A mechanistic exploration of the metabolome of African mango seeds and its potential to alleviate cognitive impairment induced by high-fat/high-carbohydrate diets: Involvement of PI3K/AKT/GSK-3ß/CREB, PERK/CHOP/Bcl-2, and AMPK/SIRT-1/mTOR Axes.

ETHNOPHARMACOLOGICAL RELEVANCE: Irvingia gabonensis (Aubry-Lecomte ex O'Rorke) Baill., also known as "African mango" or "bush mango", belonging to family Irvingiaceae, has been mostly used as food and traditional medicine for weight loss and to enhance the health. AIM OF THE STUDY: The overconsumption of high-fat and high-carbohydrate (HFHC) food induces oxidative stress, leading to neurological and cognitive dysfunction. Consequently, there is an immediate need for effective treatment. Hence, this study explored the efficacy of orlistat, metformin, and I. gabonensis seeds' total aqueous extract (IG SAE) in addressing HFHC-induced cognitive impairment by mitigating oxidative stress and their underlying mechanistic pathways. MATERIALS AND METHODS: Initially, the secondary metabolite profile of IG SAE is determined using high-performance liquid chromatography coupled with a mass detector (UHPLC/MS). The in vivo study involves two phases: an established model phase with control (10 rats on a standard diet) and HFHC diet group (50 rats) for 3 months. In the study phase, HFHC is divided into 5 groups. The first subgroup receives HFHC diet only, while the remaining groups each receive HFHC diet with either Orlistat, metformin, or IG SAE at doses of 100 mg/kg and 200 mg/kg, respectively, for 28 days. RESULTS: More than 150 phytoconstituents were characterized for the first holistic approach onto IG metabolome. Characterization of IG SAE revealed that tannins dominate metabolites in the plant. Total phenolics and flavonoids were estimated to standardize our extract (77.12 ± 7.09 µg Gallic acid equivalent/mg extract and 8.039 ± 0.53 µg Rutin equivalent/mg extract, respectively). Orlistat, metformin, and IG SAE successfully reduced the body weight, blood glucose level, lipid profile, oxidative stress and neurotransmitters levels leading to improved behavioral functions as well as histological alternation. Also, IG SAE halted inflammation, apoptosis, and endoplasmic reticulum stress, together with promoting autophagy, via modulation of PI3K/AKT/GSK-3ß/CREB, PERK/CHOP/Bcl-2 and AMPK/SIRT-1/m-TOR pathways. CONCLUSION: Metformin, orlistat, and IG SAE offer a promising multi-target therapy to mitigate HFHC diet-induced oxidative stress, addressing cognitive function. This involves diverse molecular mechanisms, particularly the modulation of inflammation, ER stress, and both PI3K/AKT/GSK-3ß/CREB and AMPK/SIRT-1/m-TOR pathways. Furthermore, the higher dose of IG SAE demonstrated effects comparable to orlistat and metformin across most studied parameters.

The potential anti-Alzheimer's activity of Oxalis corniculata Linn. Methanolic extract in experimental rats: Role of APOE4/LRP1, TLR4/NF-κß/NLRP3, Wnt 3/ß-catenin/GSK-3ß, autophagy and apoptotic cues.

ETHNOPHARMACOLOGICAL RELEVANCE: Oxalis corniculata (O. corniculata) is a member of Oxalidaceae family, widely distributed in Asia, Europe, America, and Africa, used extensively as food and its traditional folkloric uses include management of epilepsy, gastric disorders, and neurodegenerative diseases, together with its use in enhancing health. Numerous pharmacological benefits of O. corniculata are linked to its anti-inflammatory and antioxidant abilities. One of the most prevalent neurodegenerative disorders is Alzheimer's disease (AD) in which neuroinflammation and oxidative stress are its main pathogenic processes. AIM OF THE STUDY: Our research aimed to study the neuroprotective effect of the methanolic extract of Oxalis corniculata Linn. (O. corniculata ME), compared to selenium (Se) against AlCl3-induced AD. MATERIALS AND METHODS: Forty male albino rats were allocated into four groups (Gps). Gp I a control group, the rest of the animals received AlCl3 (Gp II-Gp IV). Rats in Gp III and IV were treated with Se and O. corniculata ME, respectively. RESULTS: The chemical profile of O. corniculata ME was studied using ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry, allowing the tentative identification of sixty-six compounds, including organic acids, phenolics and others, cinnamic acid and its derivatives, fatty acids, and flavonoids. AlCl3 showed deterioration in short-term memory and brain histological pictures. Our findings showed that O. corniculata ME and selenium helped to combat oxidative stress produced by accumulation of AlCl3 in the brain and in prophylaxis against AD. Thus, Selenium (Se) and O. corniculata ME restored antioxidant defense, via enhancing Nrf2/HO-1 hub, hampered neuroinflammation, via TLR4/NF-κß/NLRP3, along with dampening apoptosis, Aß generation, tau hyperphosphorylation, BACE1, ApoE4 and LRP1 levels. Treatments also promoted autophagy and modulated Wnt 3/ß-catenin/GSK3ß cue. CONCLUSIONS: It was noted that O. corniculata ME showed a notable ameliorative effect compared to Se on Nrf2/HO-1, TLR4/NF-κß/NLRP3, APOE4/LRP1, Wnt 3/ß-catenin/GSK-3ß and PERK axes.

