Intracerebroventricular Streptozotocin Research Articles

A novel pyrazole-containing selenium compound modulates the oxidative and nitrergic pathways to reverse the depression-pain syndrome in mice

Bearing in mind that pain and major depressive disorder (MDD) often share biological pathways, this condition is classified as depression-pain syndrome. Mounting evidence suggests that oxidative stress is implicated in the pathophysiology of this syndrome. The development of effective pharmacological interventions for the depression-pain syndrome is of particular importance as clinical treatments for this comorbidity have shown limited efficacy. Therefore, the present study aimed to evaluate whether the 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1H-pyrazole (SePy) was able to reverse the depression-pain syndrome induced by intracerebroventricular (i.c.v) streptozotocin (STZ) in mice and the possible modulation of oxidative and nitrergic pathways in its effect. The treatment with SePy (1 and 10 mg/kg) administered intragastrically (i.g.) reversed the increased immobility time in the tail suspension test, decreased grooming time in the splash test, latency time to nociceptive response in the hot plate test, and the response frequency of Von Frey hair (VFH) stimulation induced by STZ (0.2 mg/4 μl/per mouse). Additionally, SePy (10 mg/kg, i.g.) reversed STZ-induced alterations in the levels of reactive oxygen species, nitric oxide, and lipid peroxidation and the superoxide dismutase and catalase activities in the prefrontal cortices (PFC) and hippocampi (HC) of mice. Treatment with SePy (10 mg/kg, i.g.) also reversed the STZ-induced increased expression of inducible nitric oxide synthase (iNOS) and glycogen synthase kinase 3 beta (GSK3β) in the PFC and HC. An additional molecular docking investigation found that SePy binds to the active site of iNOS and GSK3β. Altogether, these results indicate that the antidepressant-like effect of SePy is accompanied by decreased hyperalgesia and mechanical allodynia, which were associated with its antioxidant effect.

Neurotoxic effects of high-dose piperine on hippocampal synaptic transmission and synaptic plasticity in a rat model of memory impairment

In recent years, piperine has attracted much attention due to its various biological effects as a neuroprotective agent. Therefore, clarification of the possible side effects of piperine is important to identify its potential pharmacological action. Thus, the effects of piperine on the long-term plasticity of perforant pathway to dentate gyrus synapses were studied in hippocampus of an animal model of Alzheimer's disease (AD).Adult male rats were injected with intracerebroventricular (ICV) streptozotocin (STZ) bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats were treated with different doses of piperine for 4 weeks before being used in behavioral, electrophysiological and histopathological experiments. The passive-avoidance test was conducted on all animals in order to determine the cognitive performance. Rats were placed in a stereotaxic frame to implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path. Additionally, we assessed the density of survived neurons stained by cresyl violet.In this study, chronic administration of piperine low dose improved the ICV-STZ induced learning and long-term potentiation (LTP) impairments with no significant effect on baseline synaptic activity. In contrast, remarkable learning and long-term plasticity impairments were observed in rats treated by high dose of piperine in comparison to the other groups. Interestingly, this impaired hippocampal LTP was accompanied by an obvious alteration in baseline activity and significantly decreased neuronal numbers within the hippocampus. Therefore, our data provides a new understanding of the piperine supplementation effects on hippocampal electrophysiological profile although the consequences may be either beneficial or detrimental.

Key role of MIF-related neuroinflammation in neurodegeneration and cognitive impairment in Alzheimer\u2019s disease

