Remyelinating activities of Carvedilol or alpha lipoic acid in the Cuprizone-Induced rat model of demyelination.

Multiple sclerosis (MS) is a complex and multifactorial neurodegenerative disease with unknown etiology, MS is featured by multifocal demyelinated lesions distributed throughout the brain. It is assumed to result from an interaction between genetic and environmental factors, including nutrition. Therefore, different therapeutic approaches are aiming to stimulate remyelination which could be defined as an endogenous regeneration and repair of myelin in the central nervous system. Carvedilol is an adrenergic receptor antagonist. Alpha lipoic acid (ALA) is a well-known antioxidant. Herein, we investigated the remyelination potential of Carvedilol or ALA post-Cuprizone (CPZ) intoxication. Carvedilol or ALA (20 mg/kg/d) was administrated orally for two weeks at the end of the five weeks of CPZ (0.6%) administration. CPZ provoked demyelination, enhanced oxidative stress, and stimulated neuroinflammation. Histological investigation of CPZ-induced brains showed obvious demyelination in the corpus callosum (CC). Both Carvedilol and ALA demonstrated remyelinating activities, with corresponding upregulation of the expression of MBP and PLP, the major myelin proteins, downregulation of the expression of TNF-α and MMP-9, and decrement of serum IFN-γ levels. Moreover, both Carvedilol and ALA alleviated oxidative stress, and ameliorated muscle fatigue. This study highlights the neurotherapeutic potential of Carvedilol or ALA in CPZ-induced demyelination, and offers a better model for the exploring of neuroregenerative strategies. The current study is the first to demonstrate a pro-remyelinating activity for Carvedilol, as compared to ALA, which might represent a potential additive benefit in halting demyelination and alleviating neurotoxicity. However, we could declare that Carvedilol showed a lower neuroprotective potential than ALA.

Neurotherapeutic efficacy of loaded sulforaphane on iron oxide nanoparticles against cuprizone-induced neurotoxicity: role of MMP-9 and S100ß.

Cuprizone (CUP) induces neurotoxicity and demyelination in animal models by provoking the activation of glial cells and the generation of reactive oxygen species (ROS). Sulforaphane (SF) is a phytochemical that exhibits a neuroprotective potential. In this study, we investigated the neurotherapeutic and pro-remyelinating activities of SF and SF-loaded within iron oxide nanoparticles (IONP-SF) in CUP-exposed rats. Magnetite iron oxide nanoparticles (IONPs) were prepared using the hydrothermal method that was further loaded with SF (IONP-SF). The loading of SF within the magnetite nanoparticles was assessed using FTIR, TEM, DLS, Zetasizer, and XPS. For the in vivo investigations, adult male Wistar rats (n = 40) were administrated either on a regular diet or a diet with CUP (0.2%) for 5 weeks. The rats were divided into four groups: negative control, CUP-induced, CUP + SF, and CUP + IONP-SF. CUP-exposed brains exhibited a marked elevation in lipid peroxidation, along with a significant decrease in the activities of glutathione peroxidase (GPx), and catalase (CAT). In addition, CUP intoxication downregulated the expression of myelin basic protein (MBP) and myelin proteolipid protein (PLP), upregulated the expression of Matrix metallopeptidase-9 (MMP-9) and S100ß, and increased caspase-3 immunoexpression, these results were supported histopathologically in the cerebral cortexes. Treatment of CUP-rats with either SF or IONP-SF demonstrated remyelinating and neurotherapeutic activities. We could conclude that IONP-SF was more effective than free SF in mitigating the CUP-induced downregulation of MBP, upregulation of S100ß, and caspase-3 immunoexpression.

Sulforaphane, an Nrf-2 Agonist, Modulates Oxidative Stress and Inflammation in a Rat Model of Cuprizone-Induced Cardiotoxicity and Hepatotoxicity.