In silico and in vivo analysis of the relationship between ADHD and social isolation in pups rat model: Implication of redox mechanisms, and the neuroprotective impact of Punicalagin.

Attention deficit hyperactivity disorder (ADHD) has high incidence rate among children which may be due to excessive monosodium glutamate (MSG) consumption and social isolation (SI). AIM: We aimed to explore the relationships between MSG, SI, and ADHD development and to evaluate the neuroprotective potential of Punicalagin (PUN). METHODS: Eighty male rat pups randomly distributed into eight groups. Group I is the control, and Group II is socially engaged rats treated with PUN. Groups III to VII were exposed to ADHD-inducing factors: Group III to SI, Group IV to MSG, and Group V to both SI and MSG. Furthermore, Groups VI to VIII were the same Groups III to V but additionally received PUN treatment. KEY FINDINGS: Exposure to MSG and/or SI led to pronounced behavioral anomalies, histological changes and indicative of ADHD-like symptoms in rat pups which is accompanied by inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme-oxygenase 1 (HO-1)/Glutathione (GSH) pathway, decline of the brain-derived neurotrophic factor (BDNF) expression and activation of the Toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-kB)/NLR Family Pyrin Domain Containing 3 (NLRP3) pathway. This resulted in elevated inflammatory biomarker levels, neuronal apoptosis, and disrupted neurotransmitter equilibrium. Meanwhile, pretreatment with PUN protected against all the previous alterations. SIGNIFICANCE: We established compelling associations between MSG consumption, SI, and ADHD progression. Moreover, we proved that PUN is a promising neuroprotective agent against all risk factors of ADHD.

Punicalagin's Protective Effects on Parkinson's Progression in Socially Isolated and Socialized Rats: Insights into Multifaceted Pathway.

Parkinson's disease (PD) is a gradual deterioration of dopaminergic neurons, leading to motor impairments. Social isolation (SI), a recognized stressor, has recently gained attention as a potential influencing factor in the progress of neurodegenerative illnesses. We aimed to investigate the intricate relationship between SI and PD progression, both independently and in the presence of manganese chloride (MnCl2), while evaluating the punicalagin (PUN) therapeutic effects, a natural compound established for its cytoprotective, anti-inflammatory, and anti-apoptotic activities. In this five-week experiment, seven groups of male albino rats were organized: G1 (normal control), G2 (SI), G3 (MnCl2), G4 (SI + MnCl2), G5 (SI + PUN), G6 (MnCl2 + PUN), and G7 (SI + PUN + MnCl2). The results revealed significant changes in behavior, biochemistry, and histopathology in rats exposed to SI and/or MnCl2, with the most pronounced effects detected in the SI rats concurrently exposed to MnCl2. These effects were associated with augmented oxidative stress biomarkers and reduced antioxidant activity of the Nrf2/HO-1 pathway. Additionally, inflammatory pathways (HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1 and JAK-2/STAT-3) were upregulated, while dysregulation of signaling pathways (PI3K/AKT/GSK-3ß/CREB), sustained endoplasmic reticulum stress by activation PERK/CHOP/Bcl-2, and impaired autophagy (AMPK/SIRT-1/Beclin-1 axis) were observed. Apoptosis induction and a decrease in monoamine levels were also noted. Remarkably, treatment with PUN effectively alleviated behaviour, histopathological changes, and biochemical alterations induced by SI and/or MnCl2. These findings emphasize the role of SI in PD progress and propose PUN as a potential therapeutic intervention to mitigate PD. PUN's mechanisms of action involve modulation of pathways such as HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1, JAK-2/STAT-3, PI3K/AKT/GSK-3ß/CREB, AMPK/SIRT-1, Nrf2/HO-1, and PERK/CHOP/Bcl-2.

