Pelargonidin ameliorates reserpine-induced neuronal mitochondrial dysfunction and apoptotic cascade: a comparative in vivo study.

BACKGROUND: Targeting the neuronal mitochondria as a possible intervention to guard against neurodegenerative disorder progression has been investigated in the current work via the administration of pelargonidin (PEL) to rats intoxicated by the mitochondrial toxin reserpine. The main criteria for choosing PEL were its reported antioxidant, anti-apoptotic and anti-inflammatory activities. METHODS: Male albino Wistar rats were randomized into five experimental groups; normal control, reserpinized to induce mitochondrial failure, standard PARP-1-inhibitor 1,5-isoquinolinediol (DIQ)-treated reserpinized, PEL-treated reserpinized, and GSK-3ß inhibitor (AR-A 014418) -treated reserpinized. RESULTS: PEL administration reversed the reserpine-induced abnormal behaviors marked by decreased catalepsy time. In addition, PEL restored brain glutathione with a reduction in nitric oxide content as compared to the reserpine-challenged group. Meanwhile, it improved neuronal mitochondrial function by the elevation of complex I activity associated with a low ADP/ATP ratio. Likely through its anti-inflammatory effect, PEL reduced the elevation of serum interleukin-1ß level and inhibited serum lactate dehydrogenase activity. These findings are aligned with the reduced expression of cleaved PARP and cleaved caspase-3 proteins, indicating PEL's suppressive effect on the intrinsic apoptotic pathway. Those biochemical findings were confirmed through comparable histopathological tissue examination among the experimental groups. CONCLUSIONS: In conclusion, PEL is a promising candidate for future use in the management of mitochondria-associated neuronal complications via controlling the ongoing inflammatory and degeneration cascades.

Anti-apoptotic and antioxidant effects of low dose gamma irradiation against diabetes-induced brain injury in rats.

The current study aimed to investigate the effect of different low doses of gamma irradiation on hyperglycemia-induced brain injury. The aim was further extended to investigate the sub-chronic effect of low dose radiation on the neuronal damage induced by diabetes. To induce diabetes, male albino rats were injected with dexamethasone (10 mg/kg/day, for 9 successive days, subcutaneously). Different diabetic groups were irradiated with 0.1, 0.25 and 0.5 Gy. The effect of low dose gamma irradiation on the hyperglycemia-induced brain damage based was analyzed at two levels: oxidative stress and apoptosis. The brain contents of glutathione, malondialdhyde and total nitrate/nitrite were measured to assess the oxidative stress. In order to evaluate the extent of the apoptotic changes in brain, tissue caspase-3 expression was detected using immunohistochemistry and the degree of DNA fragmentation was estimated. Moreover, brain tissues were examined using light microscopy to evaluate the histological changes in different groups and serum lactate dehydrogenase activity was determined as an indicator for the brain tissue damage. Results indicated that exposure to 0.5 Gy ameliorated the hyperglycemia and subsequently inhibited oxidative stress and apoptosis. Radiation exposure at this dose level also increased the survival rate of diabetic animals.

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.

Immune system modulation by low-dose ionizing radiation-induced adaptive response.

OBJECTIVE: Hormesis or low-dose ionizing radiation is known to induce various biological responses, a subcategory of which is the adaptive response, which has been reported to protect against higher radiation doses via multiple mechanisms. This study investigated the role of the cell-mediated immunological component of low-dose ionizing radiation-induced adaptive response. METHODS: Herein, male albino rats were exposed to whole-body gamma radiation, using a Cs137 source with low-dose ionizing radiation doses of 0.25 and 0.5 Gray (Gy); 14 days later, another irradiation session at a dose level of 5 Gy was carried on. Four days post-irradiation at 5 Gy, rats were sacrificed. The low-dose ionizing radiation-induced immuno-radiological response has been assessed through the T-cell receptor (TCR) gene expression quantification. Also, the serum levels of each of interleukins-2 and -10 (IL-2, IL-10), transforming growth factor-beta (TGF-ß), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were quantified. RESULTS: Results indicated that priming low irradiation doses resulted in significant decrements in TCR gene expression and the serum levels of IL-2, TGF-ß, and 8-OHdG with an increment in IL-10 expression compared to the irradiated group, which did not receive low priming doses. CONCLUSION: The observed low-dose ionizing radiation-induced radio-adaptive response significantly protected against high irradiation dose injuries, through immune suppression, representing a promising pre-clinical protocol that would be applied to minimize radiotherapy side effects on normal but not against the tumor cells.

Immuno-Biochemical Impacts of Gamma Irradiation in Male Rats: A Dose-Response Study.

During radiotherapy, immune-modulatory effects of radiation doses should be taken into consideration, not only the anti-tumor radiation effects. Thus, our study aimed to study how γ-radiation modulates immune response in comparison to common immune-suppressive/stimulant agents. Animals were divided into two groups. Category A received Echinacea purpura extract (EP) or irradiated at low radiation doses 0, .25 or .5 Gray (Gy), whereas Category B received cyclophosphamide (CP) or irradiated at high radiation doses 1, 2, or 5 Gy. Serum levels of immunological mediators interleukin-10 (IL-10) and tumor necrosis factor (TNF-α), as well as redox-markers malondialdehyde (MDA) and nitric oxide (NO), hemoglobin (Hgb), white and red blood cells (WBCs, RBCs), and platelet counts were assessed following irradiation. Of the immune-stimulant category, .25 Gy dose offered EP-comparable effects in TNF-α, RBCs, Hgb, and platelet counts cases. As for the immune-suppressive category; 5 Gy irradiation dose induced inflammatory/immunosuppressive responses indicated (rise in NO, TNF-α, and IL-10), and an oxidative stress status (increase in serum MDA). However, 5 Gy γ-irradiation was not observed, herein, as a single immunosuppressive agent. To conclude, during radiotherapy, immunological impact(s) of the used radiation doses should be optimized and followed-up closely to assess the risk/benefit of their usage.

