Inhibition of neuroinflammation and neuronal damage by the selective non-steroidal ERß agonist AC-186.

BACKGROUND: AC-186 (4-[4-4-Difluoro-1-(2-fluorophenyl) cyclohexyl] phenol) is a neuroprotective non-steroidal selective oestrogen receptor modulator. This study investigated whether inhibition of neuroinflammation contributed to neuroprotective activity of this compound. METHODS: BV-2 microglia were treated with AC-186 (0.65-5 µM) prior to stimulation with LPS (100 ng/mL). Levels of pro-inflammatory mediators and proteins were then evaluated. RESULTS: Treatment of LPS-activated BV-2 microglia with AC-186 resulted in significant (p < 0.05) reduction in TNFα, IL-6, NO, PGE2, iNOS and COX-2. Further investigations showed that AC-186 decreased LPS-induced elevated levels of phospho-p65, phospho-IκBα and acetyl-p65 proteins, while blocking DNA binding and luciferase activity of NF-κB. AC-186 induced significant (p < 0.05) increase in protein expression of ERß, while enhancing ERE luciferase activity in BV-2 cells. Effects of the compound on oestrogen signalling in the microglia was confirmed in knockdown experiments which revealed a loss of anti-inflammatory activity following transfection with ERß siRNA. In vitro neuroprotective activity of AC-186 was demonstrated by inhibition of activated microglia-mediated damage to HT-22 neurons. CONCLUSIONS: This study established that AC-186 produces NF-κB-mediated anti-inflammatory activity, which is proposed as a contributory mechanism involved in its neuroprotective actions. It is suggested that the anti-inflammatory activity of this compound is linked to its agonist effect on ERß.

Oral thymoquinone modulates cyclophosphamide-induced testicular toxicity in adolescent Wistar rats.

Cyclophosphamide (CYP) is an effective anti-cancer drug that is widely accepted, but it is not devoid of unintended toxic effects. Gonadal toxicity is reported as one of the side effects of its long-time use. This study examined the effects of thymoquinone (TQ) on the biological integrities of the testes after cyclophosphamide exposure. Thirty adolescent male Wistar rats (100-110 g) were divided into six groups (n = 5), receiving normal saline (NS), 20 mg/kg of CYP (CYP), 5 mg/kg of TQ (TQ5), 10 mg/kg of TQ (TQ10), 20 mg/kg of CYP and 5 mg/kg of TQ (CTQ5), and 20 mg/kg of CYP and 10 mg/kg of TQ (CTQ10) respectively. On the 22nd day, blood, semen and testicular samples were collected for the assay of serum reproductive hormones (follicle-stimulating (FSH) and luteinizing (LH) hormones), semen analysis and testicular histology and proliferating cell nuclear antigen (PCNA) expression. The results revealed that CYP exposure affected functional and structural integrities of the testes, by depleting sperm count and motility, testosterone, LH, spermatogenic and mature sperm cell population, Leydig cells and PCNA immunoreactive proliferating cells. TQ interventions were able to reverse all cytotoxic CYP impacts, but with differential activities on the hormonal concentrations, specifically LH and FSH. Cumulatively, thymoquinone may be a potent agent against cyclophosphamide effects on the physiological, regeneration and histological integrities of the testes, as observed in this study.

Testicular microanatomical and hormonal alterations following use of antiretroviral therapy in Sprague Dawley rats: Role of Naringenin.

Human immunodeficiency virus-infected man may require assisted reproductive technology not just for safer conception but also due to subfertility. The study investigated the effect of antiretroviral drugs on the fertility potentials of males and the possible protective role of Naringenin, using Sprague Dawley rats. Thirty adult male Sprague Dawley rats were grouped into-A: Distilled water; B: Highly Active Antiretroviral Therapy (HAART); C: Naringenin 40 mg/kg; D: Naringenin 80 mg/kg, E: HAART + Naringenin 40 mg/kg; F: HAART + Naringenin 80 mg/kg. The rats were euthanised after 10 weeks. Results showed a significant decrease in sperm count in group B when compared to the control and other groups. Spermatozoa with normal morphology also reduced significantly in the B group and progressive sperm motility reduced when compared to the control, D and the F group. The serum testosterone was not significantly different between groups A and B, however the groups C and D displayed significant increase when compared to groups A and B. The serum luteinising hormone was significantly higher in group B when compared to groups A, E and F. Our data suggest that Naringenin improves the male reproductive anatomy and function, therefore, it promises to be a beneficial adjuvant for mitigating HAART testicular and reproductive perturbations.

Phoenix dactylifera and polyphenols ameliorated monosodium glutamate toxicity in the dentate gyrus of Wistar rats.

