Intracerebroventricular Streptozotocin In Rats Research Articles

Pharmacokinetic study and neuropharmacological effects of atractylenolide Ⅲ to improve cognitive impairment via PI3K/AKT/GSK3β pathway in intracerebroventricular-streptozotocin rats

Ethnopharmacological relevanceThe traditional Chinese herbal remedy Atractylodes macrocephala Koidz is renowned for its purported gastrointestinal regulatory properties and immune-enhancing capabilities. Atractylenolide III (ATL III), a prominent bioactive compound in Atractylodes macrocephala Koidz, has demonstrated significant pharmacological activities. However, its impact on neuroinflammation, oxidative stress, and therapeutic potential concerning Alzheimer's disease (AD) remain inadequately investigated.Aim of the study: This study aims to assess the plasma pharmacokinetics of ATL III in Sprague-Dawley (SD) rats and elucidate its neuropharmacological effects on AD via the PI3K/AKT/GSK3β pathway. Through this research, we endeavor to furnish experimental substantiation for the advancement of novel therapeutics centered on ATL III. Materials and methodsThe pharmacokinetic profile of ATL III in SD rat plasma was analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). AD models were induced in SD rats through bilateral intracerebroventricular (ICV) administration of streptozotocin (STZ). ATL III was administered at doses of 0.6 mg/kg, 1.2 mg/kg, and 2.4 mg/kg, while donepezil (1 mg/kg) served as control. Cognitive function assessments were conducted employing behavioral tests including the Morris Water Maze and Novel Object Recognition. Neuronal pathology and histological changes were evaluated through Nissl staining and Hematoxylin-Eosin (HE) staining, respectively. Oxidative stress levels were determined by quantifying malondialdehyde (MDA) content and total superoxide dismutase (T-SOD) activity. Molecular docking analysis was employed to explore the direct binding between ATL III and its relevant targets, followed by validation using Western blot (WB) experiments to assess the expression of p-Tau, PI3K, AKT, GSK3β, and their phosphorylated forms. ResultsWithin the concentration range of 5–500 ng/mL, ATL III demonstrated exceptional linearity (R2 = 0.9991), with a quantification limit of 5 ng/mL. In male SD rats, ATL III exhibited a Tmax of 45 min, a t1/2 of 172.1 min, a Cmax of 1211 ng/L, and an AUC(0-t) of 156031 ng/L*min. Treatment with ATL III significantly attenuated Tau hyperphosphorylation in intracerebroventricular-streptozotocin (ICV-STZ) rats. Furthermore, ATL III administration mitigated neuroinflammation and oxidative stress, as evidenced by reduced Nissl body loss, alleviated histological alterations, decreased MDA content, and enhanced T-SOD activity. Molecular docking analyses revealed strong binding affinity between ATL III and the target genes PI3K, AKT, and GSK3β. Experimental validation corroborated that ATL III stimulated the phosphorylation of PI3K and AKT while reducing the phosphorylation of GSK3β. ConclusionsOur results indicate that ATL III can mitigate Tau protein phosphorylation through modulation of the PI3K/AKT/GSK3β pathway. This attenuation consequently ameliorates neuroinflammation and oxidative stress, leading to enhanced learning and memory abilities in ICV-STZ rats.

MST1 selective inhibitor Xmu-mp-1 ameliorates neuropathological changes in a rat model of sporadic Alzheimer's Disease by modulating Hippo-Wnt signaling crosstalk.

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive impairment accompanied by aberrant neuronal apoptosis. Reports suggest that the pro-apoptotic mammalian set20-like kinase 1/2 (MST1/2) instigates neuronal apoptosis via activating the Hippo signaling pathway under various stress conditions, including AD. However, whether inhibiting MST1/2 has any therapeutic benefits in AD remains unknown. Thus, we tested the therapeutic effects of intervening MST1/2 activation via the pharmacological inhibitor Xmu-mp-1 in a sporadic AD rat model. Sporadic AD was established in adult rats by intracerebroventricular streptozotocin (ICV-STZ) injection (3mg/kg body weight). Xmu-mp-1 (0.5mg/kg/body weight) was administered once every 48h for two weeks, and Donepezil (5mg/kg body weight) was used as a reference standard drug. The therapeutic effects of Xmu-mp-1 on ICV-STZ rats were determined through various behavioral, biochemical, histopathological, and molecular tests. At the behavioral level, Xmu-mp-1 improved cognitive deficits in sporadic AD rats. Further, Xmu-mp-1 treatment reduced STZ-associated tau phosphorylation, amyloid-beta deposition, oxidative stress, neurotoxicity, neuroinflammation, synaptic dysfunction, neuronal apoptosis, and neurodegeneration. Mechanistically, Xmu-mp-1 exerted these neuroprotective actions by inactivating the Hippo signaling while potentiating the Wnt/β-Catenin signaling in the AD rats. Together, the results of the present study provide compelling support that Xmu-mp-1 negated the neuronal dysregulation in the rat model of sporadic AD. Therefore, inhibiting MST/Hippo signaling and modulating its crosstalk with the Wnt/β-Catenin pathway can be a promising alternative treatment strategy against AD pathology. This is the first study providing novel mechanistic insights into the therapeutic use of Xmu-mp-1 in sporadic AD.