The protective effects of sesamol and/or the probiotic, Lactobacillus rhamnosus, against aluminum chloride-induced neurotoxicity and hepatotoxicity in rats: Modulation of Wnt/ß-catenin/GSK-3ß, JAK-2/STAT-3, PPAR-γ, inflammatory, and apoptotic pathways.

Introduction: Aluminium (Al) is accumulated in the brain causing neurotoxicity and neurodegenerative disease like Alzheimer's disease (AD), multiple sclerosis, autism and epilepsy. Hence, attenuation of Al-induced neurotoxicity has become a "hot topic" in looking for an intervention that slow down the progression of neurodegenerative diseases. Objective: Our study aims to introduce a new strategy for hampering aluminum chloride (AlCl3)-induced neurotoxicity using a combination of sesamol with the probiotic bacteria; Lactobacillus rhamnosus (L. rhamnosus) and also to test their possible ameliorative effects on AlCl3-induced hepatotoxicity. Methods: Sprague-Dawley male rats were randomly divided into five groups (n = 10/group) which are control, AlCl3, AlCl3 + Sesamol, AlCl3 + L. rhamnosus and AlCl3 + Sesamol + L. rhamnosus. We surveilled the behavioral, biochemical, and histopathological alterations centrally in the brain and peripherally in liver. Results: This work revealed that the combined therapy of sesamol and L. rhamnosus produced marked reduction in brain amyloid-ß, p-tau, GSK-3ß, inflammatory and apoptotic biomarkers, along with marked elevation in brain free ß-catenin and Wnt3a, compared to AlCl3-intoxicated rats. Also, the combined therapy exerted pronounced reduction in hepatic expressions of JAK-2/STAT-3, inflammatory (TNF-α, IL-6, NF-κB), fibrotic (MMP-2, TIMP-1, α-SMA) and apoptotic markers, (caspase-3), together with marked elevation in hepatic PPAR-γ expression, compared to AlCl3 -intoxicated rats. Behavioral and histopathological assessments substantiated the efficiency of this combined regimen in halting the effect of neurotoxicity. Discussion: Probiotics can be used as an add-on therapy with sesamol ameliorate AlCl3 -mediated neurotoxicity and hepatotoxicity.

Anti-Alzheimer Activity of Combinations of Cocoa with Vinpocetine or Other Nutraceuticals in Rat Model: Modulation of Wnt3/ß-Catenin/GSK-3ß/Nrf2/HO-1 and PERK/CHOP/Bcl-2 Pathways.

Alzheimer's disease (AD) is a devastating illness with limited therapeutic interventions. The aim of this study is to investigate the pathophysiological mechanisms underlying AD and explore the potential neuroprotective effects of cocoa, either alone or in combination with other nutraceuticals, in an animal model of aluminum-induced AD. Rats were divided into nine groups: control, aluminum chloride (AlCl3) alone, AlCl3 with cocoa alone, AlCl3 with vinpocetine (VIN), AlCl3 with epigallocatechin-3-gallate (EGCG), AlCl3 with coenzyme Q10 (CoQ10), AlCl3 with wheatgrass (WG), AlCl3 with vitamin (Vit) B complex, and AlCl3 with a combination of Vit C, Vit E, and selenium (Se). The animals were treated for five weeks, and we assessed behavioral, histopathological, and biochemical changes, focusing on oxidative stress, inflammation, Wnt/GSK-3ß/ß-catenin signaling, ER stress, autophagy, and apoptosis. AlCl3 administration induced oxidative stress, as evidenced by elevated levels of malondialdehyde (MDA) and downregulation of cellular antioxidants (Nrf2, HO-1, SOD, and TAC). AlCl3 also upregulated inflammatory biomarkers (TNF-α and IL-1ß) and GSK-3ß, leading to increased tau phosphorylation, decreased brain-derived neurotrophic factor (BDNF) expression, and downregulation of the Wnt/ß-catenin pathway. Furthermore, AlCl3 intensified C/EBP, p-PERK, GRP-78, and CHOP, indicating sustained ER stress, and decreased Beclin-1 and anti-apoptotic B-cell lymphoma 2 (Bcl-2) expressions. These alterations contributed to the observed behavioral and histological changes in the AlCl3-induced AD model. Administration of cocoa, either alone or in combination with other nutraceuticals, particularly VIN or EGCG, demonstrated remarkable amelioration of all assessed parameters. The combination of cocoa with nutraceuticals attenuated the AD-mediated deterioration by modulating interrelated pathophysiological pathways, including inflammation, antioxidant responses, GSK-3ß-Wnt/ß-catenin signaling, ER stress, and apoptosis. These findings provide insights into the intricate pathogenesis of AD and highlight the neuroprotective effects of nutraceuticals through multiple signaling pathways.

