Induction Of Alzheimer's Disease Research Articles

Investigating the Subacute Effects of Two Vestibular Stimulation Methods and Their Combination on Spatial Memory in a Rat Model of Alzheimer’s Disease

Background and Aim: Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and spatial memory deficits. Recent studies have suggested a potential link between the vestibular system and cognitive function.‏ ‏Despite advancements in understanding the role of vestibular stimulation in neurological disorders, there is a paucity of research on this subject. In this regard, this study aims to assess the subacute effects two vestibular stimulation methods and their combination on spatial memory in a rat model of AD. Methods: Thirty Wistar rats were divided into five groups of AD (without intervention), Rotational Vestibular Stimulation (RVS), noisy Galvanic Vestibular Stimulation (nGVS), nGVS+RVS, and healthy control. The intervention groups received stimulation for 14 days. After AD induction and its confirmation, to examine the sub-acute effects of the stimulation, their performance was assessed using the Morris Water Maze (MVM) test one month later. Results: Statistically significant improvements were observed in the MVM test parameters in the RVS and nGVS+RVS groups compared to the AD group, in the training days and in the probe day, especially in the time to reach the platform and the time spent in the target quarter. Time spent in goal quarter improved in the RVS group compared to the nGVS+RVS group, but the difference was not statistically significant. Conclusion: The RVS alone or in combination with nGVS can improve spatial memory of rats with AD. Keywords: Alzheimer’s disease; vestibular stimualtion; spatial memory; rat; rotational vestibular stimulation; noisy galvanic vestibular stimulation

In silico, In vitro, and In vivo Evaluation of the Anti-alzheimer’s Activity of Berberine

Background: Alzheimer’s disease (AD), a progressive neurodegenerative disease for which there is no effective cure is among the leading causes of death worldwide. Objectives: To investigate the potential anti-AD activity of berberine (BBR). Methods: In silico assessment included molecular docking and ADMET prediction. BBR’s in vitro inhibitory activity of the target selected from docking results was assessed via colorimetric inhibitor screening assay. BBR’s LC50 in adult zebrafish was determined via an Acute Toxicity Study. ZnCl2 concentration for AD induction was determined via toxicity study and T-maze test. Finally, zebrafish were treated with ZnCl2 alone or simultaneously with either BBR or donepezil and assessed via the inhibitory avoidance task, followed by ELISA of AD-related biomarker levels in brain tissue. Results: The in silico assessment showed BBR’s desirable drug properties and binding affinity on selected AD-related targets, which was the greatest docking score with AChE. The in vitro IC50 on AChE was 3.45 μM. The LC50 in adult zebrafish was calculated at 366 ppm. In the T-maze test, ZnCl2 at 2.5 ppm caused the greatest cognitive impairment accompanied by moderate freezing. In the inhibitory avoidance test, fish treated with either 100 ppm BBR or 2.5 ppm donepezil had significantly better performance than ZnCl2-treated fish. ZnCl2-treated zebrafish brain tissue had the highest Aβ levels and AChE activity of all groups, but these were significantly lower in donepeziland BBR-treated fish. ZnCl2- and donepezil-treated fish had similar TNF-α levels, whereas BBR treatment significantly lowered them close to those of untreated fish. Conclusion: BBR showed anti-amyloidogenic, anti-AChE, and anti-inflammatory effects, which support its potential use in AD therapy.

Outcome of resveratrol and resveratrol with donepezil combination on the β-amyloid plaques and neurofibrillary tangles in Alzheimer’s disease

The goal of this research was to study the effect of different doses of resveratrol (RS) and RS with donepezil (DPZ) on the deposition of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) in colchicine-induced Alzheimer’s disease (AD) brain. The study included three months old male Albino Wistar rats and consisted of six animal groups: AD model (group 1), treatment groups, RS 10 mg/kg body weight (group 2), RS 20 mg/kg body weight (group 3), RS 10 mg/kg body weight along with DPZ 1 mg/kg body weight (group 6), prophylaxis groups, RS 10 mg/kg body weight (group 4) and RS 20 mg/kg body weight (group 5). In the treatment groups, RS was given for 7 consecutive days from the day of induction of AD, and in the prophylaxis groups, we started RS 7 days even before the induction of AD and continued for seven days after the induction. The number of Aβs and NFTs at the frontal region, cornu ammonis (CA) 1,2,3,4 and dentate gyrus regions of hippocampus were evaluated. The immunohistochemical analysis was performed by using mouse anti-β-amyloid antibody for the Aβ plaques and polyclonal rabbit anti-human tau for the tau-positive neurons. The present study observed the accumulation of Aβ plaques and tau-positive neurons in the AD model. However, their numbers were significantly decreased in the treatment groups (p < 0.001). The best results were observed when RS 10 mg was given prophylactically (p < 0.01) and RS along with DPZ (p < 0.001), suggesting the neuroprotective effect of RS and its synergistic effect with the DPZ.