Monosodium glutamate (MSG) has been known to cause neurodegeneration, due to its ability to trigger excitotoxicity, and the hippocampus is one of the most affected regions. Therefore, Phoenix dactylifera (P. dactylifera) and polyphenols was employed in this study to mitigate on the deleterious effect of monosodium glutamate on the dentate gyrus of Wistar rats. Forty-eight male Wistar rats weighing between 120-150g was used for the study. The Wistar rats were grouped into eight, (n=6). Groups 1-8 received 1.6mL/kg normal saline, 4000mg\kg monosodium glutamate for 7-days, 4000mg\kg monosodium glutamate for 7-days and 100mg\kg caffeic-acid for 14-days concurrently, 4000mg\kg monosodium glutamate for 7-days and 100mg\kg Phoenix dactylifera for 14-days concurrently, 4000mg\kg monosodium glutamate for 7-days and 100mg\kg luteolin for 14-days concurrently, 100mg\kg. caffeic-acid for 14-days followed by 4000mg\kg monosodium glutamate for 7-days, 100mg\kg Phoenix dactylifera for 14-days followed by 4000mg\kg monosodium glutamate for 7-days and 100mg\kg luteolin for 14-days followed by 4000mg\kg monosodium glutamate for 7-days respectively. After the treatments, the rats underwent behavioural tests, and subsequently, the brain tissues were processed for histological and biochemical analyses. The activities of P. dactylifera and polyphenols ameliorated the deleterious effect of monosodium glutamate, through increased spontaneous alternation of the experimental animals, dominant matured granule cells of the dentate gyrus and modulated the activities of superoxide dismutase, glutathione peroxidase and malondialdehyde in the of male Wistar rats. Therefore, this study revealed that P. dactylifera and polyphenols ameliorated monosodium glutamate toxicity in the dentate gyrus of Wistar rats.

Effect of long-term administration of Cinnamomum cassia silver nanoparticles on organs (kidneys and liver) of Sprague-Dawley rats.

This study investigated the toxic effects of silver on the kidneys and livers of Sprague-Dawley rats after administering multiple doses of silver nanoparticles synthesized using extracts of Cinnamomum cassia (CcAgNPs). Twenty-four Sprague-Dawley rats (250 ± 20 g) were randomly assigned to four groups (A-D) of six animals per group and treated for 8 weeks. Group A was administered 200 mg/kg of Cinnamon Cassia extract (Cc), group B 5 mg/kg of CcAgNPs, group C 10 mg/kg of CcAgNPs, and group D normal saline. Body weight was measured weekly and fasting blood glucose was measured fortnightly. At the end of the experiment, animals were euthanized and organs (livers and kidneys) were fixed in neutral buffered formalin and processed for light microscopy (H&E). Body weight differences were significantly higher (P < 0.05) in the low-dose Cc group and the kidney to body weight ratio was not significant. Renal function analysis of proteins and ketones showed a significant increase in CcAgNP-treated rats (P < 0.05). Kidney and liver histology showed distortions in hepatocytes and sinusoidal linings with infiltrations especially in the higher dose groups. Kidney histology mirrored degenerative changes in glomerular and Bowman's capsules with bfirillary mesangial interstitium. CcAgNPs impairs renal and hepatic morphology and function after a long period of administration.

Testicular 3beta hydroxysteroid dehydrogenase in naringenin adjuvant under highly active antiretroviral therapy (HAART); preliminary data using Sprague-Dawley rats

HAART has brought relief to many living with HIV/AIDS, decreasing morbidity and mortality rates. In spite of these benefits, the treatment has been associated with reproductive disorders. This study is aimed at investigating the effects of Naringenin (Nar) on the expression of testicular 3ß-Hydroxysteroid dehydrogenase (3ß HSD) in HAART-treated Sprague-Dawley rats. 30 adult male Sprague-Dawley rats were randomly divided into six groups. The rats were fed with 30 mg/kg of HAART (Efavirenz+Embtricitabine+Tenofovir), 40mg/kg and 80 mg/kg of Nar and a combination of both HAART and Nar for a period of 70 days. Thereafter, the animals were euthanized and the testes processed. The results showed a significant decrease (p<0.05) in the expression of 3ß HSD in the HAART group compared to controls. However, the co-treatment of HAART with 40 mg/kg Nar increased significantly (p<0.05) the expression of 3ß HSD, compared to HAART and control. The relative volume fraction also showed significant increase (p<0.05) in germinal epithelium, lumen and Leydig cells of animals treated with 80 mg/kg Nar, and HAART+40 mg/kg Nar compared to control and HAART respectively. In conclusion, HAART is causes a deficiency in testicular 3ß HSD, thereby limiting spermatogenesis. However, co-treatment with 40 mg/kg Naringenin increases testicular 3ß HSD expression and enhances spermatogenesis

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