Cuprizone (CPZ) is a neurotoxic agent that is used to induce demyelination and neurotoxicity in rats. This study aimed to investigate the protective potential of sulforaphane (SF), nuclear factor E2 related factor (Nrf-2) activator, against CPZ-induced cardiotoxicity and hepatotoxicity. Male adult Wistar rats (n = 18) were fed with a regular diet or a CPZ-contained diet (0.2%) for four weeks. The rats were divided into three groups (n = 6): negative control rats, CPZ-exposed rats, and CPZ + SF treated rats. SF was intraperitoneally administrated (2 mg/kg/day) for two weeks. The anti-inflammatory and anti-oxidative functions of SF were investigated biochemically, histologically, and immunohistochemically. CPZ increased serum levels of cardiac troponin 1 (CTn1), aspartate amino transaminase (AST), alanine amino transaminase (ALT), and alkaline phosphatase (ALP). In addition, serum levels of inflammatory interferon-gamma (IFN-γ), and pro-inflammatory interleukin 1ß (IL-1ß) were significantly elevated. Moreover, CPZ administration provoked oxidative stress as manifested by declined serum levels of total antioxidant capacity (TAC), as well as, stimulated lipid peroxidation and decreased catalase activities in both cardiac and hepatic tissues. SF treatment reversed all these biochemical alterations through exerting anti-oxidative and anti-inflammatory activities, and this was supported by histopathological investigations in both cardiac and hepatic tissues. This SF-triggered modulation of oxidative stress and inflammation is strongly associated with Nrf-2 activation, as evidenced by activated immunoexpression in both cardiac and hepatic tissues. This highlights the cardioprotective and hepatoprotective activities of SF via Nrf-2 activation and enhancing catalase function.

Neuroprotective Potential of Intranasally Delivered Sulforaphane-Loaded Iron Oxide Nanoparticles Against Cisplatin-Induced Neurotoxicity.

Cisplatin (CIS) is a platinum-based chemotherapeutic drug that is widely used to treat cancer. However, its therapeutic efficiency is limited due to its potential to provoke neurotoxicity. Sulforaphane (SF) is a natural phytochemical that demonstrated several protective activities. Iron oxide nanoparticles (Fe3O4-NPs) could be used as drug carriers. This study aimed to explore the nanotoxic influence of SF-loaded within Fe3O4-NPs (N.SF), and to compare the neuroprotective potential of both N.SF and SF against CIS-induced neurotoxicity. N.SF or SF was administrated intranasally for 5 days before and 3 days after a single dose of CIS (12 mg/kg/week, i.p.) on the 6th day. Neuromuscular coordination was assessed using hanging wire and tail-flick tests. Acetylcholinesterase (AChE) activities and markers of oxidative stress were measured in the brain. In addition, the brain iron (Fe) content was estimated. CIS significantly induced a significant increase in AChE activities and lipid peroxides, and a significant decrement in glutathione (GSH) and nitric oxide (NO) contents. CIS elicited impaired neuromuscular function and thermal hyperalgesia. CIS-induced brains displayed a significant reduction in Fe content. Histopathological examination of different brain regions supported the biochemical and behavioral results. Contradict, treatment of CIS-rats with either N.SF or SF significantly decreased AChE activity, mitigated oxidative stress, and ameliorated the behavioral outcome. The histopathological features supported our results. Collectively, N.SF demonstrated superior neuroprotective activities on the behavioral, biochemical, and histopathological (striatum and cerebral cortex) aspects. N.SF could be regarded as a promising "pre-clinical" neuroprotective agent. Furthermore, this study confirmed the safe toxicological profile of Fe3O4-NPs.

Barium Oxide Doped Magnesium Silicate Nanopowders for Bone Fracture Healing: Preparation, Characterization, Antibacterial and In Vivo Animal Studies.

Magnesium silicate (MgS) nanopowders doped with barium oxide (BaO) were prepared by sol-gel technique, which were then implanted into a fracture of a tibia bone in rats for studying enhanced in vivo bone regeneration. The produced nanopowders were characterized using X-ray diffraction (XRD), Fourier transform infrared spectra (FTIR), scanning electron microscope with energy-dispersive X-ray spectrometry (SEM-EDX) and transmission electron microscope (TEM). Mechanical and bactericidal properties of the nanopowders were also determined. Increased crystallinity, particle diameter and surface area were found to decrease after the BaO doping without any notable alterations on their chemical integrities. Moreover, elevated mechanical and antibacterial characteristics were recognized for higher BaO doping concentrations. Our animal studies demonstrated that impressive new bone tissues were formed in the fractures while the prepared samples degraded, indicating that the osteogenesis and degradability of the BaO containing MgS samples were better than the control MgS. The results of the animal study indicated that the simultaneous bone formation on magnesium biomaterial silicate and barium MgS with completed bone healing after five weeks of implantations. The findings also demonstrated that the prepared samples with good biocompatibility and degradability could enhance vascularization and osteogenesis, and they have therapeutic potential to heal bone fractures.