Effect of Melilotus Extract and Exercise on Oxidative Stress and Neuroinflammation in an Alzheimer's Mouse Model

Background: Oxidative stress and neuroinflammation are key factors in the pathophysiology of Alzheimer's disease (AD). Objectives: This study aimed to investigate the effects of resistance training on gene expression and certain neuroinflammatory and oxidative stress indicators in the hippocampus and testicular tissue of male rats with AD. Methods: Fifty-five eight-week-old male Wistar rats were obtained and randomly divided into four groups: Alzheimer's control, Alzheimer's + training, Alzheimer's + melilotus, and Alzheimer's + melilotus + training. An additional 11 rats were included in a healthy control group. Alzheimer's disease was induced in the rats. The intervention protocol included resistance training and melilotus administration. In the resistance training protocol, a weight was attached to the rats' tails, requiring them to lift these weights up 26 steps of a ladder. Complementary groups also received melilotus. Seventy-two hours after the last session, the rats were euthanized, and the hippocampus was extracted for further analysis. A two-way ANOVA test was used to estimate differences between groups after the induction of AD (P ≤ 0.05). Primers were designed, cDNA was prepared, and specific tissues were analyzed. Results: The results showed that exercise and melilotus consumption decreased the levels of the beta-secretase enzyme, testicular clusterin, nerve growth factor (NGF), and Brain-Derived neurotrophic factor (BDNF) genes, and increased nuclear erythroid-related factor 2 (Nrf2), peroxiredoxin 6 (PRDX6), and lysine acetyltransferase 2B (KAT2B), with significant differences observed between the groups. Conclusions: The intervention of exercise and melilotus extract consumption positively affected health and reduced the progression of AD. The independent variables' intervention modified the expression of genes related to AD, likely due to increased brain blood flow from exercise, synaptic strengthening of neurons, and the anti-inflammatory and antioxidant properties of melilotus.

Oral administration of liposome-encapsulated thymol could alleviate the inflammatory parameters in serum and hippocampus in a rat model of Alzheimer's disease

BackgroundNeuroinflammation is closely related to Alzheimer's Disease (AD) pathology, hence supplements with anti-inflammatory property could help attenuate the progression of AD. This study was conducted to evaluate the potential anti-inflammatory effects of liposome encapsulated thymol (LET), administered orally, in prevention of Alzheimer in a rat model by anti-inflammatory mechanisms. MethodsThe rats were grouped into six groups (n = 10 animals per group), including Control healthy (Con), Alzheimer's disease (AD) model, AD model treated with free thymol in 40 and 80 mg/kg body weight (TH40 and TH80), AD model treated with LET in 40 and 80 mg/kg of body weight (LET40 and LET80). The behavioral response of step through latency (Passive Avoidance Test), concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) were assessed in serum and hippocampus. ResultsThe results showed that significant increase in concentrations of IL-1β (P = 0.001), IL-6 (P = 0.001), TNF-α (P = 0.001) and COX-2 (P = 0.001) in AD group compared with healthy control rats. AD induction significantly reduced step through latency and revealed deficits in passive avoidance performance. The results also showed the treatment with free thymol especially in higher concentrations and also LTE could decrease serum concentrations of IL-1β (P < 0.05), IL-6 (P < 0.05), TNF-α (P < 0.05), and COX-2 (P < 0.05) and increase BDNF (P < 0.05) compared with control Alzheimer rats in hippocampus and serum. There were also significant correlations between serum and hippocampus concentrations of IL-1β (r2 = 0.369, P = 0.001), IL-6 (r2 = 0.386, P = 0.001), TNF-α (r2 = 0.412, P = 0.001), and COX-2 (r2 = 0.357, P = 0.001). It means a closed and positive relation between serum and hippocampus concentrations of IL-1β, IL-6, TNF-α, and COX-2. ConclusionsLET demonstrates its ability to attenuate neuroinflammatory reaction in AD model through suppression of IL-1β, IL-6, and TNF-α and COX-2 indicators. Hence, it can ameliorate AD pathogenesis by declining inflammatory reaction.

