Buspirone attenuated methotrexate-induced hippocampal toxicity in rats by regulating Nrf2/HO-1, PPAR-γ, NF-κB/nNOS, and ROS/NLRP3/caspase-1 signaling pathways.

Methotrexate (MTX) is a chemotherapeutic agent widely used to treat a variety of tumors. Nonetheless, MTX-induced hippocampal neurotoxicity is a well-defined dose-limiting adverse effect that limits clinical utility. Proinflammatory cytokine production and oxidative stress are possible mechanisms for MTX-induced neurotoxicity. Buspirone (BSP), a partial agonist of the 5-HT1a receptor (5-HT1aR), has emerged as an anxiolytic drug. BSP has been shown to possess antioxidant and anti-inflammatory effects. The current study investigated BSP's potential anti-inflammatory and antioxidant effects in attenuating MTX-induced hippocampal toxicity. Rats received either BSP (1.5 mg/kg) orally for 10 days and MTX (20 mg/kg) i.p. on Day 5. BSP administration markedly protected hippocampal neurons from drastic degenerated neuronal changes induced by MTX. BSP significantly attenuated oxidative injury by downregulating Kelch-like ECH-associated protein 1 expression while potently elevating hippocampal Nrf2, heme oxygenase-1, and peroxisome proliferator-activated receptor expression. BSP dampened inflammation by reducing NO2 - , tumor necrosis factor-alpha, IL-6, and interleukin 1 beta levels mediated by downregulating NF-κB and neuronal nitric oxides synthase expression. Moreover, BSP potently counteracted hippocampal pyroptosis by downregulating NLRP3, ASC, and cleaved-caspase-1 proteins. Therefore, BSP may represent a promising approach to attenuate neurotoxicity in patients receiving MTX.

Accelerating Effect of Cucurbita pepo L. Fruit Extract on Excisional Wound Healing in Depressed Rats Is Mediated through Its Anti-Inflammatory and Antioxidant Effects.

Background: Chronic stress can hinder wound healing as it suppresses both the cellular and innate immune responses. Objectives: The study aims to assess the effectiveness of the administration of topical and oral Cucurbita pepo L. (CP) ethanolic extract in prompting excisional wound healing in rats exposed to chronic stress, and to explain how it works. Materials and methods: Fifty albino rats assigned to five groups (n = 10) were utilized in this study. The chronic unpredictable mild stress (CUMS) model was used for 4 weeks to induce depressive-like behavior in rats, and a forced swim test and corticosterone were assessed to confirm its occurrence. During the experiment, an excisional wound was induced in the rats and followed. Oxidant/antioxidants status and pro-inflammatory cytokines levels were measured in the serum and wound area. Gene expression of pro-inflammatory cytokines was also assessed using RT-PCR. Wound closure histopathological changes and immunohistochemical expression of CD68, CD3, and CD4 at the wound area was assessed. Results: The administration of CP, both orally and topically, significantly reduced (p < 0.001) the depressive-like behavior and corticosterone and pro-inflammatory cytokines levels, while it significantly up-regulated the antioxidant activity compared to the untreated and topically CP-treated groups. Both topically CP-treated and combined CP-treated groups showed complete re-epithelialization, reduced inflammatory cells infiltration, collagen fibers deposition, and significantly increased CD3, CD4 positive T cells count, with a superior effect in the combined CP-treated groups. Conclusion: Cucurbita pepo L., administrated both topically and orally, can enhance the wound healing process in rats with depressive-like behavior mostly through the antioxidant, anti-inflammatory, and antidepressant activities observed in this study.

Influence of halloysite nanotubes on the efficiency of Asparaginase against mice Ehrlich solid carcinoma.