Alloimperatorin from Ammi majus fruits mitigates Piroxicam-provoked gastric ulcer and hepatorenal toxicity in rats via suppressing oxidative stress and apoptosis.

INTRODUCTION: Fruits of Ammi majus, commonly called bishop's weed, contain a significant amount of furanocoumarins. Alloimperatorin (Allo, 6) was isolated from the free coumarin fraction of fruits, beside 8-hydroxypsoralen (1), methoxsalen (2), heraclin (3), isoimperatorin (4), imperatorin (5), isoheraclenin (7) and heraclenin hydrate (8). Piroxicam (Px) is a widely used pain-relieving drug that demonstrated side effects, including gastric ulceration and hepatorenal toxicity. OBJECTIVE: This study aimed to investigate the protective potential of Alloimperatorin against Px-induced gastric ulceration and hepatorenal toxicity. MATERIAL & METHODS: Rats were divided into four groups: Negative control, Px-induced rats, Allo + Px co-treated group, and Pc + Px co-treated group. Allo (25 mg/kg body weight) and Pc (25 mg/kg body weight) treatments were received 5 days before and 4 days after Px intoxication for 4 days (50 mg/kg body weight). Serum prostaglandin E2 (PG-E2) and liver and kidney functions were measured. Oxidative stress markers were evaluated in the three tissues. Histopathological features and caspase-3 immunoexpression were monitored. RESULTS & DISCUSSION: Px triggered gastric ulceration, increased indices of liver and kidney functions, decreased PG-E2 levels, provoked oxidative stress, and activated caspase-3 immunoexpression. Co-treatment with Allo demonstrated protective activities. CONCLUSION: Alloimperatorin exhibited anti-oxidative, anti-inflammatory, and anti-apoptotic activities.

Curcumin Ameliorates Doxorubicin-Induced Cardiotoxicity and Hepatotoxicity Via Suppressing Oxidative Stress and Modulating iNOS, NF-κB, and TNF-α in Rats.

Doxorubicin (DOX) is one of the widely used anti-tumor drugs. However, DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) are among the side effects that limited its therapeutic efficiency and clinical applicability. This study aimed to investigate the cardioprotective and hepatoprotective potentials of curcumin (CMN)-a bioactive polyphenolic compound-in alleviating DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) in male rats. A single intraperitoneal (i.p.) dose of DOX (20 mg/kg) was used to induce DIC and DIH. DOX-intoxicated rats were co-treated with CMN (100 mg/kg, oral) for 10 days before and 5 days after a single dose of DOX. We studied the anti-inflammatory and anti-oxidative activities of CMN on biochemical and immunohistochemical aspects. DOX disrupted cardiac and hepatic functions and stimulated oxidative stress and inflammation in both tissues that was confirmed biochemically and immunohistochemically. DOX enhanced inflammatory interferon-gamma (IFN-γ) and upregulated immunoexpression of nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-alpha (TNF-α). DOX induced structural alterations in both cardiac and hepatic tissues. CMN demonstrated cardioprotective potential through reducing cardiac troponin I (cTn1) and aspartate amino transaminase (AST). In addition, CMN significantly ameliorated liver function through decreasing alanine amino transaminase (ALT) and, gamma-glutamyl transferase (GGT), total cholesterol (TC), and triglycerides (TG). CMN demonstrated anti-inflammatory potential through decreasing IFN-γ levels and immunoexpression of iNOS, NF-κB, and TNF-α. Histopathologically, CMN restored DOX-associated cardiac and liver structural alterations. CMN showed anti-oxidative and anti-inflammatory potentials in both the cardiac and hepatic tissues. In addition, cTn1, IFN-γ, and AST could be used as blood-based biomarkers.

Hepatotoxic and Neurotoxic Potential of Iron Oxide Nanoparticles in Wistar Rats: a Biochemical and Ultrastructural Study.

