Streptozotocin-induced Alzheimer's Disease Research Articles

Anti-viral Effects of Pavetta indica Methanolic Extract and Acyclovir on Behavioral and Biochemical Parameters in Streptozotocin-induced Alzheimer's Disease in Rats.

Alzheimer's disease is a neurological dysfunction of the brain caused by neurodegeneration and oxidative stress. Some viruses, such as herpes viruses, HSV-1, and HSV-2, are causative agents of Alzheimer's disease and result in β-amyloid peptide and tau protein accumulation in the brain. Some antiviral drugs, such as valacyclovir, acyclovir, and foscarnet, reduce amyloid-beta and P-tau. Pavetta indica leaves are also reported for their antiviral properties. The current study aimed to find out the significance of using Pavetta indica methanolic extract and acyclovir against Alzheimer's disease induced by streptozotocin. Wistar rats received acyclovir and Pavetta indica methanolic extract orally at different dose ranges (50, 150, 450 mg/kg) and (125, 250, 500 mg/kg), respectively. The standard therapy, Rivastigmine (2 mg/kg), was given orally. Intracerebroventricular-streptozotocin produced significant alternations in behavioral assessments, including locomotor activity test, Morris water maze test, and elevated plus maze test. Moreover, intracerebroventricular-streptozotocin ameliorated the antioxidant defense activity by decreasing levels of catalase, superoxide dismutase, and reduced glutathione while enhancing the oxidative stress markers, including malondialdehyde, and total nitrite levels. Finally, the main findings showed that intracerebroventricular-streptozotocin significantly increased the inflammatory marker, tumor necrosis factor-α, and disturbed neurotransmitter mediators, including levels of acetylcholinesterase, glutamate, and γ-amino butyric acid. In a dose-dependent manner, acyclovir and Pavetta indica methanolic extract treatments abrogated the streptozotocin-induced behavioral and neurological abnormalities in rats. The potential therapeutic effects of PIME and acyclovir administration in intracerebroventricular-streptozotocin-treated rats may be attributed to its potential antiviral, antioxidant, and anti-inflammatory effects. The current study suggests that Pavetta indica methanolic extract and acyclovir are promising therapeutic targets against Alzheimer's disease.

Evaluation of the Effects of Repetitive Anaesthesia Administration on the Brain Tissues and Cognitive Functions of Rats with Experimental Alzheimer's Disease.

Introduction: We evaluated the effects of repeated ketamine, propofol, and ketamine + propofol administration on cognitive functions and brain tissue of elderly rat models with streptozotocin-induced Alzheimer's disease. Materials and Methods: Thirty elderly male Wistar Albino rats were divided into five groups: control (Group C), Alzheimer's (Group A), Alzheimer's + ketamine (Group AK), Alzheimer's + propofol (Group AP), and Alzheimer's + propofol + ketamine (Group APK). Alzheimer's disease was induced in Groups A, AK, AP, and APK via intracerebroventricular streptozotocin. Four weeks after surgery, ketamine, propofol, and ketamine + propofol were administered intraperitoneally for 3 days to Groups AK, AP, and APK, respectively. The radial arm maze test (RAMT) was performed in the initial, 1st, 2nd, 3rd, and 4th weeks after surgery and daily following anaesthesia. Blood and brain tissue samples were obtained. Results: The RAMT results of Groups A, AK, AP, and APK decreased compared to Group C 2 weeks after Alzheimer's disease onset. Compared to Group A, the RAMT results increased in Groups AK and APK after the first anaesthesia, and in Group AP after the second anaesthesia. Brain tissue paraoxonase-1 (PON-1) and catalase (CAT) activities were low, and the thiobarbituric acid reactive substance (TBARS) level was high in Group A compared to Group C. TBARS levels of Groups AP and APK were lower than Group A, while CAT activity was higher. PON-1 activity was higher in Groups AK, AP, and APK than in Group A. Histopathological changes decreased in Groups AP and AK. A decrease in p53 was found in Group C compared to Group A. Ketamine and propofol were found to be effective at Bcl-2 immunoexpression, but a decrease in Caspase-3 was observed in Group APK. GFAP immunoexpression increased in Group A compared to Group C and in Group AP compared to Group AK. Conclusions: Repetitive anaesthesia application was found to positively affect cognitive functions. This was supported by histopathological and biochemical markers.