Sporoderm-removed Ganoderma lucidum spores ameliorated early depression-like behavior in a rat model of sporadic Alzheimer's disease.

Introduction: Ganoderma lucidum: (G. lucidum, Lingzhi) is a medicinal and edible homologous traditional Chinese medicine that is used to treat various diseases, including Alzheimer's disease and mood disorders. We previously reported that the sporoderm-removed G. lucidum spore extract (RGLS) prevented learning and memory impairments in a rat model of sporadic Alzheimer's disease (sAD), but the effect of RGLS on depression-like behaviors in this model and its underlying molecular mechanisms of action remain unclear. Method: The present study investigated protective effects of RGLS against intracerebroventricular streptozotocin (ICV-STZ)-induced depression in a rat model of sAD and its underlying mechanism. Effects of RGLS on depression- and anxiety-like behaviors in ICV-STZ rats were assessed in the forced swim test, sucrose preference test, novelty-suppressed feeding test, and open field test. Results: Behavioral tests demonstrated that RGLS (360 and 720mg/kg) significantly ameliorated ICV-STZ-induced depression- and anxiety-like behaviors. Immunofluorescence, Western blot and enzyme-linked immunosorbent assay results further demonstrated that ICV-STZ rats exhibited microglia activation and neuroinflammatory response in the medial prefrontal cortex (mPFC), and RGLS treatment reversed these changes, reflected by the normalization of morphological changes in microglia and the expression of NF-κB, NLRP3, ASC, caspase-1 and proinflammatory cytokines. Golgi staining revealed that treatment with RGLS increased the density of mushroom spines in neurons. This increase was associated with elevated expression of brain-derived neurotrophic protein in the mPFC. Discussion: In a rat model of ICV-STZ-induced sAD, RGLS exhibits antidepressant-like effects, the mechanism of which may be related to suppression of the inflammatory response modulated by the NF-κB/NLRP3 pathway and enhancement of synaptic plasticity in the mPFC.

Protective effect of daidzein against streptozotocin-induced Alzheimer's disease via improving cognitive dysfunction and oxidative stress in rat model.

Oxidative stress is performing an essential role in developing Alzheimer's disease (AD), and age-related disorder and other neurodegenerative diseases. In existing research, we have aimed at investigating the daidzein (4',7-dihydroxyisoflavone) effect (10 and 20 mg/kg of body weight), as a free radical scavenger and antioxidant in streptozotocin (STZ) infused AD in rat model. Daidzein treatment led to significant improvement in intracerebroventricular-streptozotocin (ICV-STZ)-induced memory and learning impairments that was evaluated by Morris water maze test and spontaneous locomotor activity. It significantly restored the alterations in malondialdehyde, catalase, superoxide dismutase, and reduced glutathione levels. In addition, histopathological observations in cerebral cortex and hippocampal areas confirmed the neuroprotective effect of daidzein. These outcomes provide experimental proof showing preventive effect of daidzein on memory, learning dysfunction and oxidative stress in case of ICV-STZ rats. In conclusion, daidzein offers a potential treatment module for various neurodegenerative disorders with regard to mental deficits like AD.

Chronic administration of piperine attenuates behavioural, biochemical and histological alterations induced by intracerebroventricular streptozotocin in rats

The above article, published online on 11 June 2018 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13052), has been withdrawn by agreement between the journal Editor in Chief, Prof. Kim Brøsen, the corresponding author and Wiley Publishing. The withdrawal has been agreed due to the article having been submitted to multiple journals at the same time.

