective measures. The present study was intended to investigate whether the herbal preparation, STW 5, could offer a potentially effective agent in this respect.nnnMETHODSnIntestinal mucositis was induced in rats by exposing them to whole body gamma-irradiation (6 Gy). Rats were treated orally with STW 5 (5 or 10 ml/kg) for five days before and two days after irradiation. One day later, rats were sacrificed and segments of small intestine were examined histologically. Intestinal homogenates and serum samples were used to assess relevant parameters for apoptosis and different markers for inflammation and oxidative stress.nnnRESULTSnExposure to radiation produced dose-dependent extents of intestinal injury associated with apoptotic changes with high radiation levels. Apoptosis was associated with an increase in cytosolic calcium, depletion of mitochondrial cytochrome c, B-cell lymphoma-2 and complex I. Oxidative stress parameters (reduced glutathione, thiobarbituric acid reactive substance and total nitrate/nitrite) were deranged. Inflammation markers (tumor necrosis factor and myeloperoxidase) and indices of intestinal damage (serum diamine oxidase) were increased. STW 5 protected to a large extent against histological changes and counteracted the deranged parameters.nnnCONCLUSIONnThe findings provide experimental evidence for the potential beneficial use of STW5 in protecting against the development of radiation-induced intestinal mucositis and associated changes in tissue biomarkers.

Anti-ulcerogenic effect of aqueous propolis extract and the influence of radiation exposure.

Abstract Purpose: To study the effect of aqueous propolis extract (AEP) against indomethacin (Indo)-induced gastric ulcers in irradiated and non-irradiated rats. Materials and methods: Animals were irradiated at different radiation dose levels before the induction of ulcers. AEP was injected orally 1 hour before induction of gastric ulcers and the effects compared with those of lansoprazole (Lanso), which was used as a reference anti-ulcerogenic drug. Results: Pretreatment of rats, either irradiated or non-irradiated, with AEP effectively protected against Indo-induced gastric ulceration. This was associated with a reduction in acid output and peptic activity and an increase in the secretion of mucin. The mucosal prostaglandin E2 (PGE2) level was also increased. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) were suppressed to the same extent after treatment. Both propolis and Lanso were effective in reducing the number of gastric lesions as well as the plasma level of malondialdehyde (MDA). Conclusions: These findings indicate that the gastroprotective effect of AEP could be of value in the management of excessive gastric damage induced by radiation exposure.

The influence of irradiation on the potential chondroprotective effect of aqueous extract of propolis in rats.

Purpose:u2003Cartilage degradation usually results as a consequence of inflammatory processes in the joints. To study this phenomenon experimentally, adjuvant-induced arthritis (AIA) was used as a model of chronic inflammation under the influence of irradiation. The potential chondroprotective effect of 13% aqueous extract of propolis (AEP) in arthritic rats was investigated. Materials and methods:u2003The influence of whole body irradiation on the arthritic inflammatory response was investigated by subjecting rats to a Gamma source before the induction of arthritis. 13% AEP was injected intraperitoneally in a dose of 5 ml/kg and diclofenac was used as reference non-steroidal anti-inflammatory drug (NSAID) in a dose of 3 mg/kg. The chosen parameters for cartilage integrity were glycosaminoglycan (GAG), hydroxyproline contents in cartilage and cartilage oligomeric matrix protein (COMP) in serum. The serum levels of tumour necrosis factor-alpha (TNF-α), nitric oxide (NO) and the oxidative stress biomarkers such as blood glutathione (GSH) and plasma malondialdehyde (MDA) levels. Results:u2003Induction of arthritis led to a reduction in GAG and hydroxyproline content of femoral cartilage and a corresponding rise in COMP in serum. Previous exposure to irradiation resulted in a milder reduction of GAG and hydroxyproline and a lesser rise in COMP. Treatment of arthritic irradiated and non-irradiated rats with 13% AEP markedly prevented the breakdown of cartilage in a much more effective manner than diclofenac. Both AEP and diclofenac were equipotent in reducing the level of TNF-α and were able to normalize NO and the oxidative stress biomarkers in non-irradiated and irradiated arthritic rats. Conclusion:u2003The ability of propolis to protect cartilage degradation could therefore prove of value in the treatment of chronic arthritic diseases, offering an advantage over some NSAID, particularly those with a potential detrimental effect on cartilage integrity.

Effect of Long-Term Treatment with Fluoxetine, Clomipramine and St. John's Wort Extract on Bone Turnover in Female Irradiated Rats.

Aim: The study aimed at evaluating the bone turnover rate in irradiated female rats treated daily with fluoxetine, clomipramine or St. John’s wort extract for 8 weeks. Material and Methods: 40 rats were randomly classified into 5 experimental groups: normal, irradiated control, irradiated fluoxetine, irradiated clomipramine and irradiated St. John’s wort extract treated groups. The irradiated animals were exposed to a total dose of 15 Gy, fractionated over 5 weeks to small doses each of 1 Gy (day after day). Bone turnover rate biomarkers [serum osteocalcin (OC), urinary hydroxyproline/ creatinine ratio (Hpr/ Cr), urinary calcium/creatinine ratio (Ca/Cr)], hypothalamic pituitary adrenal [serum corticosterone], thyroid activities [serum thyroxin (T4) and thyrotrophin (TSH)], antioxidant [serum total antioxidant capacity (TAC) and malondialdehyde (MDA)] and pro-inflammatory biomarkers [serum tumor necrosis factor-alpha (TNF-α)] were done after 8 weeks from the 1st exposure to radiation. Histopathological investigations were also performed. Results: The present results revealed that irradiation induced a significant decrease in serum OC by 43.6%, and a significant increase of Hpr/ Cr and Ca/Cr by 186.4% and 192.4%, respectively. Irradiated rats showed also a significant increase in serum corticosterone, TNF-α and MDA as well as a significant decrease in serum T4, TSH levels and TAC. Treatment of irradiated rats with St. John’s wort extract, fluoxetine or clomipramine ameliorated most of the changes caused by bone-irradiation. The latter findings were confirmed by histological examination of bone tissue. Conclusions: St. John’s wort extract offers a therapeutic potential on bone comparable to traditional antidepressants like fluoxetine or clomipramine in irradiated female rats.