Herein, the impact of the halloysite nanotubes to suppress the side effects of Asparaginase (ANase) cellular proliferation was investigated. Methods: A total of 100 adult male mice was employed. These mice were divided into four equal groups; Group 1 (control), Group 2 (ESC group) of a single dose of 0.15 ml Ehrlich cells (2 × 106) intraperitoneal infusion(IP), Group 3 (ESC + ANase group) received six doses equal treatments of Intratumoral (IT) 0.07 ml Aspragnase (7 mg/kg) over two weeks. For two weeks, Group 4 (ESC + ASNase + HNTs) received an IT administration of 0.07 ml Asparaginase stocked on Halloysite nanotubes (HNTs) (30 mg/kg) three times per week. A blood specimen was collected, and the liver was removed to be investigated histologically. Results: TEM measurements for the Halloysite nanoclay showed their tubular cylindrical shape with a mean diameter of 50 nm and an average length of 1 µm, whereas The X-ray diffraction pattern of the Halloysite nanoclay showed their characteristic peaks. ESC increases the serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin than control and other groups, even as albumin and total protein were decreasing. After using Halloysite Nanotube, the rates of these variables were enhanced up to 75%. The hepatocytes histological studies showed protection against Ehrlich Solid carcinoma-induced degenerative, necrotic, and inflammatory changes up to 70%. In conclusion, halloysite nanotubes have demonstrated effective removal of Ehrlich solid carcinoma in mice using an ASNase delivery system. It promoted the ASNase to inhibit the adverse effect of ANase's on the liver and remove the tumour cells.

Ginkgo biloba extract mitigates the neurotoxicity of AlCl3 in alzheimer rat's model: role of apolipoprotein E4 and clusterin genes in stimulating ROS generation and apoptosis.

PURPOSE: Alzheimer's disease (AD) appears as a result of an increase in the accumulation of amyloid beta peptide (Aß) and a decrease in neurotransmitters (acetylcholine) within the brain cells which may be due to increase in acetylcholinesterase (AchE) activity and change in expression of Apolipoprotein E4 (ApoE4) and Clusterin (Clu) genes. The aim of the present study was using natural products such as Ginkgo biloba (G. biloba) extract that has the potential to reduce Aß formation and increase AchE inhibition with its ability to save neuronal DNA from damage. METHODS: Sixty male aged rats were divided into six experimental groups exposed to AlCl3 to induce AD model and were treated with G. biloba extract. Collected brain tissues were used to assess the apoptosis rate, reactive oxygen species (ROS) generation, AchE inhibitory activity, expression alteration in ApoE4 and Clu genes, DNA fragmentations and gutathione peroxidase (GPx) activity.Results: The results exhibited that rats exposed to AlCl3 increased significantly rate of apoptosis, ROS formation, DNA fragmentation, up-regulation of ApoE4 and Clu genes as well as decrease of AchE inhibitory activity and GPx activity compared with those in control rats. However, treatment of AlCl3-rats with G. biloba extract improved the above neurotoxicity results induced by AlCl3 exposure. CONCLUSIONS: It is therefore likely that G. biloba extract's protective properties against AD are due to its ability to activate the response against oxidative stress.

An Ethanolic Extract of Cucurbita pepo L. Seeds Modifies Neuroendocrine Disruption in Chronic Stressed Rats and Adrenal Expression of Inflammatory Markers and HSP70.

Background: Pumpkins (Cucurbita pepo L.) were described to have antioxidant, anti-inflammatory, anti-fatigue, and antidepressant-like effect. The adrenal gland is an important stress-responsive organ that maintains homeostasis during stress. Objectives: This study aimed to assess the efficacy of the administration of Cucurbita pepo L. (CP) extract in relieving behavioral, biochemical, and structural changes in the adrenal gland induced by exposure to chronic unpredictable mild stress (CUMS) and to explore the mechanism behind this impact. Materials and Methods: Forty male albino rats were divided into 4 groups (n = 10): control, CUMS, fluoxetine-treated, and CP-treated groups. Behavioral changes, corticosterone level, pro-inflammatory cytokines TNF-α and IL-6, and oxidant/antioxidant profile were assessed in the serum at the end of the experiment. Adrenal glands were processed for histopathological and immunohistochemical assessment. Gene expression of caspase-3 and Ki67 and heat shock protein 70 (HSP70) were assessed in adrenal glands using RT-PCR. Results: The CP extract significantly reduced the corticosterone level (p < 0.001), immobility time (p < 0.001), and inflammatory and oxidative changes associated with CUMS-induced depression compared to the untreated group. The CP extract alleviated CUMS-induced adrenal histopathological changes and significantly reduced apoptosis (p < 0.001) and significantly upregulated antioxidant levels in the serum. Conclusion: Cucurbita pepo L. effectively ameliorated the chronic stress-induced behavioral, biochemical, and adrenal structural changes mostly through its antioxidant and anti-inflammatory effects.

Synergistic Anti-inflammatory and Neuroprotective Effects of Cinnamomum cassia and Zingiber officinale Alleviate Diabetes-Induced Hippocampal Changes in Male Albino Rats: Structural and Molecular Evidence.

