AlCl3-induced Alzheimer's Disease Research Articles

Valsartan ameliorated cognitive decline, oxidative stress and inflammation in AlCl3-induced Alzheimer's disease in rats

Valsartan ameliorated cognitive decline, oxidative stress and inflammation in AlCl3-induced Alzheimer's disease in rats

Dietary conjugated linoleic acid downregulates the AlCl3-induced hyperactivation of compensatory and maladaptive signalling in the mouse brain cortex

Oxidative stress, hyperactivation of compensatory mechanisms (unfolded protein response, UPR; nuclear factor erythroid 2-related factor 2, Nrf2) and the stimulation of maladaptive response (inflammation/apoptosis) are interconnected pathogenic processes occurring during Alzheimer's disease (AD) progression. The neuroprotective ability of dietary Conjugated linoleic acid (CLAmix) in a mouse model of AlCl3-induced AD was recently described but, the effects of AlCl3 or CLAmix intake on these pathogenic processes are still unknown.The effects of dietary AlCl3 or CLAmix - alone and in combination - were examined in the brain cortex of twenty-eight BalbC mice divided into 4 groups (n = 7 each). The neurotoxic effects of AlCl3 were investigated in animals treated for 5 weeks with 100 mg/kg/day (AL). CLAmix supplementation (600 mg/kg bw/day) for 7 weeks (CLA) was aimed at evaluating its modulatory effects on the Nrf2 pathway while its co-treatment with AlCl3 during the last 5 weeks of CLAmix intake (CLA + AL) was used to investigate its neuroprotective ability. Untreated mice were used as controls.In the CLA group, the NADPH oxidase (NOX) activation in the brain cortex was accompanied by the modulation of the Nrf2 pathway. By contrast, in the AL mice, the significant upregulation of oxidative stress markers, compensatory pathways (UPR/Nrf2), proinflammatory cytokines (IL-6, TNFα) and the proapoptotic protein Bax levels were found as compared with control. Notably, in CLA + AL mice, the marked decrease of oxidative stress, UPR/Nrf2 markers and proinflammatory cytokines levels were associated with the significant increase of the antiapoptotic protein Bcl2.The involvement of NOX in the adaptive response elicited by CLAmix along with its protective effects against the onset of several pathogenic processes triggered by AlCl3, broadens the knowledge of the mechanism underlying the pleiotropic activity of Nrf2 activators and sheds new light on their potential therapeutic use against neurodegenerative disorders.

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

Ethnopharmacological relevanceOxalis 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 studyOur 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 methodsForty 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. ResultsThe 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-κβ/NLRP3, along with dampening apoptosis, Aβ generation, tau hyperphosphorylation, BACE1, ApoE4 and LRP1 levels. Treatments also promoted autophagy and modulated Wnt 3/β-catenin/GSK3β cue. ConclusionsIt was noted that O. corniculata ME showed a notable ameliorative effect compared to Se on Nrf2/HO-1, TLR4/NF-κβ/NLRP3, APOE4/LRP1, Wnt 3/β-catenin/GSK-3β and PERK axes.

Neuroprotective effect of plasmalogens on AlCl3-induced Alzheimer's disease zebrafish via acting on the regulatory network of ferroptosis, apoptosis and synaptic neurotransmission release with oxidative stress as the center

Plasmalogens (Pls) are considered to play a potential role in the treatment of neurodegenerative diseases. In the present study, an Alzheimer's disease (AD) model of zebrafish induced by AlCl3 was established to investigate whether the marine-derived Pls could alleviate cognitive impairments of AD zebrafish. Behavioral tests were carried out to assess the athletic ability. The transcriptional profiles of zebrafish in the control, AD model and AD_PLS group were compared and analyzed to determine the potential mechanisms of dietary Pls on AD. The study found that Pls could reverse athletic impairment in the AD zebrafish model, and the expression levels of genes related to ferroptosis, synaptic dysfunction and apoptosis were significantly altered between experimental groups. Further analysis showed that all of these genes were associated with oxidative stress (OS). These data suggest that healthy protective role of marine-derived Pls on AD zebrafish may result from inhibition of ferroptosis and neuronal apoptosis, restoring synaptic neurotransmission release, and reducing neuroinflammation. Among them, Oxidative stress is acted as the center to connect different regulation pathways. This study provides evidence to support the essential roles of OS in pathogenesis of AD, and the application of Pls in relieving AD.