Iron oxide nanoparticles (IONPs) are increasingly being employed for in vivo biomedical nanotheranostic applications. The development of novel IONPs should be accompanied by careful scrutiny of their biocompatibility. Herein, we studied the effect of administration of three formulations of IONPs, based on their starting materials along with synthesizing methods, IONPs-chloride, IONPs-lactate, and IONPs-nitrate, on biochemical and ultrastructural aspects. Different techniques were utilized to assess the effect of different starting materials on the physical, morphological, chemical, surface area, magnetic, and particle size distribution accompanied with their surface charge properties. Their nanoscale sizes were below 40 nm and demonstrated surface up to 69m2/g, and increased magnetization of 71.273 emu/g. Moreover, we investigated the effects of an oral IONP administration (100 mg/kg/day) in rat for 14 days. The liver enzymatic functions were investigated. Liver and brain tissues were analyzed for oxidative stress. Finally, a transmission electron microscope (TEM) and inductively coupled plasma optical emission spectrometer (ICP-OES) were employed to investigate the ultrastructural alterations and to estimate content of iron in the selected tissues of IONP-exposed rats. This study showed that magnetite IONPs-chloride exhibited the safest toxicological profile and thus could be regarded as a promising nanotherapeutic candidate for brain or liver disorders.

The protective impact of berberine against doxorubicin-induced nephrotoxicity in rats.

Doxorubicin (DOX) is a well-known anti-neoplastic agent that is widely employed to treat several types of malignancies. The current study was designed to investigate the renoprotective potential of berberine (BEB) on the doxorubicin (DOX)-induced nephrotoxicity and renal fibrosis. Rats were allocated into four groups; Negative Control, DOX nephrotoxic-induced group received a single dose of DOX (20 mg/kg, i.p.), BEB-group received (50 mg/kg, p.o.) for 14 days, and co-treatment group BEB + DOX where rats were pre-treated with BEB for 10 successive days, then received a single dose of DOX on the 11th day, followed by 4 days of receiving BEB. DOX resulted in nephrotoxicity manifested by significant increments in urea, creatinine, and kidney injury molecule (KIM-1), these biochemical findings were supported with the histopathological lesions in renal tissues. Moreover, DOX provoked oxidative stress through enhancing renal malondialdehyde (MDA) and hydrogen peroxide (H2O2) contents, and decreased renal catalase (CAT) activity. DOX triggered renal fibrosis represented by increased transforming growth factor beta-1 (TGF-ß1) and elevated collagen deposition. DOX stimulated apoptosis and inflammation in renal tissues as confirmed by increased immunoexpression of caspase-3 and NF-κB, respectively. These effects were alleviated by BEB co-treatment. Co-treatment with BEB markedly prohibited DOX-induced oxidative damage, inflammation, apoptosis, and fibrosis in renal tissue. Histopathological and immunohistochemical investigations showed the nephroprotective potential of BEB on renal injury, which was consistent with the biochemical findings. Accordingly, it could be concluded that the nephroprotective potential of BEB against DOX-induced kidney injury and fibrosis might be mediated by the anti-oxidant, anti-inflammatory and anti-fibrosis activities.

Neuroprotective Potential of Berberine Against Doxorubicin-Induced Toxicity in Rat's Brain.

Chemotherapy-associated neurotoxicity is one of the principal side-effects for doxorubicin (DOX)-treated cancer patients. Despite its poor-penetration across the blood-brain barrier (BBB), DOX is linked to the induction of oxidative stress and neuroinflammation. Berberine (BEB) is a natural polyphenolic alkaloid, which exhibits unique antioxidant activity and anti-inflammatory potential. The present study was performed to investigate the neuroprotective potential of BEB in a rodent model of DOX-induced neurotoxicity. Neurotoxicity was induced in rats via a single acute dose of DOX (20 mg/kg/week, i.p.). BEB was administered at 50 mg/kg/day orally for 10 days before and 4 days after DOX administration. Brain acetylcholinesterase (AChE) activities were evaluated. Oxidative stress was investigated via the colorimetric determination of lipid peroxides, glutathione reduced (GSH) contents and catalase (CAT) activities in the brain tissue. In addition, DOX-induced genotoxicity was evaluated using comet assay. DOX produced a significant elevation in AChE activities. Additionally, DOX provoked oxidative stress as evidenced from the significant elevation in lipid peroxidation along with depletion in GSH contents and CAT activities. Moreover, DOX resulted in neuroinflammation as indicated by the elevation of pro-inflammatory mediator glial fibrillary acid protein (GFAP), as well as, the pro-apoptotic nuclear factor kappa B (NF-κB) and caspase-3 in brain tissue. Co-treatment with BEB significantly counteracted DOX-induced oxidative stress, neuroinflammation and genotoxicity. Histopathological and immunohistochemical examination supported the biochemical results. BEB demonstrated neuroprotective potential through exerting cholinergic, anti-oxidative, genoprotective, anti-inflammatory, and anti-apoptotic activities. Our findings present BEB as a promising "pre-clinical" neuroprotective agent against DOX-induced neurotoxicity during anti-neoplastic therapy.