Neuroprotective effects of tenuigenin on neurobehavior, oxidative stress, and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats.

BACKGROUND:Tenuigenin (TEN), a major active component of the Chinese herb Polygala tenuifolia root, has been used to improve memory and cognitive function in Traditional Chinese Medicine for centuries.PURPOSE:The present study was designed to explore the possible neuroprotective effect of TEN on the streptozotocin (STZ)-induced rat model of sporadic Alzheimer's disease (sAD).METHODS:STZ was injected twice intracerebroventrically (3 mg/kg, ICV) on alternate days (day 1 and day 3) in Rats. Daily treatment with TEN (2, 4, and 8 mg/kg) starting from the first dose of STZ for 28 days. Memory-related behaviors were evaluated using the Morris water maze test. Hyperphosphorylation of tau proteins in hippocampus were measured by western blot assay. Superoxide dismutase activities, malondialdehyde, glutathione peroxidase and 4-hydroxy-2-nonenal adducts contents were also measured in the hippocampus.RESULTS:Treatment with TEN significantly improved STZ-induced cognitive damage, markedly reduced changes in malondialdehyde and 4-hydroxy-2-nonenal adducts, and significantly inhibited STZ-induced reduction in superoxide dismutase and glutathione peroxidase activities in the hippocampus. In addition, TEN decreased hyperphosphorylation of tau resulting from intracerebroventricular STZ (ICV-STZ) injection, and Nissl staining results showed that TEN has protective effects on hippocampal neurons.CONCLUSION:These results provide experimental evidence demonstrating preventive effect of TEN on cognitive dysfunction, oxidative stress, and hyperphosphorylation of tau in ICV-STZ rats. This study indicates that TEN may have beneficial effects in the treatment of neurodegenerative disorders such as AD.

Pre-training Catechin gavage prevents memory impairment induced by intracerebroventricular streptozotocin in rats.

Objective:To evaluate the effects of Catechin (CAT) on memory acquisition and retrieval in the animal model of sporadic alzheimer’s disease (sAD) induced by intracerebroventricular (icv) injection of streptozotocin (STZ) in passive avoidance memory test.Methods:Thirty adult rats were divided into 5 experimental groups (n=6). Animals were treated by icv saline/STZ (3 mg/kg) injection at day one and 3 after cannulation. The STZ+CAT group received 40 mg/kg CAT by daily gavages for 10 days, after icv STZ treatment and before training. The step-through latency (STL) and time spent in the dark compartment (TDC) were evaluated to examine the memory acquisition and retrieval. All tests were performed in Qom University of Medical Sciences, Qom, Iran, from April to December 2013.Results:The STZ treatment significantly decreased STL and increased the number of entries to the dark compartment on the training day. It also increased TDC, on day one and 7 after training. Pre-training gavage of CAT reversed the STL significantly (p=0.027). The CAT treatment also decreased the TDC in both early and late retrieval, in respect to STZ group.Conclusion:This data suggests that CAT as an antioxidant could improve both memory acquisition and retrieval in the animal model of sAD.

Neuroprotective effect of ebselen against intracerebroventricular streptozotocin-induced neuronal apoptosis and oxidative stress in rats

The goal of this study was to examine the neuroprotective effect of ebselen against intracerebroventricular streptozotocin (ICV-STZ)-induced oxidative stress and neuronal apoptosis in rat brain. A total of 30 adult male Sprague-Dawley rats were randomly divided into 3 groups of 10 animals each: control, ICV-STZ, and ICV-STZ treated with ebselen. The ICV-STZ group rats were injected bilaterally with ICV-STZ (3 mg/kg) on days 1 and 3, and ebselen (10 mg/kg/day) was administered for 14 days starting from 1st day of ICV-STZ injection to day 14. Rats were killed at the end of the study and brain tissues were removed for biochemical and histopathological investigation. Our results demonstrated, for the first time, the neuroprotective effect of ebselen on Alzheimer's disease (AD) model in rats. Our present study, in ICV-STZ group, showed significant increase in tissue malondialdehyde levels and significant decrease in enzymatic antioxidants superoxide dismutase and glutathione peroxidase in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that ebselen markedly reduced the ICV-STZ-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The number of apoptotic neurons was increased in frontal cortex tissue after ICV-STZ administration. Treatment of ebselen markedly reduced the number of degenerating apoptotic neurons. The study demonstrates the effectiveness of ebselen, as a powerful antioxidant, in preventing the oxidative damage and morphological changes caused by ICV-STZ in rats. Thus, ebselen may have a therapeutic value for the treatment of AD.