The consumption pattern and perception of using artificial sweeteners among the public in Tabuk region, Saudi Arabia.

Background: Obesity and weight gain have become major problems worldwide. Thus, several forms of alternative intense sweeteners are extensively used, offering a non-caloric sweet taste. To the best of our knowledge, no research has studied either the consumption pattern or the perception of using artificial sweeteners in Saudi Arabia. Objectives: Our research aimed to study the usage pattern of such artificial sweeteners in the Tabuk region and estimate the knowledge of and attitudes toward their usage among the population. Methods: A cross-sectional study promoted on multiple social media platforms and face-to-face interviews in different malls and hospitals in the Tabuk region. We grouped the participants into two major groups: the users and the non-users of artificial sweeteners. Each group has been subdivided into a healthy subgroup and those with a medical record subgroup. Participants' characteristics and their choice of sweeteners were analyzed using bivariate analysis. The age, gender, and education level of the participants were adjusted using binary logistic regression in order to adjust for potential confounders. Results: A total of 2,760 participants were included in our study. We found that more than 59% of the participants that were over 45 years old were non-hospitalized non-hospitalized diseased irrespective of their usage of artificial sweeteners. Furthermore, females, graduates, diabetics were significantly high irrespective of their subgroup. Moreover, Steviana® is the most commonly used artificial sweetener. In addition, healthy participants showed a greater perception of the usage and adverse effects of artificial sweeteners. Furthermore, bivariate analysis using logistic regression revealed significant associations (p < 0.05) with confounders such as gender, age, and education level. Conclusion: Educational programs and nutritional advice for the safe consumption and the daily permissible doses of artificial sweeteners are essential and should be directed specifically at females.

Neuroprotective Effects of Some Nutraceuticals against Manganese-Induced Parkinson's Disease in Rats: Possible Modulatory Effects on TLR4/NLRP3/NF-κB, GSK-3ß, Nrf2/HO-1, and Apoptotic Pathways.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting the substantia nigra where functions controlling body movement take place. Manganese (Mn) overexposure is linked to a neurologic syndrome resembling PD. Sesamol, thymol, wheat grass (WG), and coenzyme Q10 (CoQ10) are potent antioxidants, anti-inflammatory, and anti-apoptotic nutraceuticals. We investigated the potential protective effects of these nutraceuticals alone or in combinations against MnCl2-induced PD in rats. Seven groups of adult male Sprague Dawley rats were categorized as follows: group (I) was the control, while groups 2-7 received MnCl2 either alone (Group II) or in conjunction with oral doses of sesamol (Group III), thymol (Group IV), CoQ10 (Group V), WG (Group VI), or their combination (Group VII). All rats were subjected to four behavioral tests (open-field, swimming, Y-maze, and catalepsy tests). Biochemical changes in brain levels of monoamines, ACHE, BDNF, GSK-3ß, GABA/glutamate, as well as oxidative stress, and apoptotic and neuroinflammatory biomarkers were evaluated, together with histopathological examinations of different brain regions. Mn increased catalepsy scores, while decreasing neuromuscular co-ordination, and locomotor and exploratory activity. It also impaired vigilance, spatial memory, and decision making. Most behavioral impairments induced by Mn were improved by sesamol, thymol, WG, or CoQ10, with prominent effect by sesamol and thymol. Notably, the combination group showed more pronounced improvements, which were confirmed by biochemical, molecular, as well as histopathological findings. Sesamol or thymol showed better protection against neuronal degeneration and some behavioral impairments induced by Mn than WG or CoQ10, partly via interplay between Nrf2/HO-1, TLR4/NLRP3/NF-κB, GSK-3ß and Bax/Bcl2 pathways.

The protective effect of thymoquinone or/and thymol against monosodium glutamate-induced attention-deficit/hyperactivity disorder (ADHD)-like behavior in rats: Modulation of Nrf2/HO-1, TLR4/NF-κB/NLRP3/caspase-1 and Wnt/ß-Catenin signaling pathways in rat model.