Molecular mechanisms involved in the effects of morin in experimental hepatic encephalopathy.

This study aimed to investigate the possible usefulness of morin flavonoid in comparison to silymarin as a hepatic/neuronal-supportive agent with similar effects and higher bioavailability in a rat model of hepatic encephalopathy (HE). Morin effects on rat liver and brain were evaluated post-induction of HE by thioacetamide (TAA; 200 mg/kg/day for 3 successive days). Then, the serum activities of aspartate transaminase (AST) and alanine transaminase (ALT) together with ammonia concentration were estimated to assess the liver function. Also, the degree of brain effects was evaluated via the assessment of brain contents of reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and interleukin (IL-1ß) together with glutathione peroxidase (GPx) activity. In addition, the apoptotic and inflammatory changes in brain and liver tissues were also assessed via immunohistochemical examination. Our findings revealed a promising effect of morin against HE complications; as it corrected the liver functions, attenuated the brain/liver tissue injuries, and reduced the apoptotic and inflammatory insults of HE on both organs. These effects are comparable to those of silymarin. Morin could be introduced as a promising hepato- and neuro-therapeutic adjuvant in HE-associated neuronal complications especially in cases like silymarin intolerance.

Synthesis of novel benzothiophene derivatives as protectors against cranial irradiation-induced neuroinflammation.

Aim: Cranial irradiation results in many deleterious effects to normal tissues, including neuroinflammation. There is a need to explore radioprotective agents that could be safely used to ameliorate these effects. Method: Nine novel benzothiophene derivatives bearing pyrimidinone, pyrazolidinone, triazole and other active moieties were synthesized and evaluated as antioxidants in an in vitro screening experiment. The most potent compounds were then tested as protectors against radiation-induced neuroinflammation and oxidative stress in rat brains following cranial irradiation. Results: The most potent antioxidant compounds were compounds 3-5 and 10 . P-fluro,p- bromo and pyrido benzothiophene derivatives offered good antioxidant and anti-inflammatory effects. Conclusion: Compounds 3-5 may be introduced as nontoxic candidates for adjuvant therapeutic protocols used in head and neck tumor radiotherapeutic management.

Platelet-rich plasma-induced feedback inhibition of activin A/follistatin signaling: A mechanism for tumor-low risk skin rejuvenation in irradiated rats.

BACKGROUND: Platelet-rich plasma (PRP) is a source of natural growth factors and is emerging as a treatment modality to mitigate radiotherapy- induced adverse effects. Activin A (ACTA) is a member of the transforming growth factor-ß (TGF-ß) superfamily, which has been shown to modulate the inflammatory response and macrophages polarization between different phenotypes. The aim of this study is to determine the value of PRP in preventing radiation-induced malignancies in light of the cross-talk between PRP and activin A type II receptors (ActR-IIA)/follistatin (FST) signaling pathways where the inflammatory responses at 2 different time points were evaluated. MATERIAL AND METHODS: Male albino rats were exposed to radiation and given PRP over the course of 6 days. Rats were sacrificed on day 7 or day 28 post radiation. RESULTS: Quantitative real-time reverse transcriptase polymerase chain reaction (QRT-PCR) and western-blot showed that after 7 days of administrating of PRP, ActR-IIA/FST signaling was markedly induced and was associated with the expressions of inflammatory, natural killer and M1 macrophages markers, TNF-α, IL-1ß, IFN-γ and IL-12. By contrast, on day 28 of PRP administration, ActR-IIA/FST signaling and the expressions of proinflammatory cytokines were downregulated in parallel with inducing M2 macrophages phenotype as indicated by arginase-1, IL-10 and dectin-1. CONCLUSION: The suppression of inflammation and induction of M2 macrophages phenotype in response to PRP administration were found significantly linked to ActR-IIA/FST signaling downregulation. Furthermore, the specific M2 macrophage subtype was found to express dectin-1 receptors which have high affinity for tumor cells thereby is expected to reduce the potential for developing tumors after radiotherapy.

Semi-synthetic thymoquinone analogs: new prototypes as potential antihyperlipidemics in irradiated rats.

AIM: Thymoquinone (TQ), has been reported to possess strong antihyperlipidemic properties. However, a variety of serious side effects has been reported for TQ. The present study aimed to evaluate the potential antihyperlipidemic activity of newly synthesized TQ analogs. METHODS & RESULTS: first, novel TQ derivatives were studied against radiation-induced dyslipidemia in male rats. Second, the most promising sulfur derivatives (4-7), were further tested to elucidate their possible mechanism(s) of actions. Results showed that they possess Hydroxymethyl Glutaryl-Co A reductase inhibitory activity, as well as stimulatory effects on the activities of each of plasma Lecithin-Cholesterol Acyltransferase and lipoprotein lipase enzymes. CONCLUSION: TQ derivatives (4-7), could be considered as promising agents in pathologies implicating impaired lipid metabolism, preclinical evaluation is warranted. [Formula: see text].

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.

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

PURPOSE: To 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: Cerebral ischemia was induced in male Wistar rats (either irradiated or non-irradiated) followed by reperfusion. RESULTS: I/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 (Ca(2+)) 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-1ß (IL-1ß). Moreover, induction of I/R in irradiated rats resulted in a further increase in brain oxidative stress and cytosolic LDH activity, disturbed brain Ca(2+) 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 Ca(2+) 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-1ß. CONCLUSION: These 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.