Background: Depression has been reported as a common comorbidity in diabetes mellitus although the underlying mechanism responsible for this is not well known. Although both ginger and cinnamon has anti-diabetic, antioxidant, and neuroprotective properties, their efficacy in inhibiting neuroinflammation, when simultaneously administrated, has not been investigated yet. Objectives: The study was designed to assess the synergistic effect of Cinnamomum cassia and Zingiber officinale on regulating blood glucose, improve hippocampal structural changes and depressive-like alternations in diabetic rats, and try to identify the mechanism behind this effect. Materials and Methods: Thirty male Sprague-Dawley rats were divided into five equal groups (n = 6): the normal control, untreated streptozotocin (STZ)-diabetic, cinnamon-treated diabetic [100 mg/kg of body weight (BW)/day for 6 weeks], ginger-treated diabetic (0.5 g/kg BW/day for 6 weeks), and ginger plus cinnamon-treated diabetic groups. Forced swim test and elevated plus maze behavioral tests were performed at the end of the experiment. HOMA-IR, HOMA ß-cells, blood glucose, insulin, corticosterone, pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-6), and total anti-oxidant capacity (TAC) were assessed in the serum. BDNF mRNA level was assessed in hippocampus using qRT-PCR. Hippocampal histopathological changes were also assessed, and immunoexpression of glial fibrillary acidic protein (GFAP), caspase-3, and Ki-67 was measured. Results: Diabetes-induced depressive-like changes in the STZ group were biochemically confirmed by assessing serum corticosterone level, as well as behaviorally using FST and EPM tests. Diabetes also induced degenerative changes in the hippocampus. Treatment of diabetic rats with ginger, cinnamon, or the combination of these alleviated the degenerative structural changes and significantly up-regulated serum insulin, TAC, hippocampal BDNF mRNA, and hippocampal immunoexpression of ki67, while they significantly reduced serum blood glucose, IL-6, TNF-α, IL1ß, as well as hippocampal immunoexpression of GFAP and Caspase-3 compared to the untreated diabetic group. Improvement induced by the combination of ginger and cinnamon was superior to the single administration of either of these. Conclusion: Cinnamomum cassia and Zingiber officinale have synergistic anti-diabetic, antioxidant, anti-inflammatory, antidepressant-like, and neuroprotective effects. The use of a combination of these plants could be beneficial as alternative or complementary supplements in managing DM and decreasing its neuronal and psychiatric complications.

Musk (Moschus moschiferus) Attenuates Changes in Main Olfactory Bulb of Depressed Mice: Behavioral, Biochemical, and Histopathological Evidence.

BACKGROUND: Musk (Moschus moschiferus) has been described to have a significant impact on the central nervous system, as well as anticonvulsion and antidepressant effects. This study was designed to evaluate the efficacy of musk in alleviating alterations induced in olfactory bulb of depressed mice exposed to chronic stress and identify the mechanism behind it. METHODS: Fifty male albino mice were divided into five groups (n = 10 each): control, musk, chronic unpredictable mild stress (CUMS), fluoxetine-treated, and musk-treated groups were included in this study. Behavioral changes and serum levels of corticosterone and proinflammatory cytokines included tumor necrosis factor α, interleukin 6, and oxidant/antioxidant profile were assessed at the end of the experiment. Main olfactory bulb (MOB) has been processed for histopathological examination. Gene expression of caspase-3, glial fibrillary acidic protein, and Ki67 were assessed in the MOB using quantitative real-time polymerase chain reaction. RESULTS: The study showed that musk inhalation significantly reduced (p < 0.001) corticosterone level, immobility time, inflammatory cytokines, and oxidative stress markers in CUMS-exposed mice compared to the untreated CUMS group. Musk lessened CUMS-associated neuronal alterations in the MOB and significantly reduced apoptosis and enhanced neural cell proliferation (p < 0.001) comparable to fluoxetine. Musk significantly enhanced the level of antioxidants in the serum and significantly reduced inflammatory cytokines. The anti-inflammatory and antioxidant activity of musk and its constituents seemed to be behind its neuroprotective effect observed in this study. CONCLUSION: Musk effectively ameliorated the chronic stress-induced behavioral, biochemical, and neuronal structural changes in MOB mostly through its antioxidant and anti-inflammatory effect.