Both thymoquinone (TQ) and thymol (T) have been proved to possess a positive impact on human health. In this research, we aimed to investigate the effect of these compounds separately and together on the Attention-deficit/hyperactivity disorder (ADHD)-like behavior induced by monosodium glutamate (MSG) in rats. Forty male, Spargue Dawley rat pups (postnatal day 21), were randomly allocated into five groups: Normal saline (NS), MSG, MSG+TQ, MSG+T, and MSG+TQ+T. MSG (0.4 mg/kg/day), TQ (10 mg/kg/day) and T (30 mg/kg/day) were orally administered for 8 weeks. The behavioral tests proved that rats treated with TQ and/or T showed improved locomotor, attention and cognitive functions compared to the MSG group with more pronounced effect displayed with their combination. All treated groups showed improvement in MSG-induced aberrations in brain levels of GSH, IL-1ß, TNF-α, GFAP, glutamate, calcium, dopamine, norepinephrine, Wnt3a, ß-Catenin and BDNF. TQ and/or T treatment also enhanced the mRNA expression of Nrf2, HO-1 and Bcl2 while reducing the protein expression of TLR4, NFκB, NLRP3, caspase 1, Bax, AIF and GSK3ß as compared to the MSG group. However, the combined therapy showed more significant effects in all measured parameters. All of these findings were further confirmed by the histopathological examinations. Current results concluded that the combined therapy of TQ and T had higher protective effects than their individual supplementations against MSG-induced ADHD-like behavior in rats.

Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer's Disease through ApoE4/LRP1, Wnt3/ß-Catenin/GSK3ß, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that is associated with abnormal cognition. AD is aided in its initiation and progression by hereditary and environmental factors. Aluminum (Al) is a neurotoxic agent that causes oxidative stress, which is linked to AD progression. Additionally, Nrf2/HO-1, APOE4/LRP1, Wnt3/ß-catenin, and TLR4/NLRP3 are the main signaling pathways involved in AD pathogenesis. Several phytochemicals are promising options in delaying AD evolution. OBJECTIVES: This study aimed at studying the neuroprotective effects of some phytochemicals as morin (MOR), thymol (TML), and thymoquinone (TMQ) on physical and mental activities (PhM) in Al chloride (AlCl3)-induced AD rat model. Another objective was to determine the specificity of phytochemicals to AD signaling pathways using molecular docking. METHODS: Eighty male Dawley rats were divided into eight groups. Each group received: saline (control group), AlCl3, (ALAD), PhM, either alone or with a combination of MOR, TML, and/or TMQ for five weeks. Animals were then subjected to behavioral evaluation. Brain tissues were used for histopathological and biochemical analyses to determine the extent of neurodegeneration. The effect of phytochemicals on AlCl3-induced oxidative stress and the main signaling pathways involved in AD progression were also investigated. RESULTS: AlCl3 caused a decline in spatial learning and memory, as well as histopathological changes in the brains of rats. Phytochemicals combined with PhM restored antioxidant activities, increased HO-1 and Nrf2 levels, blocked inflammasome activation, apoptosis, TLR4 expression, amyloide-ß generation, and tau hyperphophorylation. They also brought ApoE4 and LRP1 levels back to normal and regulated Wnt3/ß-catenin/GSK3ß signaling pathway. CONCLUSIONS: The use of phytochemicals with PhM is a promising strategy for reducing AD by modulating Nrf2/HO-1, TLR4/NLRP3, APOE4/LRP1, and Wnt3/ß-catenin/GSK-3ß signaling pathways.

Neuroprotective Effect of Morin Hydrate against Attention-Deficit/Hyperactivity Disorder (ADHD) Induced by MSG and/or Protein Malnutrition in Rat Pups: Effect on Oxidative/Monoamines/Inflammatory Balance and Apoptosis.