Neuroprotective effects of edaravone on cognitive deficit, oxidative stress and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats

Oxidative stress is implicated as an important factor in the development of Alzheimer's disease (AD). In the present study, we have investigated the effects of edaravone (9mg/kg, 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, in a streptozotocin (STZ-3mg/kg) induced rat model of sporadic AD (sAD). Treatment with edaravone significantly improved STZ-induced cognitive damage as evaluated in Morris water maze and step-down tests and markedly restored changes in malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE) adducts, hydroxyl radical (OH), hydrogen peroxide (H2O2), total superoxide dismutase (T-SOD), reduced glutathione (GSH), glutathione peroxidase (GPx) and protein carbonyl (PC) levels. In addition, histomorphological observations confirmed the protective effect of edaravone on neuronal degeneration. Moreover, hyperphosphorylation of tau resulting from intracerebroventricular streptozotocin (ICV-STZ) injection was decreased by the administration of edaravone. These results provide experimental evidence demonstrating preventive effects of edaravone on cognitive dysfunction, oxidative stress and hyperphosphorylation of tau in ICV-STZ rats. Since edaravone has been used for treatment of patients with stroke, it represents a safe and established therapeutic intervention that has the potential for a novel application in the treatment of age-related neurodegenerative disorders associated with cognitive decline, such as AD.

Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type

The objective of the present study was to assess the neuroprotective role of rutin (vitamin P) and delineate the mechanism of action. Recent evidence indicates that rutin exhibits antioxidant potential and protects the brain against various oxidative stressors. More precisely, the aim of the present study was to examine the modulating impacts of rutin against cognitive deficits and oxidative damage in intracerebroventricular-streptozotocin (ICV-STZ)–infused rats. Rats were injected bilaterally with ICV-STZ (3 mg/kg), whereas sham rats received the same volume of vehicle. After 2 weeks of streptozotocin (STZ) infusion, rats were tested for cognitive performance using Morris water maze tasks and thereafter euthanized for further biochemical, histopathological, and immunohistochemical studies. Rutin pretreatment (25 mg/kg, orally, once daily for 3 weeks) significantly attenuated thiobarbituric acid reactive substances (TBARS), activity of poly ADP-ribosyl polymerase, and nitrite level and decreased level of reduced glutathione (GSH) and activities of its dependent enzymes (glutathione peroxidase [GPx] and glutathione reductase [GR]) and catalase in the hippocampus of ICV-STZ rats. ICV-STZ rats showed significant cognitive deficits, which was improved significantly by rutin supplementation. The results indicate that rutin attenuates STZ-induced inflammation by reducing the expression of cyclooxygenase-2 (COX-2), glial fibrillary acidic protein (GFAP), interleukin-8 (IL-8), inducible nitric oxide synthase (iNOS), nuclear factor-kB, and preventing the morphological changes in hippocampus. The study thereby suggests the effectiveness of rutin in preventing cognitive deficits and might be beneficial for the treatment of sporadic dementia of Alzheimer type (SDAT).

Neuroprotective effect of preadministration with Ganoderma lucidum spore on rat hippocampus

The aim of this study was to investigate if preadministration with Ganoderma lucidum spore (GLS) could (1) alleviate oxidative stress and mitochondrial dysfunction in rat hippocampus of intracerebroventricular (ICV) injection of streptozotocin (STZ), (2) protect neurons from apoptosis, and (3) improve cognitive dysfunction. Three groups of Sprague-Dawley rats were preadministrated with GLS at doses of 2.0, 4.0 and 8.0 g/kg, respectively, for 3 weeks before the ICV STZ injury. Thereafter the rats were operated with ICV STZ (1.5 mg/kg) bilaterally on days 1 and 3. The behavioral alterations, oxidative stress indexes, ATP, cytochrome oxidase (CytOx), and histopathology of hippocampal neurons were studied. The results showed that ICV STZ model rats exhibited a significant increase of malondialdehyde (MDA), a significant decrease of glutathione reductase (GR), reduced glutathione (GSH), ATP and CytOx, accompanied with marked impairments in spatial learning and memory, and severe damage of hippocampal neuron. In conclusion, preadministration with GLS at dose of 8.0 g/kg in ICV STZ rats significantly reversed these abnormalities. In conclusion, preadministration with GLS might protect hippocampus from oxidative impairment and energy metabolism disturbance of ICV STZ. This may also provide useful information for future research on the pathogenesis and prevention of Alzheimer's disease (AD).