Anti-Alzheimer Activity of Combinations of Cocoa with Vinpocetine or Other Nutraceuticals in Rat Model: Modulation of Wnt3/β-Catenin/GSK-3β/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-3β/β-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-1β) and GSK-3β, leading to increased tau phosphorylation, decreased brain-derived neurotrophic factor (BDNF) expression, and downregulation of the Wnt/β-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-3β-Wnt/β-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.

Ameliorative effects of probiotics in AlCl3-induced mouse model of Alzheimer's disease.

In recent years, gut microbiome alterations have been linked with complex underlying mechanisms of neurodegenerative disorders including Alzheimer's disease (AD). The gut microbiota modulates gut brain axis by facilitating development of hypothalamic-pituitary-adrenal axis and synthesis of neuromodulators. The study was designed to unravel the effect of combined consumption of probiotics; Lactobacillus rhamnosus GG (LGG®) and Bifidobacterium BB-12 (BB-12®) (1 × 109CFU) on AlCl3-induced AD mouse model in comparison with potent acetylcholine esterase inhibitor drug for AD, donepezil. Mice were randomly allocated to six different study groups (n = 8). Behavioral tests were conducted to assess effect of AlCl3 (300mg/kg) and probiotics treatment on cognition and anxiety through Morris Water Maze (MWM), Novel Object Recognition (NOR), Elevated Plus Maze (EPM), and Y-maze. The results indicated that the combined probiotic treatment significantly (p < 0.0001) reduced anxiety-like behavior post AlCl3 exposure. The AlCl3 + LGG® and BB-12®-treated group showed significantly improved spatial (p < 0.0001) and recognition memory (p < 0.0001) in comparison to AlCl3-treated group. The expression status of inflammatory cytokines (TNF-α and IL-1β) was also normalized upon treatment with LGG® and BB-12® post AlCl3 exposure. Our findings indicated that the probiotics LGG® and BB-12® have strong potential to overcome neuroinflammatory imbalance, cognitive deficits and anxiety-like behavior, therefore can be considered as a combination therapy for AD through modulation of gut brain axis. KEY POINTS: • Bifidobacterium BB-12 and Lactobacillus rhamnosus GG were fed to AlCl3-induced Alzheimer's disease mice. • This combination of probiotics had remarkable ameliorating effects on anxiety, neuroinflammation and cognitive deficits. • These effects may suggest that combined consumption of these probiotics instigate potential mitigation of AD associated consequences through gut brain axis modulation.

Protective effect of betulin against aluminium-induced Alzheimer-like neurodegeneration

The purpose of this study was to show the preventive properties of the botulin (Bet) and its combination with cyclodextrin in a model of neurodegenerative disease like Alzheimer's disease (AD) in rats. Betulin was obtained from birch bark using standard methodology. The AD model was induced by administering aluminum chloride AlCl3 (200 mg/kg/day) to animals for 120 days. All animals were divided into 4 groups: the control group (sham operation), the second - the AD model (Alz) without prevention with betulin, the third - the Alz+Bet receiving betulin (100 mg/kg/day, i.g., during the last 50% of the experimental days), and the Alz+Bet Complex receiving betulin in complex with cyclodextrin (100 mg/kg/day, i.g., during the last 50% of the experimental days). We showed that betulin in complex with cyclodextrin improve the spatial memory and lowered levels of the TNF-α, APLP2 and β-amyloid in rats with AlCl3-induced AD. We conclude that betulin has neuroprotective properties which may form the basis for the development of a new pharmaceutical that is effective in both the prevention and treatment of Alzheimer's disease.

Garden Cress (Lepidium sativum) Seeds Ameliorated Aluminum-Induced Alzheimer Disease in Rats Through Antioxidant, Anti-Inflammatory, and Antiapoptotic Effects.