Monosodium glutamate (MSG) is one of the most widely used food additives. However, it has been linked to protein malnutrition (PM) and various forms of toxicities such as metabolic disorders and neurotoxic effects. The current study is the first to explore the association between MSG, PM, and induced brain injury similar to attention-deficit/hyperactivity disorder (ADHD). Moreover, we determined the underlying mechanistic protective pathways of morin hydrate (MH)-a natural flavonoid with reported multiple therapeutic properties. PM was induced by feeding animals with a low protein diet and confirmed by low serum albumin measurement. Subsequently, rat pups were randomized into seven groups of 10 rats each. Group I, III, and VI were normally fed (NF) and groups II, IV, V, and VII were PM fed. Group I served as normal control NF while Group II served as PM control animals. Group III received NF + 0.4 g/kg MSG, Group IV: PM + 0.4 g/kg MSG, Group V: PM + 60 mg/kg MH, Group VI: NF + 0.4 kg/g MSG + 60 mg/kg MH and Group VII: PM + 0.4 kg/kg MSG + 60 mg/kg MH. At the end of the experimental period, animals were subjected to behavioral and biochemical tests. Our results showed that treatment of rats with a combination of MSG + PM-fed exhibited inferior outcomes as evidenced by deteriorated effects on behavioral, neurochemical, and histopathological analyses when compared to rats who had received MSG or PM alone. Interestingly, MH improved animals' behavior, increased brain monoamines, brain-derived neuroprotective factor (BDNF), antioxidant status and protein expression of Nrf2/HO-1. This also was accompanied by a significant decrease in brain MDA, inflammatory markers (NF-kB, TNF-α and IL1ß), and suppression of TLR4/NLRP3/caspase-1 axis. Taken together, MSG and/or PM are associated with neuronal dysfunction. Our findings suggest MH as a potential neuroprotective agent against brain insults via targeting Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathways.

Evaluating the neuroprotective activities of vinpocetine, punicalagin, niacin and vitamin E against behavioural and motor disabilities of manganese-induced Parkinson's disease in Sprague Dawley rats.

The current study investigated the neuroprotective activity of some drugs and nutriceuticals with antioxidant and anti-inflammatory potential on the pathogenesis of Parkinson's disease (PD). Rats were categorized into seven groups: Rats received tween80 daily for 5 weeks as a control group, MnCl2 (10 mg/kg, i.p) either alone (group II) or in combination with vinpocetine (VIN) (20 mg/kg) (group III), punicalagin (PUN) (30 mg/kg) (group IV), niacin (85 mg/kg) (group V), vitamin E (Vit E) (100 mg/kg) (group VI) or their combination (group VII). Motor activities was examined using open-field and catalepsy. Striatal monamines, acetylcholinesterase, excitatory/inhibitory neurotransmitters, redox status, pro-oxidant content, brain inflammatory, apoptotic and antioxidant biomarkers levels were assessed. Besides, histopathological investigations of different brain regions were determined. Groups (IV -GVII) showed improved motor functions of PD rats. Applied drugs significantly increased the brain levels of monoamines with the strongest effect to PUN. Meanwhile, they significantly decreased levels of acetylcholinesterase with a strongest effect to PUN. Moreover, they exhibited significant neuronal protection and anti-inflammatory abilities through significant reduction of the brain levels of COX2, TNF-α and Il-1ß with a strongest effect to the PUN. Interestingly; groups (IV - GVII) showed restored glutamate/GABA balance and exhibited a pronounced decrease in caspase-3 content and GSK-3ß protein expression levels. In addition, they significantly increased Bcl2 mRNA expression levels with a strongest effect for PUN. All these findings were further confirmed by the histopathological examinations. As a conclusion, we propose VIN and PUN to mitigate the progression of PD via their antioxidant, anti-inflammatory, anti-apoptotic, neurotrophic and neurogenic activities.

Melatonin and zinc supplements with physical and mental activities subside neurodegeneration and hepatorenal injury induced by aluminum chloride in rats: Inclusion of GSK-3ß-Wnt/ß-catenin signaling pathway.