The Effect of Aqueous Crocus sativus L. Extract on Intracerebroventricular Streptozotocin-induced Cognitive Deficits in Rat: a Behavioral Analysis

Intracerebroventricular (ICV) injection of streptozotocin (STZ) causes cognitive impairment in rats. The beneficial effect of Crocus sativus L. extract (CSE) was evaluated on ICV STZ-induced learning, memory, and cognitive impairment in male rats. For this purpose, rats were injected with ICV STZ bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats received CSE (60 mg/kg; i.p.) every other day, starting one day before surgery, for three weeks. The learning and memory performance was assessed using passive avoidance paradigm, and for spatial cognition evaluation, Y-maze task was used. It was found that CSE-treated STZinjected rats show higher correct choices and lower errors in Y maze than vehicle-treated STZinjected rats. In addition, CSE administration significantly attenuated learning and memory impairment in treated STZ-injected group in passive avoidance test. Therefore, these results demonstrate the effectiveness of CSE in preventing the cognitive deficits caused by ICV STZ in rats and its potential in the treatment of neurodegenerative diseases such as Alzheimer’s disease (AD).

Effects of Pycnogenol and vitamin E on cognitive deficits and oxidative damage induced by intracerebroventricular streptozotocin in rats

Oxidative stress plays a crucial role in the progression of cognitive decline in Alzheimer's disease (AD). Considerable attention has been focused on increasing the internal antioxidant defenses in response to AD. This study was designed to examine and compare the pretreatment effects of Pycnogenol (PYC) and vitamin E (Vit E) on cognitive deficits and oxidative damage in the hippocampus and cerebral cortex of intracerebroventricular streptozotocin (ICV-STZ)-infused rats. Rats pretreated with PYC (10 mg/kg), Vit E (100 mg/kg), and vehicle (intraperitoneal; once daily for 3 weeks) were bilaterally injected with ICV-STZ (3 mg/kg), whereas sham rats received the same volume of vehicle. After 2 weeks of ICV-STZ infusion, rats were tested for cognitive performance using passive avoidance and water maze tasks, and then killed for biochemical assays. ICV-STZ induced significant declines in cognitive performance and choline acetyltransferase activity in the hippocampus, which were significantly attenuated with PYC and Vit E. Pretreatment with PYC and Vit E produced a significantly enhanced glutathione level and Na+/K+-ATPase activity and decreased thiobarbituric acid reactive substances and protein carbonyl. These findings suggest that PYC and Vit E may provide a promising approach for the treatment of oxidative stress-related neurodegeneration in conditions such as AD.

Pretreatment with Rhodiola Rosea Extract Reduces Cognitive Impairment Induced by Intracerebroventricular Streptozotocin in Rats: Implication of Anti-oxidative and Neuroprotective Effects

To investigate the pretreatment effects of Rhodiola rosea (R. rosea) extract on cognitive dysfunction, oxidative stress in hippocampus and hippocampal neuron injury in a rat model of Alzheimer's disease (AD). Male Sprague-Dawley rats were pretreated with R. rosea extract at doses of 1.5, 3.0, and 6.0 g/kg for 3 weeks, followed by bilateral intracerebroventricular injection with streptozotocin (1.5 mg/kg) on days 1 and 3. Behavioral alterations were monitored after 2 weeks from the lesion using Morris water maze task. Three weeks after the lesion, the rats were sacrificed for measuring the malondialdehyde (MDA), glutathione reductase (GR) and reduced glutathione (GSH) levels in hippocampus and histopathology of hippocampal neurons. The MDA level was significantly increased while the GR and GSH levels were significantly decreased with striking impairments in spatial learning and memory and severe damage to hippocampal neurons in the model rat induced by intracerebroventricular injection of streptozotocin. These abnormalities were significantly improved by pretreatment with R. rosea extract (3.0 g/kg). R. rosea extract can protect rats against cognitive deficits, neuronal injury and oxidative stress induced by intracerebroventricular injection of streptozotocin, and may be used as a potential agent in treatment of neurodegenerative diseases such as AD.