Bioaccumulation of aluminum in the brain is associated with adverse neuroinflammatory and neurodegenerative changes, such as those seen in Alzheimer's disease (AD). This study aimed to assess the impact of the administration of Lepidium sativum (LS) extract on behavioral, biochemical, and cerebral histopathological changes in rats with AlCl3-induced AD and explore the mechanism behind this effect. This study was conducted on 40 male albino rats divided into four groups (n=10): LS (control, 20 mg/kg body weight for 8 weeks), AD (AlCl3, 10 mg/kg body weight), and an LS-treated AD group. Behavioral assessment included radial armed maze and active avoidance training tests. Proinflammatory cytokines, oxidant/antioxidant markers, Aβ, AchE, tau protein, TGFβ1, homocysteine, folic acid, and vitamin B12 were biochemically assessed in the serum. The cerebral cortex was histopathologically examined. AlCl3 administration significantly impaired rats' memory, indicating AD-like behavioral changes, significantly increased (P<0.001) oxidative stress markers, enhanced proinflammatory cytokines, and significantly increased AChE (P<0.001) adding to cytotoxic effects and neuronal loss in the cerebral cortex. LS administration significantly improved the antioxidant parameters, reduced proinflammatory cytokines, and alleviated AD-associated histopathological changes. LS ameliorated AlCl3-induced changes through its antioxidant, anti-inflammatory, and antiapoptotic effects, suggesting that it has a neuroprotective effect.

Protective effect of hot peppers against amyloid β peptide and brain injury in AlCl3-induced Alzheimer's disease in rats.

This study investigated the therapeutic effect of red hot pepper (Capsicum annuum) methanolic extract in induced Alzheimer's disease using AlCl3 in male rats. Rats were injected with AlCl3 intraperitoneally (IP) daily for two months. Starting from the 2nd month of AlCl3, rats received, in addition, IP treatments with Capsicum extract (25 and 50 mg/kg) or saline. Other groups received only saline or Capsicum extract at 50 mg/kg for two months. Brain levels of reduced glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) were determined. Additionally, paraoxonase-1 (PON-1) activity, interleukin-6 (IL-6), Aβ-peptide, and acetylcholinesterase (AChE) concentrations in the brain were measured. Behavioral testing included wire-hanging tests for neuromuscular strength and memory tests such as Y-maze and Morris water maze. Histopathology of the brain was also done. Compared with saline-treated rats, AlCl3 caused significant elevation of brain oxidative stress as GSH level and PON-1 activity were depleted along with MDA and NO level elevation in the brain. There were also significant increases in brain Aβ-peptide, IL-6, and AChE levels. Behavioral testing indicated that AlCl3 decreased neuromuscular strength and impaired memory performance. Capsicum extract given to AlCl3-treated rats significantly alleviated oxidative stress and decreased Aβ-peptide and IL-6 in the brain. It also improved grip strength and memory functioning and prevented neuronal degeneration in the cerebral cortex, hippocampus, and substantia nigra of AlCl3-treated rats. Short-term administration of ASA (50 mg/kg) has adverse effects on male reproductive function in mice. Co-administration of melatonin protects against ASA-induced impairment of male reproductive function by preventing the reduction in serum TAC and testosterone levels seen with ASA treatment alone.

RETRACTED ARTICLE: Evaluating the neuroprotective effect of Spirulina platensis–loaded niosomes against Alzheimer’s disease induced in rats

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss, changes in behavior, and avoidance of social bonds. Aluminum is one of the main risk factors in the development of AD. Spirulina platensis (SP) is a microalga that improves motor and cognitive skills and prevents cerebral endothelial damage. SP could be delivered in a more controlled and targeted manner using nanoparticles like niosomes. The purpose of this research was to develop a SP-loaded niosome (SPLN) formulation as a drug delivery system to investigate the effectiveness and toxicity of SP as an AD therapy using the AlCl3-induced AD rat model. A niosomal formulation that consists of Tween 60, cholesterol, and dihexadecyl phosphate in a molar ratio of 1:2:0.1 was chosen as an optimum formulation. AD was induced in rats by orally administering AlCl3. Compared with the AlCl3 control, the group treated with the SPLN formulation showed enhancement of the recognition and working memories by increasing the difference score, the discrimination ratio, and the spontaneous alternation behavior. Additionally, it revealed a significant increase in AchE genes, restored the reduced brain neurotransmitters, and improved brain oxidative status. In conclusion, SPLN formulation could be considered an effective AD therapy.

