H3 relaxin mediated neuroprotection in Alzheimer's disease pathology induced by streptozotocin in mouse models: Impact on memory improvement, autophagy and PI3K/Akt-mTOR signalling pathway.

Sporadic dementia of Alzheimer’s type (SDAT) pathogenesis has not been revealed completely due to the difficulty in creating an appropriate animal model. The purpose of this study was to investigate the effect of single-dose intraperitoneal (IP) induction of streptozotocin (STZ) and lipopolysaccharide (LPS) on the β-amyloid levels and the brain function of experimental rats. Eighteen rats were divided into three groups i.e. control, TRE1 (STZ 60 mg.kg-1 BW + LPS 3 mg.kg-1 BW), and TRE2 (STZ 30 mg.kg-1 BW + LPS 1.5 mg.kg-1 BW). The substances were administered in a single dose. Behavioral tests were started at day-30 after injection, we performed Morris water maze (MWM) and novel object recognition (NOR) tests. Afterward, we measured whole brain and serum β-amyloid levels, as one of the biomarkers of Alzheimer’s Disease (AD), using the ELISA method. In MWM tests, the escape latency and time spent in the target quadrant of treatment groups were significantly higher than those in control at the day-5 MWM test and probe trial. The rats in treatment groups have negative discrimination indexes in NOR tasks, indicating that the rats could not remember the familiar object. Intraperitoneal STZ and LPS significantly increase soluble brain β-amyloid levels of treatment groups than those in the control group. In conclusion, the treatment of STZ (60 mg.kg-1 BW) and LPS (3 mg.kg-1 BW) indicated spatial and recognition memory impairment, along with an increase of brain soluble β-amyloid level in rats.

Alzheimer's disease (AD) is associated with reduced insulin level and impairment of insulin receptor (IR) signaling in the brain, which correlates to amyloid pathology, neuroinflammation, and synaptic neurotoxicity. Clinical studies show that intranasal insulin improves memory in AD patients without peripheral hypoglycemia. However, neuroprotective molecular mechanism of the beneficial effect of intranasal insulin in AD pathology is unexplored. Therefore, we investigated the role of intranasal insulin on intracerebroventricular (ICV) streptozotocin (STZ)-induced memory impairment in rats as evaluated in the Morris water maze test. STZ (ICV) treated rats had shown memory impairment along with a significant decrease in IR signaling molecules (IR, pIRS-1, pAkt, and pGSK-3α/β expression) and IDE expression in both hippocampus and cerebral cortex. Intranasal insulin delivery prevented these changes. Moreover, intranasal insulin was found to inhibit significantly glial cell activation (GFAP and Iba-1 expression), neuroinflammation (COX-2 expression, NFκB translocation, TNF-α, and IL-10 level) and amyloidogenic protein expression (BACE-1 and Aβ1-42 expression) in STZ (ICV)-injected rats. STZ (ICV)-induced caspase activation and postsynaptic neurotoxicity were also prevented by treatment with intranasal insulin. Our findings reveal that insulin has the neuroprotective effect and clearly signifies the potential use of intranasal insulin delivery for the treatment of AD. Graphical Abstract Neuroprotective effects of intranasal insulin administration on streptozotocin (ICV)-induced memory impairment in rats.

Dulaglutide ameliorates STZ induced AD-like impairment of learning and memory ability by modulating hyperphosphorylation of tau and NFs through GSK3β

Alzheimer's disease (AD) is characterized by cognitive deterioration, oxidative stress and neuroinflammation. Reliable preclinical models for sporadic AD are lacking. The intracerebroventricular (ICV) streptozotocin (STZ) model simulates pathology of sporadic AD; its timeline remains ambiguous. We assessed multiple endpoints in male Wistar rats 1 and 3 months post-ICV STZ (3mg/kg; n = 72; control, sham, STZ). Spatial and associative memory was tested via the Morris Water Maze and Passive Avoidance Task. Hippocampal superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), and brain-derived neurotrophic factor (BDNF) were measured by ELISA; neuronal integrity and amyloid deposits by hematoxylin-eosin (H&E) and Congo red staining. STZ groups (3-months vs. 1-month) exhibited cognitive deficits: increased escape latency (80.14 ± 5.75 vs. 65.68 ± 11.51s; P = 0.008), decreased time in the target quadrant (7.32 ± 0.71 vs. 11.6 ± 1.99s; P = 0.019), platform crossings (0.83 ± 0.4 vs. 2.5 ± 0.83; P < 0.001) and step-through latency (3.89 ± 1.14 vs. 12.43 ± 3.28s; P = 0.011). SOD activity decreased (6.28 ± 0.76 vs. 10.11 ± 1.26 U/mg; P = 0.015), TNF-α increased (71.17 ± 2.16 vs. 58.06 ± 2.22 pg/mg; P = 0.004) and BDNF declined (47.09 ± 9.21 vs. 86.83 ± 8.51 pg/mg; P < 0.001). Histology revealed neuronal shrinkage, vacuolation and amyloid deposits in 3-months STZ rats. The ICV STZ model recapitulates AD features: cognitive decline, oxidative stress, neuroinflammation and compromised neurotrophic support. Limitations such as lack of neurofibrillary tangles and sex evaluations require investigation. Studies exploring tau pathology, sex differences, and long-term dynamics may refine therapeutic strategies.