Protective effects of selegiline against amyloid beta-induced anxiety-like behavior and memory impairment.

Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various aspects of memory performance, anxiety, and oxidative stress in an AD rat model induced by intracerebroventricular injection of amyloid beta1-42 (Aβ1-42). Oral administration of SEL at a dose of 0.5mg/kg/day was performed for 30 consecutive days. Following the 30 days, several tests, including the open-field, elevated plus-maze, novel object recognition, Morris water maze, and passive avoidance learning were conducted to assess locomotor activity, anxiety-like behavior, recognition memory, spatial memory, and passive avoidance memory, respectively. The results indicate that the induction of AD in rats led to recognition memory, spatial memory, and passive avoidance memory impairments, as well as increased anxiety. Additionally, the AD rats exhibited a decrease in total antioxidant capacity and an increase in total oxidant status levels, suggesting an imbalance in oxidative-antioxidant status. However, the administration of SEL improved memory performance, reduced anxiety, and modulated oxidative-antioxidant status in AD rats. These findings provide evidence that SEL may alleviate anxiety-like behavior and cognitive deficits induced by Aβ through modulation of oxidative-antioxidant status.

Evaluation of Neuroprotective effect of Cassia occidentalis L. against Colchicine Induced Memory Impairment in Wistar Rats

Background: Alzheimer’s disease (AD) is a progressive neurological disorder that develops with aging. Objective: In this research, we have examined the anti - Alzheimer’s effect of ethanolic extract from roots of Cassia occidentalis L. on colchicine-induced Alzheimer’s in Wistar rats Methods: Ethanolic extract was obtained and spectroscopic, chromatography analysis was performed. Acute toxicity studies using Organization of Economic Co-operation and Development (OECD) Guidelines 423 were performed to examine and make sure that there were no signs of toxic effects. The induction of AD was done using colchicine which leads to symptoms like neurotoxicity, neuroinflammation, and neurodegeneration. In this experiment, a thorough analysis of body weight, behavioral parameters, locomotor activity, and biochemical evaluation was performed to estimate the medicinal properties of Cassia occidentalis L in treating Alzheimer’s disease. Results: Pharmacognostic analysis showed the presence of vascular bundles, starch grains, fibers, calcium oxalate crystals, elongated parenchyma, and collenchyma mucilage as shown in the supplementary files. Locomotor activity, Escape latency time, Conditioned avoidance response, and Transfer latency were improved with treatment. Interleukin- 6 (IL - 6) levels were reduced significantly in the Colchicine + 200 Cassia mg/kg group (739.2 ± 0.37 pg/ml) than in the Colchicine Group (850.6±0.40 pg/ml). Tumor necrosis factor (TNF-α) was decreased in the Colchicine + 200 Cassia mg/kg Group (1030.93±0.51 pg/ml) than in the Colchicine Group (1455.06±1.25 pg/ml). A significant decrease in total protein level was observed in the Colchicine Group (2.52±0.10 mg/ml), (3.33±0.90 mg/ml) as compared to Colchicine + 200 Cassia mg/kg Group (5.27±0.09 mg/ml, (5.01±0.10 mg/ml) respectively, in the Hippocampus and Entorhinal cortex. The levels of antioxidant enzymes such as Catalase (CAT), Serum superoxide dismutase (SOD), Reduced glutathione (GSH) and Malondialdehyde (MDA) were measured. When compared to the Colchicine Group (7.33±0.16 nM/ mg, the MDA level was lower in the Colchicine + 100 Cassia mg/kg Group (3.20±0.01 nM/ mg). The level of CAT in Colchicine + 200 Cassia mg/kg Group (7.01±0.03 μmoles of H2O2/mg of protein) was seen to be increased when compared to Colchicine Group (3.32 ± 0.17 μmoles of H2O2/mg of protein). The level of SOD in Colchicine + 200 Cassia mg/kg Group (7.43±0.02 U mg -1 of protein) was seen to be increased when compared with Colchicine Group (4.55±0.03 U mg -1 of protein). The level of GSH in Colchicine + 200 Cassia mg/kg Group (10.07±0.19 nM/mg -1 of protein) was increased when compared with the Colchicine Group (5.82±0.11nM/mg -1 of protein). Histopathology of the Hippocampus and Entorhinal cortex showed diminished amyloid plaques, and neurodegeneration in the treatment groups Conclusion: The present study showed that ethanolic extract from the roots of Cassia occidentalis L. At 100 and 200 mg/kg doses in Wistar rats improved memory damage, by reducing oxidative stress. Levels of the antioxidant enzymes as CAT, and SOD, GSH were increased and MDA was decreased. The cytokine levels in the serum of Wistar rats of IL-6 level and TNF-α level were reduced significantly. Estimation of total protein level was found to be increased. It restored neuronal degeneration in the Hippocampus, and Entorhinal cortex and reduced oxidative stress. This suggests that the ethanolic extract of Cassia occidentalis L. could be an effective therapeutic treatment for neurodegenerative diseases like AD.