The neuroprotective effect of ginsenoside Rb1 on the cerebral cortex changes induced by aluminium chloride in a mouse model of Alzheimer's disease: A histological, immunohistochemical, and biochemical study

Alzheimer's disease (AD) is one of the most common types of dementia among neurodegenerative disorders characterized by attention deficits and memory loss. Panax ginseng is a traditional Chinese herbal remedy that has been employed for millennia to manage dementia linked with aging and memory impairment. Ginsenoside Rb1 is one of Panax ginseng's most abundant components. The present work evaluated the neuroprotective effects of ginsenoside Rb1 on the cerebral cortex of AlCl3-induced AD in adult male albino mice. Forty male mice were alienated arbitrarily into; control group, ginsenoside Rb1 group (70 mg/kg/day), AlCl3 group (50 mg/kg/day), and ginsenoside Rb1-AlCl3 group that received ginsenoside Rb1 one hour before AlCl3. Oxidative stress parameters, Amyloid β (Aβ) and phosphorylated tau protein, and acetylcholine esterase (AChE) activity were measured. Cerebral cortex sections were evaluated histologically by light microscopic examination and immunohistochemistry. AlCl3-induced memory impairment, Aβ and phosphorylated tau protein accumulation, and AChE elevation. Moreover, histopathological alterations in the cerebral cortex were reported in the form of irregular shrunken neurons and the surrounding neuropil showed vacuolation. Some neurons appeared with darkly stained nuclei, others had faintly stained ones. The synaptophysin expression was significantly decreased, while the expression of cleaved caspase-3, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1) were significantly elevated. It's interesting to note that these changes were attenuated in mice pretreated with ginsenoside Rb1. Collected data indicated that ginsenoside Rb1 showed a potential neuroprotective effect against cerebral cortex changes caused by AlCl3 via suppression of Amyloid β and phosphorylated tau protein formation, oxidative stress correction, anti-apoptotic effect, and by minimizing gliosis.

The Possible Effects of Vitamin D3 on AlCl3-Induced Histological and Morphometric Alterations of Adult Male Albino Rat Hippocampus.

Alzheimer's disease (AD) is a challenging neurodegenerative disease, and Vitamin D was proved to have neuroprotective effects. This study was conducted to evaluate the potential neuroprotective effects of Vitamin D3 supplementation on AlCl3-induced AD rat model in different hippocampal subregions (CA1, CA2, and CA3). It also aimed to compare the protective effects of protective versus therapeutic effects of Vitamin D3 regiments on the number of degenerated neurons and the neuronal layer thickness. Twenty-four adult male Albino Wister rats were sorted into GI: control; GII: AlCl3-AD model (100 mg/kg) orally for 42 days; GIII: Rats were co-treated with AlCl3 (as GII) and Vitamin D3 (400 IU/kg/day) orally for 42 days; GIV: Rats were treated with AlCl3 for 42 days then with Vitamin D3 for further 2 weeks. Sagittal sections (5 μ) from paraffin-processed brains previously fixed in 10% neutral-buffered formalin were stained with hematoxylin and eosin to evaluate the thickness and number of degenerated neurons in the hippocampal CA1, CA2, and CA3 subregions. The results of this study were expressed as mean ± standard deviation and analyzed by using IBM SPSS Statistics for Windows, version 23 (IBM SPSS, IBM Corp., Armonk, N.Y., USA). P < 0.05 was considered statistically significant. Vitamin D3 supplementations modulated the degenerative changes observed in the hippocampus of AD rat model. In all hippocampal subregions, the thickness was higher in rats treated with Vitamin D3 after the AD induction than rats treated with Vitamin D3 during AD induction. However, this increase was only significant in CA2. Comparison of the number of degenerated neurons between both groups treated with Vitamin D3 revealed that in CA1, the number of degenerated neurons did not statistically differ between the two groups. However, it was insignificantly lower in CA2 in rats treated with Vitamin D3 after the AD induction, and in CA3, it was insignificantly lower in rats treated with Vitamin D3 during the AD induction. Vitamin D3 was found to be effective in ameliorating histological and morphometric alterations in AlCl3-induced AD in rat model and could be proposed as both preventive and therapeutic supplements in high-risk AD patients.