Oxidative stress is the leading cause of neurodegenerative diseases, especially Alzheimer´s disease (AD). The plant Persicaria flaccida (PF) is known in Bengali as red Biskatali belongs to family Polygonaceae. Preliminary studies have shown the antioxidant, anti-inflammatory, analgesic, neuroprotective activities of Biskatali. In this consequence, methanolic extract of PF (MEPF) was selected to explore the ability of this plant to enhance cognitive functions, brain antioxidant enzymes and anti-acetylcholinesterase activity which can be used for the treatment of AD. The objective of this study was to investigate the effects of MEPF on cognitive performance, brain antioxidant enzymes and acetylcholinesterase activity in rats by using behavioral and biochemical study. Treatment with MEPF (i.e., 100 and 200 mg/kg b.w.) was investigated for 14 days in Swiss albino male rats and its effects on different types of memory were examined using Elevated Plus Maze (EPM) test, Passive Avoidance (PA) test, Morris Water Maze (MWM) test as well as level of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSR), glutathione-S-transferase (GST) and contents of thiobarbituric acid reactive substances (TBARS) in rat brain tissue homogenates. Acetylcholinesterase (AChE) activity was determined by colorimetric method. Administration of highest dose of MEPF significantly (P < 0.05, P < 0.01) decreased retention transfer latency (RTL) of rats on 7th and 14th day compared to the control group in EPM test. In PA test highest dose of MEPF meaningfully (P < 0.05, P < 0.01) increased step-through latency (STL) of rats on 7th, 12th, 13th and 14th day with respect to control group. Both doses of MEPF markedly (P < 0.01, P < 0.001) decreased escape latency (EL), increased time spent in the target quadrant (TSTQ) and time spent in the annuli (TSA) of rats on successive days as compared to that of control group in MWM test. MEPF administration, especially highest dose significantly (P < 0.05, P < 0.01, P < 0.001) increased the level of CAT, SOD, GSR, GST & GSH-Px and considerably (P < 0.01, P < 0.001) decreased TBARS level & AChE activity in the brain tissue homogenates of rats compared to the control group. Behavioral and biochemical studies suggest that MEPF promotes cognitive function by improving different types of memory and reduces oxidative stress by increasing the level of brain antioxidant markers and anti-acetylcholinesterase activity. Therefore, this plant extract can be used for enhancing memory in neurodegenerative disorders like AD.

Danisco invests in second-generation bioethanol project with DuPont

Nitric oxide impairs spatial learning and memory in a rat model of Alzheimer’s disease via disturbance of glutamate response in the hippocampal dentate gyrus during spatial learning

Increased serum insulin levels and reduced peripheral insulin activities seen in insulin resistance syndrome are associated with age-dependent cognitive impairment and Sporadic Alzheimer's Disease (SAD), suggesting a disturbance in the insulin signalling system in the brain and possibly being one of the causes of dementia. Therefore, the streptozotocin (STZ)-induced animal may be an appropriate model for the investigation of SAD and related dementia. This study was designed to investigate the beneficial effect of Curcumin (CUR), a neuroprotective agent, on intracerebroventricular (ICV) STZ-induced cognitive impairment in rats. For this purpose, adult male Wistar rats were bilaterally ICV injected with STZ (3 mg/kg). An artificial cerebrospinal fluid (aCSF) was given to the control group (SHAM) instead of STZ on days 1 and 3. Learning and memory performance were assessed using the "passive avoidance task" and the "Morris water maze test". After confirmation of acquisition impairment with these tests, the STZ group was divided into two subgroups: STZ + vehicle (Vh) and STZ + CUR. The rats in the SHAM and STZ + Vh groups were administered intraperitoneally with 0.5 ml Vh and the rats in the STZ + CUR group were treated intraperitoneally with CUR (300 mg kg(-1) day(-1) in Vh) for 10 days starting from the 25th day after STZ injection. The Morris water maze test was reapplied on the 35th day after STZ injection and all of the rats were sacrificed on day 36 for quantitation of IGF-1 and for histopathological evaluation. Rats in the STZ + CUR group were found to have a higher performance in cognitive tests than rats in the STZ + Vh group (P < 0.01). In parallel with the cognitive tests, IGF-1 levels were decreased in all of the STZ-injected groups (1.78 +/- 0.34) compared to the SHAM group (3.46 +/- 0.41). In contrast, CUR treatment significantly increased IGF-1 levels (P < 0.001). The degree of neuronal loss decreased after CUR treatment compared to the SHAM group (P < 0.02). These results clearly indicate that CUR treatment is effective in reducing the cognitive impairment caused by STZ in rats, and may be a potential therapeutic agent for altering neurodegeneration in SAD.