Cacao consumption improves passive avoidance memory impairment in a rat model of Alzheimer's disease: the role of hippocampal synaptic plasticity and oxidative stress.

Introduction: Alzheimer's disease (AD) causes progressive loss of cognitive function and synaptic plasticity, which is the most common form of dementia. The present study was designed to scrutinize the effects of cacao on passive avoidance memory function and to identify the roles of hippocampal synaptic plasticity and oxidative stress in an AD rat model induced by unilateral intracerebroventricular (UICV) injection of amyloid-beta (Aβ). Methods: Oral administration of cacao (500 mg/kg/ day) was given for 2 consecutive months. A memory retention test was conducted 24 h after passive avoidance training was completed. Subsequently, the amplitude of population spike (PS) and slope of field excitatory postsynaptic potentials (fEPSPs) were assessed at hippocampal long-term potentiation (LTP) in perforant pathway-dentate gyrus (PP-DG) synapses. Moreover, total thiol group (TTG) and malondialdehyde (MDA) concentrations were evaluated in the plasma. Furthermore, compact Aβ plaques were detected in the hippocampal DG by performing Congo red staining. Results: As a result of AD induction, passive avoidance memory was impaired; also, reduced fEPSP slopes, PS amplitudes, and content of TTG, and increase in MDA levels in the rats were observed. In contrast, cacao treatment ameliorated passive avoidance memory impairment, improved hippocampal LTP impairment, modulated oxidative-antioxidative status, and delayed Aβ plaques production in AD rats. Disscussion: Conclusively, cacao alleviates Aβ-induced cognitive deficit, probably by the amelioration of hippocampal LTP impairment, modulation of oxidative-antioxidative status, and inhibition of Aβ plaque accumulation.

Effects of Cycloastragenol on Alzheimer's Disease in Rats by Reducing Oxidative Stress, Inflammation, and Apoptosis.

As individuals age, they may develop Alzheimer's disease (AD), which is characterized by difficulties in speech, memory loss, and other issues related to neural function. Cycloastragenol is an active ingredient of Astragalus trojanus and has been used to treat inflammation, aging, heart disease, and cancer. This study aimed to explore the potential therapeutic benefits of cycloastragenol in rats with experimentally induced AD. Moreover, the underlying molecular mechanisms were also evaluated by measuring Nrf2 and HO-1, which are involved in oxidative stress, NFκB and TNF-α, which are involved in inflammation, and BCL2, BAX, and caspase-3, which are involved in apoptosis. Sprague-Dawley rats were given 70 mg/kg of aluminum chloride intraperitoneally daily for six weeks to induce AD. Following AD induction, the rats were given 25 mg/kg of cycloastragenol daily by oral gavage for three weeks. Hippocampal sections were stained with hematoxylin/ eosin and with anti-caspase-3 antibodies. The Nrf2, HO-1, NFκB, TNF-α, BCL2, BAX, and caspase-3 gene expressions and protein levels in the samples were analyzed. Cycloastragenol significantly improved rats' behavioral test performance. It also strengthened the organization of the hippocampus. Cycloastragenol significantly improved behavioral performance and improved hippocampal structure in rats. It caused a marked decrease in the expression of NFκB, TNF-α, BAX, and caspase-3, which was associated with an increase in the expression of BCL2, Nrf2, and HO-1. Cycloastragenol improved the structure of the hippocampus in rats with AD. It enhanced the outcomes of behavioral tests, decreased the concentration of AChE in the brain, and exerted antioxidant and anti-inflammatory effects. Antiapoptotic effects were also noted, leading to significant improvements in cognitive function, memory, and behavior in treated rats.