Amylovis-201 enhances physiological memory formation and rescues memory and hippocampal cell loss in a streptozotocin-induced Alzheimer's disease animal model

Alzheimer's disease is the most common neurodegenerative disease, and its treatment is lacking. In this work, we tested Amylovis-201, a naphthalene-derived compound, as a possible therapeutic candidate for the treatment of AD. For this purpose, we performed three experiments. In the first and third experiment, animals received a bilateral administration of streptozotocin and, starting 24 h after injection, a daily dose of Amylovis-201 (orally), for 17 days or for the whole time of the experiment respectively (28 days), after which learning and memory, as well as the number of hippocampal dentate gyrus cells, were assessed. In the second experiment, healthy animals received a single dose of Amylovis-201, 10 min or 5 h after the learning section to assess whether this substance could promote specific mechanisms involved in memory trace formation. Our data show that, administration of a single dose of Amylovis-201, 10 min after the end of training, but not at 5 h, produces a prolongation in memory duration, probably because it modulates specific mechanisms involved in memory trace consolidation. Furthermore, daily administration of Amylovis-201 to animals with bilateral intracerebroventricular injection of STZ produces a reduction in the loss of the hippocampus dentate gyrus cells and an improvement in spatial memory, probably because Amylovis-201 can interact with some of the protein kinases of the insulin signaling cascade, also involved in neural plasticity, and thereby halt or reverse some of the effects of STZ. Taking to account these results, Amylovis-201 is a good candidate for the therapeutic treatment of AD.

Voglibose attenuates cognitive impairment, Aβ aggregation, oxidative stress, and neuroinflammation in streptozotocin-induced Alzheimer's disease rat model.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease hallmarked by Amyloid-β (Aβ) aggregation, cognitive impairment, and neuronal and synaptic loss. In this study, AD was induced in male Wistar rats (n = 6) by the administration of intracerebroventricular-streptozotocin (ICV-STZ-3mg/kg/day), and Voglibose (Vog) was administered at various doses (10, 25, and 50mg/kg), while Galantamine (3mg/kg) acted as a reference standard drug. Behavioral alterations in both spatial and non-spatial memory functions were evaluated in the experimental rats. At the end of the study, all experimental rats were sacrificed, and their brain parts, the cortex and hippocampus, were subjected to biochemical, western blot, and histopathological analysis. In our study results, the statistically significant dose-dependent results from the behavioral tests show the Voglibose-treated groups significantly improved (p < 0.0001) spatial and non-spatial memory functions when compared with ICV-STZ-treated group. Meanwhile, when compared with ICV-STZ-treated rats, treatment with Voglibose (10, 25, and 50mg/kg) showed the activities of both acetylcholinesterase (AChE) and malondialdehyde (MDA) were significantly attenuated (p < 0.0001), while the operation of antioxidant enzymes was considerably enhanced (p < 0.0001). The molecular estimation showed that it significantly attenuates (p < 0.0001) the TNF-α, IL-1β, and CRP activity, and the western blot results demonstrate the significantly attenuated Aβ aggregation. The histopathological results showed that the Voglibose treatment had an effective improvement in clear cytoplasm and healthy neuronal cells. In conclusion, our results suggest that Voglibose has potent neuroprotective effects against the ICV-STZ-induced AD model. Furthermore, these results support the possibility of Voglibose as a therapeutic approach to improving cognitive function, suggesting that controlling Aβ aggregation might be a novel target for the development of AD.

Effects of thymoquinone and memantine alone and in combination on memory and hippocampal morphology in rats with streptozotocin-induced Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Thymoquinone (TQ) has broad biological functions, including antiinflammatory, antioxidant, neuroprotective properties. Memantine (MEM) is indicated for the symptomatic treatment of moderate to severe AD. We aimed to evaluate the effect of TQ alone or in combination with MEM on memory and hippocampal morphology in an STZ-induced rat AD model. Thirty male rats were included in this study. The AD model was created by giving ICV STZ. The rats were divided into 5 groups (n = 6 each). Group 1 (control group): The rats received only ICV-STZ 3 mg/kg for 2 weeks. Group 2 (sham group): In addition to ICV STZ, 9% NaCl, 1 mL/day i.p. for 2 weeks of injection, was applied. Group 3 (TQ group): In addition to ICV STZ, rats received TQ 10 mg/kg i.p. for 2 weeks. Group 4 (MEM group): In addition to ICV STZ, rats were given MEM at a dose of 5 mg/kg for two weeks. Group 5 (TQ+MEM group): In addition to ICV STZ, this group was given TQ (10 mg/kg/day, i.p.) and MEM (5 mg/kg/day, i.p.) for 2 weeks. On the 15th day, passive avoidance learning (PAL) was applied to all groups. Then, rats were sacrificed, neurons in the hippocampal CA1, CA2, CA3 regions were evaluated. Groups 3, 4, 5 had longer latency periods than groups 1 and 2. The neuron density in the CA1, CA2, CA3 regions had decreased in groups 1 and 2 compared to groups 3, 4, 5. There were significantly more neurons in groups 3, 4, 5 than in groups 1 and 2. We found that TQ alone and in combination with MEM showed ameliorative effects on memory and hippocampal morphology. TQ may offer a promising treatment strategy for AD.