20S-Protopanaxatriol improves cognitive function of Alzheimer's disease by promoting endogenous neurogenesis.

Neurogenesis in Alzheimer's disease (AD) is impaired, and thus promoting neurogenesis is a promising strategy for treating AD-related cognition impairment. Here, we found that 20S-protopanaxatriol (PPT) can alleviate cognitive deficits in an AlCl3-induced AD zebrafish model in Y and T maze tests and increase the HUC expression of the telencephalon. PPT promotes neural stem cell (NSC) line differentiation into neurons under AD condition. PPT significantly alleviated the apoptosis and cell cycle arrest of NSCs induced by amyloid-beta. Next, we investigated the molecular mechanism of PPT in treating AD by network pharmacology and molecular docking. PPT could target PIK3CA and PI3K/AKT signaling pathways. PPT significantly reversed the reduced expression level of PIK3CA (PI3K p110), p-PI3Kp85 and p-AKT of NSCs under AD condition. These results suggested that PPT alleviated the cognitive dysfunction of AD and promoted NSC proliferation and neurogenesis through the PI3K/AKT pathway. Therefore, PPT might be a potential candidate to treat AD-related cognitive decline via enhancing endogenous neurogenesis.

Cationic biopolymer decorated Asiatic Acid and Centella asiatica extract incorporated liposomes for treating early-stage Alzheimer's disease: An In-vitro and In-vivo investigation.

Background:Asiatic acid (AA) is a naturally occurring triterpenoid derivative of Centella asiatica (CA) with neuroprotective effect.The study aimed to design an ideal oral drug delivery system to treat Alzheimer's disease (AD) and develop chitosan-embedded liposomes comprising an extract of CA (CLCAE) and compare them with the chitosan-coated liposomes of asiatic acid (CLAA) for oral delivery to treat the initial phases of AD. Methods:The solvent evaporation technique was used to develop CLCAE and CLAA, optimised with the experiment's design, and was further evaluated. Results:Nuclear magnetic resonance (NMR) studies confirmed coating with chitosan. Transmission electron microscopy(TEM) and atomic force microscopy (AFM) indicated the successful formation of CLCAE and CLAA. Differential scanning colorimetry (DSC) confirmed the drug-phospholipid complex. Furthermore, the rate of in vitrorelease of CLCAE and CLAA was found to be 69.43±0.3 % and 85.3±0.3 %, respectively, in 24 h. Ex vivopermeation of CLCAE and CLAA was found to be 48±0.3 % and 78±0.3 %, respectively. In the Alcl3-induced AD model in rats, disease progression was confirmed by Y-maze, the preliminary histopathology evaluation showed significantly higher efficacy of the prepared liposomes (CLCAE and CLAA) compared to the Centella asiatica extract (CAE) and they were found to have equivalent efficacy to the standard drug (rivastigmine tartrate). The considerable increase in pharmacodynamic parameters in terms of neuronal count in the CLAA group indicated the protective role against Alcl3 toxicity and was also confirmed by assessing acetylcholine (Ach) levels. The pharmacokinetic study, such as C max, T max, and area under curve (AUC) parameters, proved an increase in AA bioavailability in the form of CLAA compared to the pure AA and CLCAE forms. Conclusion:The preclinical study suggested that CLAA was found to have better stability and an ideal oral drug delivery system to treat AD.