The effect of 8 weeks of interval training combined with the consumption of cineole, linalool, and bourbonene on MAPK/Arc gene expression and learning in rats with Alzheimer’s disease

Background and aims: This research aimed to investigate the effect of 8 weeks of interval training and the use of cineole, linalool, and bourbonene on MAPK/Arc gene expression and learning in Alzheimer’s disease (AD) rats. Methods: In this experimental study, 40 AD rats were randomized into eight groups, including (1) control, (2) AD, (3) AD+aerobic training (AT), (4) AD+linalool, cineole, and bourbonene (LCB), (5) AD+AT+LCB, (6) AT+AD, (7) LCB+AD, and (8) AT+LCB+AD. AD was induced by injecting amyloid-beta (Aβ1)-42 into the hippocampus of rats. The interval training protocol was performed five days per week for eight weeks before and after AD induction. Linalool at a concentration of 25 mg/kg, cineole at a concentration of 10 µM, and β-bourbonene at a concentration of 10 µg/mL were used for eight weeks. One-way analysis of variance was used for between-group comparisons, and Tukey’s test was used for pairwise comparisons at P≤0.05. Results: AD induction caused a significant decrease in MAPK/Arc gene expression in hippocampal tissue (P=0.001). Interval exercise and consumption of three herbal drugs significantly increased gene expression of Arc (P=0.001) and MAPK (P=0.001). AD induction decreased learning (P=0.001). Interval exercise and consumption of three herbal medicines caused a significant increase in learning (P=0.001). Conclusion: Interval exercise and using three herbal medicines have more favorable effects on improving MAPK/Arc gene expression and learning in AD than each alone.

High-intensity interval training combined with cannabidiol supplementation improves cognitive impairment by regulating the expression of apolipoprotein E, presenilin-1, and glutamate proteins in a rat model of amyloid β-induced Alzheimer's disease.

Alzheimer's disease (AD) is a major public concern and one of the primary types of dementia characterized by memory impairment and cognitive decline. Although the properties of exercise training and cannabidiol (CBD) treatments for improving AD have recently been revealed, the exact mechanisms remain unknown. Therefore, this study highlights the interactive impact of high-intensity interval training (HIIT) and CBD administration on improving cognitive impairment in a rat model of amyloid beta (Aꞵ)-induced AD through modulating the expression of apolipoprotein E (APOE), presenilin-1, and glutamate proteins. After acclimatization, the animals were randomly assigned into seven subgroups: control (CNT), Sham, Alzheimer (AL), Alzheimer + HIIT (AL + HIIT), Alzheimer + cannabidiol (AL + CBD), Alzheimer + CBD + HIIT (AL + CBD + HIIT), and model (sacrificed ten days after surgery to confirm the induction of AD) groups. To induce AD, rats received an intrahippocampal injection of Aꞵ. The animals in exercise groups performed the HIIT protocol, and the rats in CBD groups were administered 20 mg/kg CBD suspended in sesame oil for six weeks. Following the experimental protocol, serum and hippocampus tissue were collected for histopathological and western blot analysis. Our findings indicated that both HIIT and CBD treatments were efficacious in ameliorating Aꞵ deposition and modulating biomarkers of AD, including APOE, presenilin-1, and glutamate. However, the interactive effect of HIIT and CBD supplementation was more effective. Our findings demonstrated the positive therapeutic effect of HIIT and CBD interventions, particularly HIIT combined with CBD, on alleviating AD.

Combined Donepezil with Astaxanthin via Nanostructured Lipid Carriers Effective Delivery to Brain for Alzheimer's Disease in Rat Model.

Donepezil (DPL), a specific acetylcholinesterase inhibitor, is used as a first-line treatment to improve cognitive deficits in Alzheimer's disease (AD) and it might have a disease modifying effect. Astaxanthin (AST) is a natural potent antioxidant with neuroprotective, anti-amyloidogenic, anti-apoptotic, and anti-inflammatory effects. This study aimed to prepare nanostructured lipid carriers (NLCs) co-loaded with donepezil and astaxanthin (DPL/AST-NLCs) and evaluate their in vivo efficacy in an AD-like rat model 30 days after daily intranasal administration. DPL/AST-NLCs were prepared using a hot high-shear homogenization technique, in vitro examined for their physicochemical parameters and in vivo evaluated. AD induction in rats was performed by aluminum chloride. The cortex and hippocampus were isolated from the brain of rats for biochemical testing and histopathological examination. DPL/AST-NLCs showed z-average diameter 149.9 ± 3.21 nm, polydispersity index 0.224 ± 0.017, zeta potential -33.7 ± 4.71 mV, entrapment efficiency 81.25 ±1.98% (donepezil) and 93.85 ±1.75% (astaxanthin), in vitro sustained release of both donepezil and astaxanthin for 24 h, spherical morphology by transmission electron microscopy, and they were stable at 4-8 ± 2°C for six months. Differential scanning calorimetry revealed that donepezil and astaxanthin were molecularly dispersed in the NLC matrix in an amorphous state. The DPL/AST-NLC-treated rats showed significantly lower levels of nuclear factor-kappa B, malondialdehyde, β-site amyloid precursor protein cleaving enzyme-1, caspase-3, amyloid beta (Aβ1‑42), and acetylcholinesterase, and significantly higher levels of glutathione and acetylcholine in the cortex and hippocampus than the AD-like untreated rats and that treated with donepezil-NLCs. DPL/AST-NLCs showed significantly higher anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, anti-inflammatory, and anti-apoptotic effects, resulting in significant improvement in the cortical and hippocampal histopathology. Nose-to-brain delivery of DPL/AST-NLCs is a promising strategy for the management of AD.