Streptozotocin-induced Alzheimer's disease investigation by one-dimensional plasmonic grating chip

Recently, there has been significant interest in researching brain insulin resistance as it has been hypothesized that it may play a role in the progression of Alzheimer's disease. Alzheimer’s disease (AD) is brain dementia that contributes to damage to the neuron cells and then patient death. This dementia is ranked as the fifth more dangerous disease in the world. Streptozotocin (STZ) is used to induce Alzheimer’s disease experimentally. STZ is toxic to the pancreatic beta cells and induces insulin resistance. Neuroplasmonin techniques have been used to investigate the ability of STZ on the activity of cultured neuron cells. Neuroplasmonic is a novel technology that combines nanotechnology and biosensor. This technique has been used to record neuron signals in vivo and in vitro. Also, it has many facilities such as label-free detection, real-time analysis, biological compatibility, small sample, high throughput, and low detection limit. In this paper, we introduce a one-dimensional electro-plasmonic nanograting platform that consists of a straight nanorod of gold embedded in a dielectric layer of polycarbonate. The chip is connected with an externally applied voltage to induce tunable PIT and increase the sensor sensitivity. To evaluate the sensing performance of the electro-plasmonic sensor, this chip was cultured with Human Nucleus Pulposus Cells (HNPC). The first step was to measure the neuron cell activity in a healthy case. The next step was to measure the activity of neuron cells injected with different concentrations of STZ (0.5, 1, 2 mM) to induce the formation of Alzheimer’s disease in the cultured neuron cells. The results indicated that the electro-plasmonics sensor had a high sensitivity to the cells' activity and showed good results for the effecting STZ on the neuron cell’s activities.

Inhibition of GluN2B pathway is involved in the neuroprotective effect of silibinin on streptozotocin-induced Alzheimer's disease models

BackgroundOver-activation of N-methyl-D-aspartate receptors (NMDARs) is involved in sporadic Alzheimer's disease. Silibinin, a natural flavonoid gained from the seeds of Silybum marianum, exerts neuroprotective effects on sporadic AD models, but its impacts on NMDARs remain unknown. PurposeTo study silibinin's regulatory effects on NMDARs pathway in sporadic AD models. MethodsMTT assay, western blotting, confocal microscopy, flow cytometry, RT-PCR, and siRNA transfection etc. were used for cellular and molecular studies. The direct interactions between silibinin and NMDAR subunits were evaluated by computational molecular docking, drug affinity responsive target stability (DARTS) assay and cellular thermal shift assay (CETSA). Y maze test, novel objects recognition test and Morris water maze test were conducted to examine the learning and memory ability of rats. ResultsAn in vitro AD model was established by treating HT22 murine hippocampal neurons with streptozotocin (STZ), as evidenced by the amyloid β (Aβ) deposition and hyperphosphorylation of tau proteins. Silibinin shows protection of neurons against STZ-induced cell damage. It is noteworthy that STZ-induced cellular calcium influx is inhibited by silibinin-treatment, indicating the possible modulation of calcium channels. Studies on NMDARs, the most widely distributed calcium channel, by using molecular docking, DARTS and CESTA, reveal that the GluN2B subunit, but not GluN2A, is the potential target of silibinin. Further studies using the pharmacological agonist (NMDA) and the GluN2B-specific inhibitor (Ifenprodil) or siRNA, indicate that the protection by silibinin treatment from STZ-induced cytotoxicity is medicated through interference with GluN2B-containing NMDARs, followed by the upregulation of CaMKIIα/ BDNF/ TrkB signaling pathway and improved levels of synaptic proteins (SYP and PSD-95). The results in vivo using rats intracerebroventricularly injected with STZ (ICV-STZ), a well-established sporadic AD model, confirm that silibinin improves learning and memory ability in association with modulation of the GluN2B/CaMKIIα/ BDNF/TrkB signaling pathway. ConclusionInhibiting over-activation of GluN2B-containing NMDARs is involved in the neuroprotective effect of silibinin on STZ-induced sporadic AD models.