Regulatory Effect of Adipose-Derived Mesenchymal Stem Cells and/ or Acitretin on Adam10 Gene in Alzheimer's Disease Rat Model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by progressive cognitive deterioration. All recent therapeutic strategies tend to inhibit the generation of the Aβ peptide. These approaches tend to mediate both α - and γ -secretases to undergo the nonamyloidogenic pathway. ADAM10 is the main α-secretase that cleaves APP, and it is regulated by the metabolic product of vitamin A (retinoic acid), which is being widely used recently in AD research as a target for treatment. Mesenchymal stem cells (MSCs) are also used recently as a promising regenerative therapy for AD. The present study aimed to: (1) study the effect of MSCs with/without acitretin on the regulation of Adam10 gene expression in AlCl3-induced AD rat model, and (2) validate the hypothesis that AD is a time-dependent progressive disease that spreads spontaneously even after the stopping of exposure to AlCl3. The experimental work has been designed to include three successive phases; AlCl3 induction phase (I), AlCl3 withdrawal phase (W), and therapeutic phase (T). Forty-five male albino Wistar rats were randomly divided into 2 main groups: the control (C) group (15 rats) and AD group (30 rats). The therapeutic potential of MSCs with/without acitretin has been evaluated at behavioral, physiological, molecular, and histopathological levels. Among the three therapeutic groups, combined administration of both MSC and acitretin showed the best compensatory effects on most of the measured parameters. The present study approved that AD is a time-dependent progressive disease which spreads spontaneously without more AlCl3 exposure.

Melatonin and zinc supplements with physical and mental activities subside neurodegeneration and hepatorenal injury induced by aluminum chloride in rats: Inclusion of GSK-3β-Wnt/β-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. MethodsSeven 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-β (Aβ), tau levels, and brain derived neurotrophic factor (BDNF). Moreover, the GSK-3β-Wnt/β-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. ResultsThe 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-3β-Wnt/β-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. ConclusionsCombining Mel and Zn supplements with PMA defends against AlCl3-induced AD by modulating GSK-3β-Wnt/β-catenin signaling and palliates the associated hepatorenal dysfunction.

Protective Effects of Bacillus coagulans JA845 against D-Galactose/AlCl3-Induced Cognitive Decline, Oxidative Stress and Neuroinflammation.

Recently, the efficacy of probiotics in treatment of neurodegenerative disorders has been reported in animal and clinical studies. Here, we assessed the effects of Bacillus coagulans JA845 in counteracting the symptoms of D-galactose (D-gal)/AlCl3-induced Alzheimer's disease (AD) in a mice model through behavioral test, histological assessment and biochemical analysis. Ten weeks of pre-treatment with B. coagulans JA845 prevented cognitive decline, attenuated hippocampal lesion and protected neuronal integrity, which demonstrated the neuroprotective features of B. coagulans JA845 in vivo. We also found that supplementation of B. coagulans JA845 alleviated amyloid-beta deposits and hyperphosphorylated tau in hippocampus of D-gal/AlCl3-induced AD model mice. Furthermore, B. coagulans JA845 administration attenuated oxidative stress and decreased serum concentration of inflammatory cytokines by regulating the Nrf2/HO-1 and MyD88/TRAF6/NF-κB pathway. Our results demonstrated for the first time that B. coagulans has the potential to help prevent cognitive decline and might be a novel therapeutic approach for the treatment of neurodegenerative diseases.

Effect of quercetin as therapeutic and protective agent in Aluminum Chloride-induced Alzheimer's disease rats