Functional Nanomaterials for the Diagnosis of Alzheimer's Disease: Recent Progress and Future Perspectives.

Alzheimer's disease (AD) is one of the main causes of dementia worldwide, whereby neuronal death or malfunction leads to cognitive impairment in the elderly population. AD is highly prevalent, with increased projections over the next few decades. Yet current diagnostic methods for AD occur only after the presentation of clinical symptoms. Evidence in the literature points to potential mechanisms of AD induction beginning before clinical symptoms start to present, such as the formation of amyloid beta (Aβ) extracellular plaques and neurofibrillary tangles (NFTs). Biomarkers of AD, including Aβ 40, Aβ 42, and tau protein, amongst others, show promise for early AD diagnosis. Additional progress is made in the application of biosensing modalities to measure and detect significant changes in these AD biomarkers within patient samples, such as cerebral spinal fluid (CSF) and blood, serum, or plasma. Herein, a comprehensive review of the emerging nano-biomaterial approaches to develop biosensors for AD biomarkers' detection is provided. Advances, challenges, and potential of electrochemical, optical, and colorimetric biosensors, focusing on nanoparticle-based (metallic, magnetic, quantum dots) and nanostructure-based biomaterials are discussed. Finally, the criteria for incorporating these emerging nano-biomaterials in clinical settings are presented and assessed, as they hold great potential for enhancing early-onset AD diagnostics.

Minocycline effects on memory and learning impairment in the beta-amyloid-induced Alzheimer’s disease model in male rats using behavioral, biochemical, and histological methods

Alzheimer’s disease (AD), as an advanced neurodegenerative disease, is characterized by the everlasting impairment of memory, which is determined by hyperphosphorylation of intracellular Tau protein and accumulation of beta-amyloid (Aβ) in the extracellular space. Minocycline is an antioxidant with neuroprotective effects that can freely cross the blood-brain barrier (BBB). This study investigated the effect of minocycline on the changes in learning and memory functions, activities of blood serum antioxidant enzymes, neuronal loss, and the number of Aβ plaques after AD induced by Aβ in male rats. Healthy adult male Wistar rats (200–220g) were divided randomly into 11 groups (n = 10). The rats received minocycline (50 and 100 mg/kg/day; per os (P.O.)) before, after, and before/after AD induction for 30 days. At the end of the treatment course, behavioral performance was measured by standardized behavioral paradigms. Subsequently, brain samples and blood serum were collected for histological and biochemical analysis. The results indicated that Aβ injection impaired learning and memory performances in the Morris water maze test, reduced exploratory/locomotor activities in the open field test, and enhanced anxiety-like behavior in the elevated plus maze. The behavioral deficits were accompanied by hippocampal oxidative stress (decreased glutathione (GSH) peroxidase enzyme activity and increased malondialdehyde (MDA) levels in the brain (hippocampus) tissue), increased number of Aβ plaques, and neuronal loss in the hippocampus evidenced by Thioflavin S and H&E staining, respectively. Minocycline improved anxiety-like behavior, recovered Aβ-induced learning and memory deficits, increased GSH and decreased MDA levels, and prevented neuronal loss and the accumulation of Aβ plaques. Our results demonstrated that minocycline has neuroprotective effects and can reduce memory dysfunction, which are due to its antioxidant and anti-apoptotic effects.

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.

Effects of diverse Types of Toxoplasma gondii on the outcome of Alzheimer's disease in the rat model.