Alzheimer's disease (AD) is an irreversible, progressive cognitive dysfunction. Inflammaging is the greatest common factor between AD and hepatorenal malfunction. This study aimed to use melatonin (MEL) and zinc sulfate (Zn) in addition to physical and mental activities (PMA) to ameliorate AlCl3-induced AD as well as investigate their impact on the associated hepatorenal impairment. METHODS: Seven groups of rats each received: saline (control group), AlCl3 (70 mg/kg, i.p.), PMA, either alone or with a combination of Mel (10 mg/kg, p.o) and/or Zn (16 mg/kg, p.o). Neurological deterioration was assessed after 5 weeks using behavioral tests, histopathological examination, and measurements of acetylcholinesterase (ACHE), brain monoamines, oxidative stress, and inflammatory markers, Amyloid precursor protein (APP), amyloid-ß (Aß), tau levels, and brain derived neurotrophic factor (BDNF). Moreover, the GSK-3ß-Wnt/ß-catenin signaling pathway was assessed. Additionally, oxidative stress and inflammatory markers were determined in liver and kidney tissues with concurrent evaluation of hepatic and renal functions. RESULTS: The histopathological examination revealed a cerebral cortex and hippocampus deterioration in the AD group with a decline in spatial learning and memory, besides a significant increase in AD markers in the brain and disturbance in GSK-3ß-Wnt/ß-catenin signaling. The AD group showed hepatorenal injuries supported by elevated oxidative stress and inflammatory markers. However, adding Mel and Zn to PMA significantly attenuated the neurodegeneration and enhanced hepatic and renal functions by ameliorating oxidant and inflammatory markers. CONCLUSIONS: Combining Mel and Zn supplements with PMA defends against AlCl3-induced AD by modulating GSK-3ß-Wnt/ß-catenin signaling and palliates the associated hepatorenal dysfunction.

Fluoxetine ameliorates Alzheimer's disease progression and prevents the exacerbation of cardiovascular dysfunction of socially isolated depressed rats through activation of Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathway.

Depression is a risk factor for Alzheimer's (AD) and cardiovascular diseases (CVD). Therefore, depression treatment restricts its deteriorating effects on mood, memory and CV system. Fluoxetine is the most widely used antidepressant drug, it has neuroprotective effect through its antioxidant/anti-inflammatory properties. The current study investigated for the first-time the cross link between depression, AD and CVD besides, role of fluoxetine in mitigating such disorders. Depression was induced in rats by social isolation (SI) for 12 weeks, AlCL3 (70 mg/kg/day, i.p.) was used to induce AD which was administered either in SI or normal control (NC) grouped rats starting at 8th week till the end of the experiment, fluoxetine (10 mg/kg/day, p.o) treatment also was started at 8th week. SI and AD showed a statistically significant deteriorated effect on behavioral, neurochemical and histopathological analysis which was exaggerated when two disorder combined than each alone. Fluoxetine treatment showed protective effect against SI, AD and prevents exacerbation of CVD. Fluoxetine improved animals' behavior, increased brain monoamines, BDNF besides increased antioxidant defense mechanism of SOD, TAC contents and increased protein expression of Nrf2/HO-1 with significant decrease of AChE activity, ß-amyloid, Tau protein, MDA, TNF-α, IL1ß contents as well as decreased protein expression of NF-kB, TLR4, NLRP3 and caspase1. It also showed cardioprotective effects as it improved lipid profile with pronounced decrease of cardiac enzymes of CK-MB, troponin and MEF2. In conclusion, fluoxetine represents as a promising drug against central and peripheral disorders through its anti-inflammatory/antioxidant effects via targeting antioxidant Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathways.

The influence of vinpocetine alone or in combination with Epigallocatechin-3-gallate, Coenzyme COQ10, Vitamin E and Selenium as a potential neuroprotective combination against aluminium-induced Alzheimer's disease in Wistar Albino Rats.

Alzheimer's disease (AD) is one of such diseases that represent the most prominent cause of dementia in elderly people. To explore the possible neuroprotective effect as well as mechanism of action of Vinpocetine either alone or in combination with EGCG, CoQ10, or VE & Se in ameliorating aluminum chloride-induced AD in rats. Rats were received AlCl3 (70 mg/kg) intraperitoneal daily dose for 30 days along with EGCG (10 mg/kg, I.P), CoQ10 (200 mg/kg, P.O), VE (100 mg/kg, P.O) & Se (1 mg/kg, P.O) as well as Vinpocetine (20 mg/kg, P.O) either alone or in combination. Results revealed that the combination of Vinpocetine with EGCG showed the best neuroprotection. This protection in the brain was indicated by the significant decrease in Aß and ACHE. The same pattern of results were shown in the levels of monoamines and BDNF. In addition, the combination of Vinpocetine with EGCG showed more pronounced anti-inflammatory (TNF-α, IL-1ß) and antioxidant (MDA, SOD, TAC) effects in comparison to other combinations. These results were confirmed using histopathological examinations as well as DNA fragmentation assays. Vinpocetine with EGCG showed pronounced protection on neurons against AD induced by AlCl3 in rats.