Alzheimer's disease (AD) is a neurodegenerative disease clinically characterized by progressive cognitive impairment. This work aimed to investigate the role of quercetin (Q) in the treatment and protection of AlCl3-induced AD in rats through exploring the molecular mechanisms underlying its neuroprotective and therapeutic properties. In this study, male Wistar rats were allocated to two experiments: experiment I (therapeutic effect of quercetin) in which the rats were divided into: normal control group (C-Saline) which was induced with saline for 56 days, C-Q50 group, which was administered orally with Q (50 mg/kg) for 28 days after induction saline for 28 days, AD (AlCl3-Saline) group received AlCl3 (50 mg/kg) intraperitoneally for 28 days followed by saline for 28 days, and the AlCl3-Q50 group received Q (50 mg/kg) orally for 28 days after induction with AlCl3 for 28 days. In experiment II rats were divided into: normal control (NC) group, Q50 (50 mg/ kg) group, AlCl3 (AD) group, and AlCl3 + Q50 group which was co-administrated with AlCl3 + Q50 for 56 successive days. Dopamine (DA) and acetylcholinesterase) AChE (levels were estimated for all rat groups. The results showed that post-treatment of the AD-induced rats with Q50 as well as co-administration of AlCl3with Q50, significantly reduced the AChE level in serum, significantly increased the DA level, and significantly increased the body weight change compared to the AlCl3group, but did not show any significant change in the brain weight. We concluded that quercetin significantly improved the cholinergic and dopaminergic dysfunctions by lowering the Acetylcholine esterase level and restoring the dopamine level

Neuroprotective effect of Betalain against AlCl3-induced Alzheimer's disease in Sprague Dawley Rats via putative modulation of oxidative stress and nuclear factor kappa B (NF-κB) signaling pathway

Alzheimer's disease (AD) is the most progressive form of neurodegenerative disease, which severely impairs cognitive function. Oxidative stress is identified to contribute to the mechanisms responsible for the pathogenesis of such neurodegenerative diseases. Aluminum is a potent neurotoxin for inducing oxidative stress associated with neurodegenerative diseases. The treatment for AD is limited; hence more treatment options are the need of the day. Betalain is known for its multitude of medicinal assets, including anti-inflammatory activity. Hence, this study was intended to investigate the possible protective effect of betalain against aluminum chloride (AlCl3) induced AD on Sprague Dawley (SD) rats. AlCl3 (100 mg/kg) was administrated orally to induce the AD in SD rats. The rats were supplemented with low and high betalain doses (10 mg/kg and 20 mg/kg) for four weeks. At the end of the experiment, the rats were subjected to behavioral examination and sacrificed to study the biochemical and histological parameters. The results showed attenuation of memory and learning capacity, suppression of lipid oxidation (MDA) through regulation of antioxidant content (SOD, CAT, and GSH) and inhibition of lactate dehydrogenase (LDH), nitric oxide (NO), acetylcholinesterase (AChE), and transmembrane protein (Na+K+ATPase) activity. In addition, the NF-ƙB associated mRNA expression (TNF-α IL-6, Il-1β, iNOS, COX-2) was decreased, as evidenced in histopathological results. The present investigation established that the betalain treatment ameliorated the AlCl3 induced AD by modulating NF-κB pathway activation.

Plasmalogens improve swimming performance by modulating the expression of genes involved in amino acid and lipid metabolism, oxidative stress, and ferroptosis in an Alzheimer's disease zebrafish model.

Plasmalogens (PLs) are critical to human health. Studies have reported a link between the downregulation of PLs levels and cognitive impairments in patients with Alzheimer's disease (AD). However, the underlying mechanisms remain to be clarified. In the present study, an AlCl3-induced AD zebrafish model was established, and the model was used to elucidate the neuroprotective effects of PLs on AD by analysing the transcriptional profiles of zebrafish in the control, AD model, AD_PL, and PL groups. Chronic AlCl3 exposure caused swimming performance impairments in the zebrafish, yet PLs supplementation could improve the dyskinesia recovery rate in the AD zebrafish model. Through transcriptional profiling, a total of 5413 statistically significant differentially expressed genes (DEGs) were identified among the groups. In addition to the DEGs involved in amino acid metabolism, we found that the genes related to iron homeostasis, lipid peroxidation, and oxidative stress, all of which contribute to ferroptosis, were dramatically altered among different groups. These results suggest that seafood-derived PLs, in addition to their role in eliminating oxidative stress, can improve the swimming performance in AlCl3-exposed zebrafish partly by suppressing neuronal ferroptosis and accelerating synaptic transmission at the transcriptional level. This study provides evidence for PLs to be developed as a functional food supplement to relieve AD symptoms.