Toxoplasma gondii has lifelong persistence in the brain and its cysts can affect gene expression and change diverse biological functions of neurons. Many studies indicated T. gondii infection as a risk factor for the development of behavioral changes and neurodegenerative diseases such as Alzheimer's disease (AD), although the etiopathogenetic link between them has not been exactly elucidated. The current study aimed to examine the effects of chronic toxoplasmosis infection with Types I, II, and III strains (RH, PRU, and VEG) alone and in combination on cognitive impairments and neuronal death in the Aβ1-42-induced rat model of Alzheimer's disease. In the chronic toxoplasmosis phase, Alzheimer's induction was conducted by injecting Aβ1-42 oligomers into the rat brain hippocampus. Behavioral tests were conducted 10 days after the AD induction. Real-time PCR was performed to evaluate T. gondii parasite burden by amplification of the B1 gene. Cytokines IL-1β, TNF-α, and IL-10 were assayed in brain tissue supernatant using ELISA. Also, histopathological examinations were conducted to calculate inflammatory changes and neuronal death in the brain. Our findings showed that chronic toxoplasmosis infection with PRU reduces cognitive disorders, while the RH strain of T. gondii plays a destructive role and aggravates cognitive impairments in AD. Also, infection with a combination of PRU and VEG strains significantly improved spatial learning and memory impairments in Alzheimer's rat model. Histopathological findings also confirmed the results of behavioral tests, so that in AβPRU and AβPRU+VEG groups, neuronal death and infiltration of inflammatory cells were negligible and significantly less than in Alzheimer's and AβRH groups. Our findings indicate that chronic toxoplasmosis infection with PRU strain alone, also in combination with VEG strain can significantly improve cognitive disorders in AD rats, while RH strain plays a destructive role in AD pathogenesis.

Antioxidant properties of Trifolium resupinatum and its therapeutic potential for Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by a progressive deterioration in cognitive function, which typically begins with impairment in memory. Persian clover (Trifolium resupinatum) is an annual plant found in central Asia. Due to its contents (high flavonoid and isoflavones), extensive researches have been done on its therapeutic properties, such as multiple sclerosis (MS) treatment. In this study, we investigate the neuroprotective effects of this plant on Streptozotocin (STZ)-induced AD in rats. This research aimed to evaluate the neuroprotective effect of Trifolium resupinatum on the spatial learning and memory, superoxide dismutase (SOD), expressions of β amyloid 1-42 (Ab 1-42 ), and b amyloid 1-40 (Ab 1-40 ) in the hippocampus of STZ-induced Alzheimer rats. Our data showed that Trifolium resupinatum extract administration for two weeks before and one week after AD induction significantly improves maze escape latency ( p = 0.027, 0.001 and 0.02 in 100, 200, and 300 mg of the extract, respectively) and maze retention time ( p = 0.003, 0.04 and 0.001 in 100, 200, and 300 mg of the extract, respectively). Also, the administration of this extract significantly increases the SOD levels from 1.72+0.20 to 2.31+0.45 ( p = 0.009), 2.48+0.32 ( p = 0.001) and 2.33+0.32 ( p = 0.007) and decreases the expressions of Ab 1-42 ) ( p = 0.001 in all concentrations of the extract) and Ab 1-40 ) ( p = 0.001 in all concentrations of the extract) in the rat's hippocampus. This study suggests that the alcoholic extract of Trifolium resupinatum has anti-Alzheimer and neuroprotective effects on rats.

Brain Targeting of Citicoline Sodium via Hyaluronic Acid-Decorated Novel Nano-Transbilosomes for Mitigation of Alzheimer's Disease in a Rat Model: Formulation, Optimization, in vitro and in vivo Assessment.