Protective Role of Capsaicin in Neurological Disorders: An Overview.

Different pathological conditions that begin with slow and progressive deformations, cause irreversible affliction by producing loss of neurons and synapses. Commonly it is referred to as 'protein misfolding' diseases or proteinopathies and comprises the latest definition of neurological disorders (ND). Protein misfolding dynamics, proteasomal dysfunction, aggregation, defective degradation, oxidative stress, free radical formation, mitochondrial dysfunctions, impaired bioenergetics, DNA damage, neuronal Golgi apparatus fragmentation, axonal transport disruption, Neurotrophins (NTFs) dysfunction, neuroinflammatory or neuroimmune processes, and neurohumoral changes are the several mechanisms that embark the pathogenesis of ND. Capsaicin (8-Methyl-N-vanillyl-6-nonenamide) one of the major phenolic components in chili peppers (Capsicum) distinctively triggers the unmyelinated C-fiber and acts on Transient Receptor Potential Vanilloid-1, which is a Ca2+ permeable, non-selective cation channel. Several studies have shown the neuroprotective role of capsaicin against oxidative damage, behavioral impairment, with 6-hydroxydopamine (6-OHDA) induced Parkinson's disease, pentylenetetrazol-induced seizures, global cerebral ischemia, and streptozotocin-induced Alzheimer's disease. Based on these lines of evidence, capsaicin can be considered as a potential constituent to develop suitable neuro-pharmacotherapeutics for the management and treatment of ND. Furthermore, exploring newer horizons and carrying out proper clinical trials would help to bring out the promising effects of capsaicin to be recommended as a neuroprotectant.

The Effect of Lidocaine on the Experimental Model of Streptozotocin-Induced Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease caused by the accumulation of amyloid plaques in the cerebral cortex and hippocampus. In this study, the effects of local anesthetic lidocaine on neurodegeneration markers and memory were investigated for the first time in streptozotocin-induced rat AD model. Streptozotocin (STZ) was administered intracerebroventricularly (ICV) into Wistar rats to develop AD model. For lidocaine group (n=14), lidocaine (5 mg/kg) was administered intraperitoneally (IP) in addition to STZ injection. Control group animals (n=9) were treated with saline for 21 days. Morris Water Maze (MWM) test was performed to evaluate memory after the injections were completed. Also, the serum levels of TAR DNA-binding protein-43 (TDP-43), amyloid precursor protein (APP), β-secretase 1, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), response element binding protein (CREB), c-FOS were measured using ELISA test and compared between groups. Lidocaine group animals showed lower escape latency and time in quadrant scores in MWM inferring better memory performance. Furthermore, lidocaine administration caused a significant decline in TDP-43 levels. However, the expression of APP and β-secretase were significantly higher in AD and lidocaine groups compared to control group. Moreover, lidocaine group markedly had higher serum NGF, BDNF, CREB, and c-FOS levels compared to those in the AD group. In addition to neuroprotective effects in STZ-induced AD model, Lidocaine also appears to improve memory. This effect might be associated with increased levels of several growth factors and associated intracellular molecules. The therapeutic role of lidocaine in the pathophysiology of AD should be studied in the future.

Galantamine tethered hydrogel as a novel therapeutic target for streptozotocin-induced Alzheimer's disease in Wistar rats