The protective potential of alpha lipoic acid on amiodarone-induced pulmonary fibrosis and hepatic injury in rats.

Amiodarone (AMD) is a widely used antiarrhythmic drug prescribed to treat cardiac tachyarrhythmias; however, AMD has been reported to provoke pulmonary fibrosis (PF) and hepatotoxicity. This study aimed to investigate the influence of alpha lipoic acid (ALA) on AMD-induced PF and hepatotoxicity in male Wistar rats. AMD administration resulted in elevated lung contents of hydroxyproline (Hyp), malondialdehyde (MDA), and increased serum levels of transforming growth factor beta-1 (TGF-ß1), interferon-γ (IFN-γ), alanine amino transaminase (ALT), aspartate amino transaminase (AST), total cholesterol (TC), and glucose. On the other side, lung content of glutathione reduced (GSH) and serum levels of total anti-oxidant capacity (TAC) were significantly decreased. Histopathologically, AMD caused PF, produced a mild hepatic injury, and increased expression of alpha smooth muscle actin (α-SMA). Treatment with ALA produced a significant reversal of the oxidative stress, fibrosis, and inflammation parameters with reductions in α-SMA expressions, leading to amelioration of histopathological lesions. ALA might provide supportive therapy in AMD-receiving cardiovascular patients.

A proposed insight into the anti-viral potential of metallic nanoparticles against novel coronavirus disease-19 (COVID-19).

BACKGROUND: Over the last ten months since December 2019, the world has faced infectious emerging novel coronavirus disease-2019 (COVID-19) outbreaks that had a massive global impact affecting over 185 countries. MAIN BODY: Emerging novel COVID-19 is a global health emergency on a pandemic scale that represents a terror to human health through its ability to escape anti-viral measures. Such viral infections impose a great socioeconomic burden, besides global health challenges. This imposes a pressing need for the development of anti-viral therapeutic agents and diagnostic tools that demonstrate multifunctional, target-specific, and non-toxic properties. Nanotheranostics is regarded as a promising approach for the management of different viral infections. Nanotheranostics facilitates targeted drug-delivery of anti-viral therapeutics as well as contributing to the development of diagnostic systems. Multifunctional metallic nanoparticles (NPs) have emerged as innovative theranostic agents that enable sustainable treatment and effective diagnosis. Here we have reviewed current advances in the use of theranostic metallic NPs to fight against COVID-19, and discussed the application as well as limitations associated with nanotechnology-based theranostic approaches. CONCLUSION: This review verified the potential use of some metal-based NPs as anti-viral nanotheranostic agents. Metal-based NPs could act as carriers that enable the sustainable and targeted delivery of active anti-viral molecules, or as diagnostic agents that allow rapid and sensitive diagnosis of viral infections.