Alzheimer's disease (AD) is one of the furthermost advanced neurodegenerative disorders resulting in cognitive and behavioral impairment. Citicoline sodium (CIT) boosts the brain's secretion of acetylcholine, which aids in membrane regeneration and repair. However, it suffers from poor blood-brain barrier (BBB) permeation, which results in lower levels of CIT in the brain. This study targeted to encapsulate CIT into novel nano-platform transbilosomes decorated with hyaluronic acid CIT-HA*TBLs to achieve enhanced drug delivery from the nose to the brain. A method of thin-film hydration was utilized to prepare different formulae of CIT-TBLs using the Box-Behnken design. The optimized formula was then hyuloranated via integration of HA to form the CIT-HA*TBLs formula. Furthermore, AD induction was performed by aluminum chloride (Alcl3), animals were allocated, and brain hippocampus tissue was isolated for ELISA and qRT-PCR analysis of malondialdehyde (MDA), nuclear factor kappa B (NF-kB), and microRNA-137 (miR-137) coupled with immunohistochemical amyloid-beta (Aβ1-42) expression and histopathological finding. The hyuloranated CIT-HA*TBLs formula, which contained the following ingredients: PL (300 mg), Sp 60 (43.97 mg), and SDC (20 mg). They produced spherical droplets at the nanoscale (178.94 ±12.4 nm), had a high entrapment efficiency with 74.92± 5.54%, had a sustained release profile of CIT with 81.27 ±3.8% release, and had ex vivo permeation of CIT with 512.43±19.58 μg/cm2. In vivo tests showed that CIT-HA*TBL thermogel dramatically reduces the hippocampus expression of miR-137 and (Aβ1-42) expression, boosting cholinergic neurotransmission and decreasing MDA and NF-kB production. Furthermore, CIT-HA*TBLs thermogel mitigate histopathological damage in compared to the other groups. Succinctly, the innovative loading of CIT-HA*TBLs thermogel is a prospectively invaluable intranasal drug delivery system that can raise the efficacy of CIT in Alzheimer's management.

The Effect of Aerobic Training before Alzheimer’s Induction on the Expression of Calcineurin and Ca2+/Calmodulin-dependent Protein Kinase II Gene in the Hippocampus of Rats with Alzheimer’s Disease

Background and Objectives Regular aerobic exercise improves learning, memory, and cognitive and Synaptic Plasticity in Alzheimer’s disease (AD) patients. The aim of this study was to evaluate the levels of calcineurin and Ca2+/calmodulin-dependent protein kinase II mRNA after four weeks of aerobic training exercises and before AD induction in the hippocampus of male Wistar rats. Subjects and Methods Thirty 8-week-old rats with an average weight of 195±20 g were initially randomly divided into two groups of aerobic exercise or rest for four weeks. Then, each group was divided into three groups of AD, sham, and injection. Then, 48 hours after the last training session, Aβ1-42, or DMSO was injected into the hippocampus. Finally, after the isolation of the hippocampus, CaN mRNA and CaMKII mRNA levels were measured. Results The results of this study showed that there was a significant difference between the groups in mRNA CaN and CaMKII mRNA levels (P&lt;0.05). The results showed that aerobic exercise and AD pre-induction had a significant effect on increasing calcineurin and Ca2+/calmodulin-dependent protein kinase II levels. Conclusion Overall, the findings of the present study showed that four weeks of aerobic training improves the molecular signaling of neuroplasticity in AD rats.

Changes in Some Observational Cardiac Parameters and Cardiac PGC1-α Expression Following Eight Weeks of Endurance Training and Saffron Consumption in Animal Models of Alzheimer’s Disease

Introduction: The link between Alzheimer’s disease (AD) and heart disease has recently been reported. Previous studies have reported the beneficial role of endurance training (ET) and saffron (Sa) on the heart and nervous system health, but their interactive effect is not yet well known. Therefore, the aim of this study was to determine changes in some observational cardiac parameters and cardiac PGC1-α expression after 8 weeks of ET and Sa consumption in animal models of AD. Methods: In this experimental trial, 40 rats with AD (by intraperitoneal injection of 8 mg/kg neurotoxin trimethyltin) were divided into (1) AD, (2) sham (Sh), (3) Sa, (4) ET, and (5) ET+Sa groups. Additionally, to evaluate the effect of AD induction on the research variables, 8 healthy rats were included in the healthy control (HC) group. Groups 4 and 5 ran for 8 weeks, three 15-30 minute sessions per week at a speed of 20-15 m/min. Groups 3 and 5 received 25 mg/ kg aqueous extract of Sa peritoneally each day. To analyze the data, dependent samples t test, one-way analysis of variance and Tukey’s post hoc test, analysis of covariance with Bonferroni’s post hoc test in SPSS version 22.0 were used (P≥0.05). Results: In the Sa and ET+Sa groups, heart weight, heart weight to body weight ratio, and cardiac PGC1-α expression were higher and the body weight of these groups was significantly lower compared with the AD group (P≤0.05). Moreover, in the ET group, heart weight was higher than body weight and total body weight was lower compared to the AD group (P≤0.05). Conclusion: It seems that Sa and ET+Sa interaction improve heart function and some parameters related to heart health by increasing PGC1-α expression, but the effect of training depends on its type and intensity, which should be further studied.