Chronic treatment with tocotrienol, an isoform of vitamin E, prevents intracerebroventricular streptozotocin-induced cognitive impairment and oxidative–nitrosative stress in rats

Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, which is associated with increased oxidative stress in the brain of rats. In the present study, we investigated the effect of both the isoforms of vitamin E, α-tocopherol and tocotrienol against ICV STZ-induced cognitive impairment and oxidative–nitrosative stress in rats. Adult male Wistar rats were injected with ICV STZ (3 mg/kg) bilaterally. The learning and memory behavior was assessed using Morris water maze and elevated plus maze. The rats were sacrificed on day 21 and parameters of oxidative stress, nitrite levels and acetylcholinesterase activity were measured in brain homogenate. α-Tocopherol as well as tocotrienol treated groups showed significantly less cognitive impairment in both the behavioral paradigms but the effect was more potent with tocotrienol. Both isoforms of vitamin E effectively attenuated the reduction in glutathione and catalase and reduced the malonaldehyde, nitrite as well as cholinesterase activity in the brains of ICV STZ rats in a dose dependent manner. The study demonstrates the effectiveness of vitamin E isoforms, of which tocotrienol being more potent in preventing the cognitive deficits caused by ICV STZ in rats and suggests its potential in the treatment of neurodegenerative diseases such as Alzheimer's disease.

Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer's type

Selenium (Se), a nutritionally essential trace element with known antioxidant potential, protects the brain from oxidative damage in various models of neurodegeneration. Intracerebroventricular-streptozotocin (ICV-STZ) in rats causes impairment of brain glucose and energy metabolism along with oxidative damage and cholinergic dysfunction, and provides a relevant model for sporadic dementia of Alzheimer's type (SDAT). The present study demonstrates the therapeutic efficacy of Se on cognitive deficits and oxidative damage in ICV-STZ in rats. Male Wistar rats were pre-treated with sodium selenite, a salt of Se (0.1 mg/kg; body weight) for 7 days and then were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle. After two ICV-STZ infusions, rats were tested for memory deficits in passive avoidance and Morris water maze (MWM) tests and then were sacrificed for biochemical and histopatholgical assays. ICV-STZ-infused rats showed significant loss in learning and memory ability, which were significantly improved by Se supplementation. A significant increase in thio-barbituric acid reactive species (TBARS), protein carbonyl (PC) and a significant decrease in reduced glutathione (GSH), antioxidant enzymes (glutathione peroxidase [GPx] and glutathione reductase [GR]) and adenosine triphosphate (ATP) in the hippocampus and cerebral cortex and choline acetyltransferase (ChAT) in hippocampus were observed in ICV-STZ rats. Se supplementation significantly ameliorated all alterations induced by ICV-STZ in rats. Our study reveals that Se, as a powerful antioxidant, prevents cognitive deficits, oxidative damage and morphological changes in the ICV-STZ rats. Thus, it may have a therapeutic value for the treatment of SDAT.

Effect of Naringenin on Intracerebroventricular Streptozotocin-Induced Cognitive Deficits in Rat: A Behavioral Analysis

Intracerebroventricular (ICV) injection of streptozotocin (STZ) causes cognitive impairment in rats. The beneficial effect of naringenin (NAR) was investigated on ICV STZ-induced learning, memory, and cognitive impairment in male rats. For this purpose, rats were injected with ICV STZ bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats received NAR (50 mg/kg/day p.o.) starting 1 day pre-surgery for 3 weeks. The learning and memory performance was assessed using passive avoidance paradigm, and for spatial cognition evaluation, radial eight-arm maze (RAM) task was used. It was found out that NAR-treated STZ-injected rats show higher correct choices and lower errors in RAM than vehicle-treated STZ-injected rats. In addition, NAR administration significantly attenuated learning and memory impairment in treated STZ-injected group in passive avoidance test. Therefore, these results demonstrate the effectiveness of NAR in preventing the cognitive deficits caused by ICV STZ in rats and its potential in the treatment of neurodegenerative diseases such as Alzheimer’s disease.

Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats

Memory impairment induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in rats is associated with impaired brain glucose and energy metabolism, oxidative stress and impaired cholinergic neurotransmission. Treatment with antioxidants and cholinergic agonists has been reported to produce beneficial effect in this model. However, no reports are available on drugs that improve glucose utilization and metabolism. In the present study, we evaluated the effects of pioglitazone on cognitive performance, oxidative stress and glucose utilization in ICV STZ injected rats (3 mg/kg, on day 1 and 3). Pioglitazone (10 and 30 mg/kg) was administered per oral (p.o.) for 14 days, starting 5 days prior to STZ injection. Cognitive performance was assessed using step-through passive avoidance and Morris water maze task. Malondialdehyde (MDA) and glutathione levels in brain were estimated as parameters of oxidative stress. Glucose utilization by brain was assessed as the amount of glucose consumed from the media by the brain. ICV STZ injected rats showed a severe deficit in learning and memory associated with increased MDA levels (+ 67.5%), decreased glutathione levels (− 29.2%) and impaired cerebral glucose utilization (− 44.4%). In contrast pioglitazone treatment improved cognitive performance, lowered oxidative stress and improved cerebral glucose utilization in ICV STZ rats. The present study demonstrates the beneficial effects of pioglitazone in the ICV STZ induced cognitive deficits, which can be exploited for the dementia associated with diabetes and age-related neurodegenerative disorder, where oxidative stress and impaired glucose and energy metabolism are involved.

Protective effect of alpha lipoic acid and trans resveratrol on spatial memory deficits caused by intracerebroventricular streptozotocin in rats

while eliciting variable immune response and reducing brain amyloid burden to different degrees (J. Neurosci. 24, 2004). Objective(s): 1) To determine the therapeutic benefit of K6A 1-30 in 2 year old Tg2576 mice with treatment starting at 11vs. 19 months. 2) To assess the immune response and therapeutic effect of our vaccines in Microcebus murinus, a lemur primate that develops plaques and tangles as seen in AD. Methods: Mice were immunized with K6A 1-30 in alum adjuvant which promotes a humoral immune response. At 2 years of age, sensorimotor and cognitive tests were performed, and brains then processed for amyloid burden measurements. Young lemurs were immunized with A 1-42 and several nontoxic A homologs in alum and bled at various time points between injections. Older lemurs are currently going through behavioral assessment prior to vaccination. Conclusions: In the mice, K6A 1-30 improved cognition when therapy was initiated at 11 months but not at 19 months. Amyloid burden analysis is underway. Cerebral bleeding has not been observed in brains from mice with high antibody titer examined so far. In the lemurs, all the peptides elicited a moderate to robust IgM titer. A 1-42 and K6A 1-30 resulted in a high IgG titer similar to the mouse response. A 1-30[E18E19] produced a low IgG reponse as in the mouse. K6A 130[E18E19] gave rise to a strong IgG titer whereas in the mouse this derivative elicited a low IgG titer. Bleeds at 5 months after last injection are in progress. The mouse findings indicate that immunotherapy at an old age may not be beneficial. The immune response in the mouse vs. the lemur primate differs for some of the A homolog vaccines.

Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats

Intracerebroventricular (ICV) injection of streptozotocin (STZ) causes cognitive impairment in rats. ICV STZ is known to impair cholinergic neurotransmission by decreasing choline acetyltransferase (ChAT) levels, glucose and energy metabolism in brain and synthesis of acetyl CoA. However, no reports are available regarding the cholinesterase inhibitors in this model. In aging brain, reduced energy metabolism increases glutamate release, which is blocked by L-type calcium channel blockers. These calcium channel blockers have shown beneficial effects on learning and memory in various models of cognitive impairment. The present study was designed to investigate the influence of chronic administration of donepezil (cholinesterase inhibitor, 1 and 3 mg/kg) and lercanidipine (L-type calcium channel blocker, 0.3 and 1 mg/kg) on cognitive impairment in male Sprague-Dawley rats injected twice with ICV STZ (3 mg/kg) bilaterally on days 1 and 3. ICV STZ injected rats developed a severe deficit in learning and memory indicated by deficits in passive avoidance paradigm and elevated plus maze as compared to control rats. Cholinesterase activity in brain was significantly increased in ICV STZ injected rats. Donepezil dose-dependently inhibited cholinesterase activity and improved performance in memory tests at both the doses. Lercanidipine (0.3 mg/kg) showed significant improvement in memory. When administered together, the effect of combination of these two drugs on memory and cholinesterase activity was higher than that obtained with either of the drugs when used alone.