The neuropathological impact of COVID-19: a review.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) outbreak has become a challenging global issue after its emergence in December 2019. Due to the high adaptation of the virus, COVID-19 demonstrated a high transmission and infectivity potentials. Several studies demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induce deleterious neurological manifestations through interacting with the central nervous system (CNS). MAIN BODY: The neuroinvasive potential of SARS-CoV-2 might contribute to its fatal behavior. Understanding the underlying mechanisms of this novel neuropathogen might contribute to the development of effective therapeutic strategies. The manifestations of neural damage in COVID-19 patients ranged from headache to severe encephalopathy and progression of preexisting neural disorders, it is speculated that neuroinvasion is strongly linked to the fatal respiratory dysfunction. The underlying neuropathological impact of emerging pneumonia (COVID-19) is still unclear. CONCLUSION: This review demonstrated the urgent need to understand the neuropathology of COVID-19, to manage the current borderless viral outbreak of SARS-CoV-2 and its comorbidities. Moreover, SARS-CoV-2 could be regarded as an opportunistic neuropathogen that affects several vital functions in the human body.

Synergistic anti-atherosclerotic role of combined treatment of omega-3 and co-enzyme Q10 in hypercholesterolemia-induced obese rats.

Hypercholesterolemia is a metabolic disorder associated with atherosclerosis. This study aimed to investigate the effects of omega-3 and/or coenzyme Q10 (CoQ10) on hypercholesterolemia-induced atherosclerosis. Rats were divided into five groups; (1): served as the negative control, (2): served as hypercholesterolemic (HC) control, (3): HC-rats administrated omega-3 orally, (4): HC-rats administrated CoQ10 orally, and (5): HC-rats administered the combination treatment of both omega-3 and CoQ10. Lipid profile was assayed and cardiovascular risk indices were calculated. Serum levels of Adiponectin (APN) and creatine kinase (CK-MB) were determined using ELISA. Besides, oxidative stress markers, malondialdehyde (MDA), nitric oxide (NO) and glutathione (GSH) were assayed in the heart homogenate. Histopathological investigation of the aortae and heart tissues were investigated. The results revealed that atherogenic HC-rats demonstrated a significant elevation in lipid profiles, except for HDL-C, along with decreased levels of APN, but increased CK-MB activities. Hypercholesterolemia increased lipid peroxidation, reduced NO production, and decreased GSH content in the cardiac tissue. Treatment of atherogenic HC-rats with omega-3 and/or CoQ10 improved dyslipidemia and ameliorated most of the HC-induced biochemical and histopathological changes. The histological observations of aortae and cardiac tissues validated our biochemical results. We concluded that the combined treatment of nutraceuticals such as omega-3 and CoQ10 demonstrated the best outcome, demonstrating their anti-hyperlipidemic, cardioprotective, and atheroprotective potentials. Together, this study supports a beneficial role of dietary co-administration of omega-3 and CoQ10 in obese patients who are prone to develop cardiovascular disorders.

Combination of Omega 3 and Coenzyme Q10 Exerts Neuroprotective Potential Against Hypercholesterolemia-Induced Alzheimer's-Like Disease in Rats.

Alzheimer's disease (AD) is the most common form of dementia that progressively disrupts neurocognitive function, which has neither cure nor effective treatment. Hypercholesterolemia might be involved in brain alterations that could evolve into AD. The present study aims to evaluate the potential of omega-3, Co-enzyme Q10 (Co-Q10), as well as their combination in ameliorating hypercholesterolemia-initiated AD-like disease. We adapted a hypercholesterolemic (HC) rat model, a model of oxidative stress-mediated neurodegeneration, to study AD-like pathology. Hypercholesterolemia resulted in increased lipid peroxidation coupled with declined nitric oxide production, reduced glutathione levels, and decreased antioxidant activities of glutathione-s-transferase (GST) and glutathione peroxidase (GSH-Px) in the brain. Moreover, hypercholesterolemia resulted in decreased acetylcholine (ACh) levels and increased acetylcholine-esterase (AChE) activity, along with an increment of tumor necrosis factor and amyloid-ß 42. Behaviorally, HC-rats demonstrated depressive-like behavior and declined memory. Treatment of HC-rats with omega-3 and Co-Q10 (alone or in combination) alleviated the brain oxidative stress and inflammation, regulated cholinergic functioning, and enhanced the functional outcome. These findings were verified by the histopathological investigation of brain tissues. This neuroprotective potential of omega-3 and Co-Q10 was achieved through anti-oxidative, anti-inflammatory, anti-amyloidogenic, pro-cholinergic, and memory-enhancing activities against HC-induced AD-like disease; suggesting that they may be useful as prophylactic and therapeutic agents against the neurotoxic effects of hypercholesterolemia.