Introduction: Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia. Main neuropathological features of AD include extracellular β-amyloid (Aβ)-containing plaques, intraneuronal aggregates of hyperphosphorylated τ-protein and neurofilaments, microglial activation and clustering around Aβ plaques and synaptic loss. 5XFAD transgenic mice are a model of AD, exhibiting rapid brain accumulation of Aβ and microgliosis. The aim of the study was to characterize the effects of streptozocin (STZ)-indced diabetes on learning and memory of 5XFAD and wild-type (WT) mice in Morris water maze (MWM) at ages 2 and 6 months and on brain amyloid load. Methods and results: Mice were injected with STZ 90 mg/kg or vehicle i.p., once daily for 2 consecutive days. MWM was performed on week 9 and histological analysis of brains of mice injected with STZ or vehicle at 2 months of age was performed on week 16. STZ treatment did not affect locomotion or vision of mice in MWM. At both 2 and 6 months of age, STZ treatment impaired memory of both 5XFAD and WT. Learning was significantly impaired in STZ-treatedc 5XFAD mice at 2 months. Surprisingly, Congo Red-positive area fraction (%) of hippocampus and amygdala was decreased 5XFAD mice treated with STZ at 2 months. Plaque diameter was not different between STZ treated and vehicle treated 5XFAD mice. Conclusions: Insulin deficiency could affect cognition through mechanisms unrelated to Aβ metabolism. Also different mechanisms may underlie effects of STZ treatment on learning and memory in different age gruops, possibly including enhancement of brain amyloid deposition and inhibition of neural cell precursor proliferation. We also hypothesize that STZ treatment might increase the soluble brain amyloid fraction in this model, since it is currently acknowledged that oligomeric (soluble) rather than fibrillar Aβ species disrupt cognitive function in AD.

Background/Aims: Apoptosis, fibrosis and NLRP3 inflammasome activation are involved in the development of diabetic cardiomyopathy (DCM). Human recombinant relaxin-3 (H3 relaxin) is a novel bioactive peptide that inhibits cardiac injury; however, whether H3 relaxin prevents cardiac injury in rats with DCM and the underlying mechanisms are unknown. Methods: To investigate the effect of H3 relaxin on DCM, we performed a study using H3 relaxin treatment in male Sprague-Dawley (SD) rats with streptozotocin (STZ)-induced diabetes (DM). We measured apoptosis, fibrosis and NLRP3 inflammasome markers in the rat hearts four and eight weeks after the rats were injected with STZ (65 mg/kg) by western blot analysis. Subsequently, 2 or 6 weeks after the STZ treatment, the rats were treated with H3 relaxin [2 µg/kg/d (A group) or 0.2 µg/kg/d (B group)] for 2 weeks. Cardiac function was evaluated by echocardiography to determine the extent of myocardial injury in the DM rats. The protein levels of apoptosis, fibrosis and NLRP3 inflammasome markers were used to assess myocardial injury. In addition, we determined the plasma levels of IL-1β and IL-18 using a Milliplex MAP Rat Cytokine/Chemokine Magnetic Bead Panel kit. Results: The protein expression of cleaved caspase-8, caspase-9 and caspase-3 as well as fibrosis markers increased at 4 and 8 weeks in the STZ-induced diabetic hearts compared with the levels in the control group. Furthermore, the NLRP3 inflammasome was substantially activated in STZ-induced diabetic hearts, leading to increased IL-1β and IL-18 levels. Compared with the DM group, the A group exhibited substantially better cardiac function. The protein levels of apoptosis markers were attenuated by H3 relaxin, indicating that H3 relaxin inhibited myocardial apoptosis in the hearts of diabetic rats. The protein expression of fibrosis markers was inhibited by H3 relaxin. Additionally, the protein expression and activation of the NLRP3 inflammasome were also effectively attenuated by H3 relaxin. Conclusions: This study is the first to demonstrate that H3 relaxin plays an anti-apoptotic, anti-fibrotic and anti-inflammatory role in DCM.