Amyloid-β (Aβ) plaque formation, neuronal cell death, and cognitive impairment are the unique symptoms of Alzheimer's disease (AD). No single step remedy is available to treat AD, so the present study aimed to improve the drugability and minimize the abnormal behavioral and biochemical activities in streptozotocin (STZ) induced AD experimental Wistar rats. In particular, we explored the utilization of methacrylated gelatin (GelMA), which is a biopolymeric hydrogel that mimics the natural tissue environment. The synthesized biopolymeric gel contained the drug galantamine (Gal). Investigations were conducted to evaluate the behavioral activities of STZ-induced AD experimental rats under STZ ​+ ​GelMA ​+ ​Gal treatment. The experimental groups comprised the control and STZ, STZ ​+ ​GelMA, STZ ​+ ​Gal, and STZ ​+ ​GelMA ​+ ​Gal (10 ​mg/kg) treated rats. Intracerebroventricular STZ ensures cognitive decline in terms of an increase in the escape latency period, with a decrease in the spontaneous alteration of behavioral activities. Our results indicated decrease Aβ aggregation in the hydrogel-based drug treatment group and significant decreases in the levels of acetylcholinesterase and lipid peroxidation (p ​< ​0.001). In addition, the glutathione and superoxide dismutase activities appeared to be improved in the STZ ​+ ​GelMA ​+ ​Gal group compared with the other treatment groups. Furthermore, histopathological and immunohistochemical experiments showed that the GelMA ​+ ​Gal treated AD rats exhibited significantly improved behavioral and biochemical activities compared with the STZ treated AD rats. Therefore, STZ ​+ ​GelMA ​+ ​Gal administration from the pre-plaque stage may have a potential clinical application in the prevention of AD. Thus, we conclude that hydrogel-based Gal drugs are efficient at decreasing Aβ aggregation and improving the neuroinflammatory process, antioxidant activity, and neuronal growth.

Deferoxamine preconditioning enhances the protective effects of stem cells in streptozotocin-induced Alzheimer's disease

AimsStem cell-based therapy is one of the promising strategies in the treatment of Alzheimer's disease (AD), but the short lifespan and low homing of transplanted cells continue to be a major obstacle in this method. Preconditioning of stem cells before transplantation could increase cell therapy efficiency. Herein, we examined whether the treatment of stem cells with deferoxamine (DEF) prior to graft could enhance the neuroprotective effects of stem cells in the streptozotocin (STZ)-treated male rats. Materials and methodsAfter induction of the AD model, the rats were transplanted with DEF-preconditioned Adipose-derived mesenchymal stem cells (AMSCs) or untreated cells. Memory function, antioxidant capacity, cell density, and homing of transplanted cells were assessed using Morris water maze and shuttle box tasks as well as biochemical and histochemical methods. Key findingsTransplantation of AMSCs caused a memory improvement when compared to the AD model. The injection of DEF-preconditioned AMSCs was more effective in improving learning and memory than the untreated cells through an increase in the antioxidant capacity. Moreover, the homing of transplanted cells was higher in the rats that received the preconditioned cells than that of the naïve cell-injected group. SignificanceIt seems that the transplantation of DEF-treated cells may increase the efficiency of stem cells via an increase in the antioxidant capacity.

Neuroprotective effect of lacosamide on cognitive dysfunction in Streptozotocin induced Alzheimer disease

Abstract Alzheimer disease (AD) is a chronic and progressive neurodegenerative disorder characterized by memory loss and cognition impairment. A link has been established between AD and epilepsy sharing multiple mechanisms and pathogenesis. Similar Hippocampal changes have been found between both diseases. Choosing antiepileptic drug in AD patient represent a great a challenge especially with increase seizure risk in AD patients. Lacosamide, antiepileptic drug, was reported to have a neuroprotective effect in animal models and a histone deacetylase inhibition activity. This study was designed to investigate the potential effect of chronic lacosamide treatment in Streptozotocin induced AD in male Wistar rats. Methods AD animal model was induced with single bilateral intracerebroventricular injection of STZ (3 mg/kg) on day one. Lacosamide (30 mg/kg orally, once daily) was administrated for 21 days. Cognitive function assessment was done with Morris Water Maze (MWM) and Y Maze tasks. APP and MAPT mRNA level were measured. Results ICV-STZ caused significant prolongation in Escape latency time and reduction in time spent in target quadrant in MWM and reduction in spontaneous alteration ratio in Y Maze compared to control group. STZ induced Up-regulation in Amyloid precursor protein and Microtubule associated protein tau gene expression. Chronic Lacosamide treatment attenuated STZ induced cognitive impairment and mitigated APP and MAPT induced expression with STZ. Conclusion Lacosamide has a neuroprotective effect against STZ induced cognitive deficits ameliorating Aβ and Tau pathology.