Attenuative Effects of Fluoxetine and Triticum aestivum against Aluminum-Induced Alzheimer's Disease in Rats: The Possible Consequences on Hepatotoxicity and Nephrotoxicity.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurological illness that causes considerable cognitive impairment. Hepatic and renal dysfunction may worsen AD by disrupting ß-amyloid homeostasis at the periphery and by causing metabolic dysfunction. Wheatgrass (Triticum aestivum) has been shown to have antioxidant and anti-inflammatory properties. This work aims to study the effect of aluminum on neuronal cells, its consequences on the liver and kidneys, and the possible role of fluoxetine and wheatgrass juice in attenuating these pathological conditions. METHOD: Rats were divided into five groups. Control, AD (AlCl3), Fluoxetine (Fluoxetine and AlCl3), Wheatgrass (Wheatgrass and AlCl3), and combination group (fluoxetine, wheatgrass, and AlCl3). All groups were assigned daily to different treatments for five weeks. CONCLUSIONS: AlCl3 elevated liver and kidney enzymes, over-production of oxidative stress, and inflammatory markers. Besides, accumulation of tau protein and Aß, the elevation of ACHE and GSK-3ß, down-regulation of BDNF, and ß-catenin expression in the brain. Histopathological examinations of the liver, kidney, and brain confirmed this toxicity, while treating AD groups with fluoxetine, wheatgrass, or a combination alleviates toxic insults. CONCLUSION: Fluoxetine and wheatgrass combination demonstrated a more significant neuroprotective impact in treating AD than fluoxetine alone and has protective effects on liver and kidney tissues.

Omega-3 Rich Oils Attenuate ADHD-Like Behaviour Induced by Dietary Monosodium Glutamate in Rats.

<b>Background and Objective:</b> Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity and cognitive dysfunction. The present study was designed to examine the possible modulatory effect of Fish, Walnuts or Fenugreek Oils against Attention Deficit Hyperactivity Disorder (ADHD)-like Behavior induced by Monosodium Glutamate (MSG) in Rats. <b>Materials and Methods:</b> Fifty weaning rats were divided into five groups, (each group contain 10 rats) as follows: Group 1: Normal control rats were fed on a balanced diet. Groups from 2-5 rats were fed on a balanced diet+MSG (0.4 g kg¹ diet), Group 2 served as a positive control group whereas group 3, 4 and 5 treated with Fish, Walnuts and Fenugreek oil, respectively, (200 mg kg¹ b.wt.) by intra-gastric tube. Biochemical and behavioural parameters were tested as well as microscopic examination of brain tissue was done. <b>Results:</b> MSG ingestion caused marked disruption in locomotors activity, memory function and brain tissue structure along with significant abnormalities in some bio-markers and reduction in the gene expression level of Bcl-2 in brain tissue. However, treatment with the tested oils showed remarkable effect by reversing the condition. <b>Conclusion:</b> Dietary supplementation with walnut; fenugreek or fish oils at the tested dose could modulate the condition of ADHD in rats.

Natural antioxidants enhance the power of physical and mental activities versus risk factors inducing progression of Alzheimer's disease in rats.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease that is exacerbated by social isolation (SI) and protein malnutrition (PM). Antioxidants, physical and mental activities (Ph&M) can maintain cognitive functions and protect against dementia. OBJECTIVE: To investigate the impact of Epigallocatechin-3-gallate (EGCG), Vitamin E (VE), Vitamin C (VC), and Selenium (Se), in enhancing the potential effect of Ph&M versus SI&PM as risk factors in the progression of AD in rats. METHODS: Aluminum chloride (70 mg/kg, I.P for 5 weeks) was used to induce AD in rats that either normally fed or socially isolated and protein malnourished (SI&PM). Simultaneously, rats were weekly exposed to Ph&M either alone or in combination with EGCG (10 mg/kg, I.P), VC (400 mg/kg, P.O), VE (100 mg/kg, P.O), and Se (1 mg/kg, P.O). RESULTS: The combination protocol of EGCG, VE, VC, and Se together with Ph&M significantly increased brain monoamines, superoxide dismutase (SOD), total antioxidant capacity (TAC) and brain-derived neurotrophic factor (BDNF) in AD, SI&PM and SI&PM/AD groups. Additionally, this regimen significantly mitigated brain acetylcholine esterase (ACHE), ß-amyloid (Aß), Tau protein, ß-secretase, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and Interleukin 1ß (IL-1ß) as well as DNA fragmentation. These biochemical findings were supported by the histopathological examinations of brain tissue. CONCLUSION: The combination protocol of antioxidants with Ph&M activities mitigated SI&PM-induced progressive risk of AD.