Brain-targeted Tet-1 peptide-PLGA nanoparticles for berberine delivery against STZ-induced Alzheimer’s disease in a rat model: Alleviation of hippocampal synaptic dysfunction, Tau pathology, and amyloidogenesis

Synergistic enhancing-memory effect of D-serine and RU360, a mitochondrial calcium uniporter blocker in rat model of Alzheimer's disease

FGF-18 alleviates memory impairments and neuropathological changes in a rat model of Alzheimer's disease

This study aimed to determine the effects of 8weeks of an administration of Bifidobacterium bifidum and Lactobacillus plantarum combined with exercise training on neurotoxicity of Aβ, spatial learning, acetylcholine (ACH), and vascular endothelial growth factor (VEGF) in Alzheimer rats. Twenty-five Wistar rats were randomly divided into 5 groups (n = 5 in each): (1) healthy control (control), (2) Alzheimer disease (AD), (3) AD with treadmill exercise (AD + Exe), (4) AD with probiotic (combined administration of Bifidobacterium bifidum and Lactobacillus plantarum) treatment (AD + Pro), and (5) AD with treadmill exercise and probiotic treatment (AD + Exe + Pro). AD was induced by intra-cerebroventricular injection of Aβ1-42 peptide. Then, the training groups exercised on treadmill for 8weeks, 5days per weeks. The rats were treated daily with probiotic supplements via gavage for 8weeks. The Morris water maze (MWM) test was administered to measure spatial learning. Then, the animals were sacrificed and Vegf and ACH were analyzed using the qPCR and immunohistochemistry (IHC) methods, respectively. Results showed that the β-amyloid plaques were significantly increased in the brains of the AD group compared with the control group (p < 0.001). The combined use of probiotics and exercise training significantly increased the time spent in the target quadrant after removing the platform, compared with the ADgroup in the Morris water maze test (p < 0.001). Crystal violet analysis showed that sole (p < 0.01) and combined exercise training and probiotic supplementation (p < 0.001) significantly reduced the number of dead cells in the brains of rats compared with the AD group. AD significantly decreased Vegf mRNA and ACH in the CA1 area of the hippocampus (p < 0.001). However, mono and combined therapy (exercise and probiotics) significantly increased ACH in the rats' brain compared with the AD group. Overall, 8weeks of an administration of Bifidobacterium bifidum and Lactobacillus plantarum combined with exercise training can improve spatial learning impairment in the AD rats. Exercise and probiotics seem to offer potential benefits to AD patients by upregulating ACH.

Context: Prosopis cineraria (L.) Druce (Leguminosae), a plant of the Thar Desert of India and Pakistan is used traditionally by local people for the treatment of memory disorders and to arrest wandering of the mind.Objective: The study includes scientific validation of P. cineraria for nootropic activity. To elucidate the possible mechanism, the anticholinesterase activity was also investigated in different parts of the brain.Materials and methods: Methanol extract of P. cineraria stem bark (200, 400 and 600 mg/kg body weight p.o.) was administered once in a day for 7 days to rats and these rats were then subjected to Morris water-maze (MWM) test for spatial reference memory (SRM) and spatial working memory (SWM) versions of memory testing. The inhibitory effect of the extract on acetylcholinesterase (AChE) in discrete rat brain regions (prefrontal cortex [PFC], hippocampus [HIP] and amygdala [AMY]) was also investigated using acetyl thiocholine iodide and dithiobisnitrobenzoic acid reagent.Results and discussion: The oral administrations of methanol extract of P. cineraria in all doses tested, significantly (p < 0.05) improved both spatial reference and working memories in the MWM test in terms of decrease in escape latency during SRM and increase in time spent in the target quadrant during SWM probe trial. A ceiling effect was observed at 400 mg/kg. Pre-treatment for 7 days significantly inhibited the activity of AChE in the HIP, PFC and AMY.Conclusion: The extract exerted significant nootropic activity in the MWM test which may be attributed to the inhibition of brain AChE.