The bile acid TUDCA improves glucose metabolism in streptozotocin-induced Alzheimer's disease mice model

Alzheimer's disease (AD) is a neurodegenerative disorder and the major cause of dementia. According to predictions of the World Health Organization, more than 150 million people worldwide will suffer from dementia by 2050. An increasing number of studies have associated AD with type 2 diabetes mellitus (T2DM), since most of the features found in T2DM are also observed in AD, such as insulin resistance and glucose intolerance. In this sense, some bile acids have emerged as new therapeutic targets to treat AD and metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA), reduces amyloid oligomer accumulation and improves cognition in APP/PS1 mice model of AD, and also improves glucose-insulin homeostasis in obese and type 2 diabetic mice. Herein, we investigated the effect of TUDCA upon glucose metabolism in streptozotocin-induced AD mice model (Stz). The Stz mice that received 300 mg/kg TUDCA during 10 days (Stz + TUDCA), showed improvement in glucose tolerance and insulin sensitivity, reduced fasted and fed glycemia, increased islet mass and β-cell area, as well as increased glucose-stimulated insulin secretion, compared with Stz mice that received only PBS. Stz + TUDCA mice also displayed lower neuroinflammation, reduced protein content of amyloid oligomer in the hippocampus, improved memory test and increased protein content of insulin receptor β-subunit in the hippocampus. In conclusion, TUDCA treatment enhanced glucose homeostasis in the streptozotocin-induced Alzheimer's disease mice model, pointing this bile acid as a good strategy to counteract glucose homeostasis disturbance in AD pathology.

Protective Effects of Co-administration of Zinc and Selenium Against Streptozotocin-Induced Alzheimer's Disease: Behavioral, Mitochondrial Oxidative Stress, and GPR39 Expression Alterations in Rats.

Changes in the concentrations of trace metals such as zinc (Zn) and selenium (Se) can pathologically lead to neurodegenerative conditions such as the Alzheimer's disease (AD). Previous studies have shown that mitochondrial dysfunction plays an important role in the pathogenesis of AD. Several male Wistar rats were randomly divided into five groups: sham group, AD group that received 3mg/kg of streptozotocin (STZ) intracerebroventricularly, AD + Zn group that received 10mg/kg of Zn intraperitoneally (i.p.) for 1week, AD + Se group that received 0.1mg/kg of Se i.p. for 1week, and AD + Zn + Se group that received 10mg/kg of Zn i.p. plus 0.1mg/kg of Se i.p. for 1week. At end of the study, behavioral tests and mitochondrial oxidative stress and GPR39 gene expression evaluations were carried out. Co-administration of Zn and Se significantly decreased the potential collapse of mitochondrial membrane, reactive oxygen species levels, and lipid peroxidation levels while significantly increased cognitive performance, superoxide dismutase (SOD), glutathione peroxidase, and catalase activity in the brain mitochondria compared with the STZ group. In addition, no significant changes were observed in GPR39 expression in the co-treated group. Findings of the current study showed that ZnR/GPR39 receptor, mitochondrial dysfunction, and oxidative stress play important roles in the pathogenesis of AD. Co-treatment of Zn and Se improved the cognitive performance, mitochondrial dysfunction, and oxidative stress caused by STZ-induced AD. Therefore, therapeutic approaches to improve mitochondrial function could be effective in preventing the initiation and progression of AD.

Metformin loaded phosphatidylserine nanoliposomes improve memory deficit and reduce neuroinflammation in streptozotocin-induced Alzheimer's disease model

Alzheimer's disease (AD) is closely associated with neuroinflammation development in the brain. Co-delivery of metformin (MET) with phosphatidylserine liposomes neuroprotectant may be beneficial in ameliorating AD-related symptoms like memory impairment and inflammation. Therefore, we aimed to prepare metformin containing phosphatidylserine nanoliposomes formulation (MET-PSL) and to evaluate its effect on rats subjected to AD. Alzheimer's disease model was induced by bilateral intracerebroventricular injection of streptozotocin (3 mg/kg) into rat brains using the stereotactic technique. MET-PSL, MET, and PSL alone were administered intraperitoneally to AD-induced animals and factors including learning and memory storage in addition to cytokine and tissue inflammatory changes were evaluated after a 22-day experiment period. The learning and memory parameters significantly (P < 0.05) improved in AD-rats treated with MET-PSL. Moreover, MET-PSL administration significantly (P < 0.05) decreased cytokine levels of IL1-β, TNF-α, and TGF-β in hippocampal tissues of rats with AD. Histological results indicated a considerable reduction in inflammatory and necrotic neural cells along with significantly (P < 0.05) increased neurogenesis in MET-PSL treated rats. Furthermore, our results showed that MET-PSL formulation could potentially act better than the free form of MET and PSL alone in the recovery process of rats with AD. In general, our data suggest that combination therapy of metformin loaded phosphatidylserine liposomes may enhance the therapeutic performance in AD patients of a clinical study.

Phosphoinositide 3-kinase inhibitor AS605240 ameliorates streptozotocin-induced Alzheimer's disease like sporadic dementia in experimental rats.

The quest for chemical entities able to curb the action of the phosphoinositide 3-kinase, (PI3K)/protein kinase B (AKT) signaling pathways is evolving as a potential therapeutic strategy for the treatment and/or prevention of neurodegenerative disorders including Alzheimer's disease (AD). In this study, the effects of a PI3K inhibitor, AS605240 on cognitive dysfunction and antioxidative defense parameters against intra-cerebroventricular-streptozotocin (ICV-STZ)-induced rat model of sporadic AD was evaluated. ICV administration of a single dose of STZ (3 mg/kg) was performed to induce behavioral and biochemical changes in rats using the stereotaxic technique. Animals were administered with varying doses of AS605240 (5, 10 and 15 mg/kg) orally, 1 h before ICV-STZ on day 1 and continued once daily for four weeks. The behavioral parameters (passive avoidance and Morris water maze), antioxidative defense parameters, amyloid-beta (Aβ) protein expression by Western blotting and immunostaining technique were estimated in brain tissue. AS605240 dose-dependently and significantly (p < 0.05 and p < 0.01 and p < 0.001) improved ICV-STZ-induced cognitive impairment and attenuated the altered antioxidative related parameters including superoxide dismutase, lipid peroxidation, glutathione and nitrite levels. Further, the increased Aβ protein expression levels in brain tissue were markedly restored with AS605240 treatment. In conclusion, our study demonstrated that AS605240 exhibited immense potential in attenuating STZ-induced sporadic AD features in rats and may be developed as a therapeutic agent in the treatment and management of sporadic AD.

β-Carotene: A Natural Compound Improves Cognitive Impairment and Oxidative Stress in a Mouse Model of Streptozotocin-Induced Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a cascade of changes in cognitive, behavioral, and social activities. Several areas of the brain are involved in the regulation of memory. Of most importance are the amygdala and hippocampus. Antioxidant therapy is used for the palliative treatment of different degenerative diseases like diabetes, cirrhosis, and Parkinson’s, etc. The objective of this study was to assess the effectiveness of exogenous antioxidants, in particular, β carotene (1.02 and 2.05 mg/kg) against intracerebroventricular injected streptozotocin-induced memory impairment in mice. Streptozotocin (3 mg/kg, i.c.v) was administered in two separate doses (on 1st and 3rd days of treatment) for neurodegeneration. Fifty Albino mice (male) were selected in the protocol, and they were classified into five groups (Group I—control, Group II—disease, Group III—standard, Group IV–V—β-carotene-treated) to investigate the cognitive enhancement effect of selected antioxidants. The cognitive performance was observed following the elevated plus-maze, passive avoidance, and open field paradigms. Acetylcholine esterase, β-amyloid protein, and biochemical markers of oxidative stress such as glutathione peroxidase, superoxide dismutase, and catalase were analyzed in brain homogenates. In silico activity against acetylcholinesterase (AChE) was determined by the molecular modeling of β-carotene. β-carotene at a dose of 2.05 mg/kg was found to attenuate the deleterious effects of streptozotocin-induced behavioral and biochemical impairments, including the inhibition of acetylcholinesterase activity. The in silico studies confirmed the binding capacity of β-carotene with the acetylcholinesterase enzyme. The administration of β-carotene attenuated streptozotocin-induced cognitive deficit via its anti-oxidative effects, inhibition of acetylcholinesterase, and the reduction of amyloid β-protein fragments. These results suggest that β-carotene could be useful for the treatment of neurodegenerative diseases such as Alzheimer’s disease.

Effects of recurrent sevoflurane anesthesia on cognitive functions with streptozotocin induced Alzheimer disease.

We aimed to investigate the effects of recurrent sevoflurane anesthesia on cognitive functions in Alzheimer Disease. Rats were divided into 4 groups as followed: control (Group C), sevoflurane (Group S), Alzheimer's (Group A) and Alzheimer's + sevoflurane (Group AS)]. Cognitive functions were evaluated with Radial Arm Maze Test (RAMT). Alzheimer model was created by administering 3 mg/kg (10 μl) STZ. Sevoflurane was administered to S and AS groups. Serum samples and hippocampus tissues were analyzed. In RAM test, the entry-exit data were significantly decreased in A and AS groups. After the 2nd and 3rd administration of anesthesia, the numbers were significantly decreased in Group S. Glial-fibrillary-acidic protein levels were significantly higher in AS compared to the C and S groups. The brain tissue caspase 3 activity was less than 1% in all rats in the Group C, 3 % in 2 rats and 1 % in 1 rat in the Group AS. In A and AS group, serum catalase, myeloperoxidase and ferroxidase activities were found to be higher than in the other groups and myeloperoxidase activity was higher in the AS than in the A Group. Serum native thiol, total thiol and disulfide levels were found to be significantly different in the A and AS groups. Sevoflurane anesthesia negatively affected the cognitive functions (Tab. 5, Fig. 10, Ref. 51).

Impaired chemoreflex correlates with decreased c-Fos in respiratory brainstem centers of the streptozotocin-induced Alzheimer's disease rat model

Besides impairment in cognition and memory, patients with Alzheimer's disease (AD) often exhibit marked dysfunction in respiratory control. Sleep-disordered breathing (SDB) is commonly found in cases of AD, resulting in periods of hypoxia during sleep. Early structural changes in brainstem areas controlling respiratory function may account for SDB in the course of AD. However, to date the underlying mechanisms for these complications are not known. The streptozotocin (STZ)-induced rat model of AD exhibits abnormal responses to hypoxia and increased astrogliosis in a key region for respiratory control. In this study we further defined the pathophysiological respiratory response of STZ-AD rats to 10% O2. In addition, we analyzed hypoxia-induced neuronal activation in respiratory and cardiovascular nuclei of the dorsal and ventral brainstem. Two hours of hypoxia induced a transient increase in tidal volume that was followed by a prolonged increase in respiratory rate. Only respiratory rate was significantly blunted in the STZ-AD model, which continued over the entire duration of the hypoxic episode. Analysis of c-Fos expression as a marker for neuronal activation showed abundant labeling throughout the nTS, nuclei of the ventral respiratory column, and A1/C1 cells of cardiovascular centers in the ventral brainstem. STZ-AD rats showed a significant decrease of c-Fos labeling in the caudal/medial nTS, rostral ventral respiratory group, and Bötzinger complex. c-Fos in other respiratory centers and A1/C1 cells was unaltered when compared to control. The results of this study document a region-specific impact of STZ-induced AD in respiratory brainstem nuclei. This decrease in c-Fos expression correlates with the observed blunting of respiration to hypoxia in the STZ-AD rat model.

5-Hydroxytryptamine receptor 6 antagonist, SB258585 exerts neuroprotection in a rat model of Streptozotocin-induced Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline. It has been suggested that 5-hydroxytryptamine receptor 6 (5-HT6R) might be involved in AD pathology. The aim of this study was to evaluate the effect of a 5-HT6R antagonist on cognition, learning, memory, and hippocampal apoptosis in an experimental rat model of AD. AD was induced by intracerebroventricular (icv) administration of streptozotocin (STZ; 3mg/kg, 10μL, twice). Adult, male rats were divided into the following groups: control, sham, AD (saline treatment, 1μL icv for 30days), and AD + SB258585 (5-HT6R antagonist, 1μg/μL icv for 30days). Following the treatment period, novel object recognition (NOR) and passive avoidance learning (PAL) tests were conducted to measure cognition, as well as learning and memory, respectively. TUNEL staining was used to evaluate apoptosis in the hippocampus. This study demonstrates that icv STZ injections induce apoptosis in hippocampal cells, decrease the NOR discrimination index, increase the number of trials needed to reach acquisition and the time spent in the dark compartment during PAL, as compared with sham and control groups. Subsequent administration of SB258585 in the STZ treated rats increased the NOR discrimination index, decreased the number of trials till acquisition and the time spent in the dark compartment during PAL, while decreasing neuronal apoptosis, as compared to the untreated AD group. Thus, we conclude that long-term administration of the 5-HT6R antagonist SB258585, ameliorates AD-associated cognitive and behavioral impairments through the suppression of apoptosis in the hippocampus.