BackgroundMacrophage Migration Inhibitory Factor (MIF) is a potent proinflammatory cytokine that promotes the production of other immune mediators. MIF is produced by most cell types in the brain including microglia, astrocytes and neurons. Enhanced expression of MIF might contribute to the persistent activation of glial, chronic neuroinflammation and neurodegeneration. Here, we investigated the effect of MIF on inflammatory markers and spatial learning in a mouse model of sporadic AD and on tau pathology in AD patients.MethodsWe examined the effects of MIF deficiency and pharmacological MIF inhibition in vitro and in vivo. In vitro, quantitative PCR and ELISA were used to assess cytokine production of STZ-treated glial cells. In vivo, C57BL/6 mice were subjected to intracerebroventricular streptozotocin injection (3 mg/kg, ICV-STZ). Neuroinflammation and contextual learning performance were assessed using quantitative PCR and fear conditioning, respectively. Pharmacological MIF inhibition was achieved with intraperitoneal injections of ISO-1 (daily, IP, 20 mg/kg in 5% DMSO in 0.9% NaCl) for 4 weeks following ICV-STZ injection. The findings from ISO-1 treated mice were confirmed in MIF knockout C57BL/6. To assess the role of MIF in human AD, cerebrospinal fluid levels of MIF and hyperphosphorylated tau were measured using ELISA.ResultsAdministration ICV-STZ resulted in hippocampal dependent cognitive impairment. MIF inhibition with ISO-1 significantly improved the STZ-induced impairment in contextual memory performance, indicating MIF-related inflammation as a major contributor to ICV-STZ-induced memory deficits. Furthermore, inhibition of the MIF resulted in reduced cytokine production in vitro and in vivo.In human subjects with AD at early clinical stages, cerebrospinal fluid levels of MIF were increased in comparison with age-matched controls, and correlated with biomarkers of tau hyper-phosphorylation and neuronal injury hinting at MIF levels as a potential biomarker for early-stage AD.ConclusionsThe present study indicates the key role of MIF in controlling the chronic cytokine release in neuroinflammation related to tau hyperphosphorylation, neurodegeneration, and clinical manifestations of AD, suggesting the potential of MIF inhibition as therapeutic strategy to slow down neurodegeneration and clinical disease progression.

Effect of amyloid toxicity or chronic cerebral hypoperfusion on brain insulin resistance in a rat model with intracerebroventricular streptozotocin

Sporadic Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder affected by amyloid and vascular pathogenesis. Brain insulin resistance (BIR) has been suggested as one of the pathomechanisms of sporadic AD. We investigated how the amyloid and vascular pathogenesis of AD interacts with BIR. We examined experimental groups mimicking amyloid pathogenesis following intracerebroventriculr (icv) injection of amyloid β or vascular pathogenesis following permanent ligation of the bilateral common carotid arteries in Wistar rats that had undergone icv injection of streptozotocin. Behavioral tests and pathologic studies were performed. Cognitive impairments were induced by BIR superimposed by amyloid or vascular pathogenesis. Neuroinflammation in the white matter and hippocampus was aggravated by an interaction between BIR and vascular pathogenesis. Amyloid-associated pathology in the white matter was enhanced by BIR and vascular pathogenesis. Tau-associated pathology in the hippocampus was altered by BIR in a relation with amyloid or vascular pathogenesis. Our study may provide useful experimental insights based on an integrated approach to the influence of amyloid and vascular pathogenesis on BIR, permitting better understanding of the heterogeneous pathogenesis of sporadic AD. Pathologic responses in sporadic AD may differ depending on amyloid and vascular pathogenesis and may sometimes be synergistically aggravated when combined with BIR.

Ebselen reversed peripheral oxidative stress induced by a mouse model of sporadic Alzheimer's disease.

Intracerebroventricular streptozotocin injection (icv STZ) is a well established sporadic Alzheimer's disease (AD) model in rodents. AD is characterized by neuronal degeneration accompanied by central oxidative stress. Studies also indicate peripheral oxidative damage in AD, but if the icv STZ model of sporadic AD mimics this feature is an open question. This study aimed to investigate if icv STZ administration induces peripheral oxidative stress and the antioxidant action of Ebselen, compared to the reference drug (donepezil), in this sporadic AD model. Male adult Swiss mice received icv STZ (days 1 and 3). Mice received Ebselen (10mg/kg, i.p) or Donepezil (5mg/kg, i.p) for 14days. Mice were killed and the kidney and liver were excised to determine parameters of oxidative stress and toxicity markers. The mice icv STZ-injected showed peripheral oxidative stress. Ebselen reversed renal lipid peroxidation in the icv STZ administered mice by modulating NPSH levels, SOD and CAT activities, whereas Donepezil, modulated only NPSH levels. Ebselen and Donepezil counteracted hepatic lipid peroxidation in STZ-injected mice by modulating NPSH levels and CAT activity. The δ-ALA-D activity was inhibited in the kidney, but not in the liver, whereas the icv STZ-injected mice had an increase in the GST activity in both tissues. Ebselen reversed the increase in the hepatic GST activity of the STZ-injected mice. Donepezil increased renal GST activity in the control mice. In conclusion, this study demonstrates that the icv STZ administration induced peripheral oxidative stress. Ebselen, similar to Donepezil, was effective against peripheral oxidative stress in a mouse model of sporadic AD.

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.

Pinus Roxburghii Sarg. Ameliorates Alzheimer?s disease- Type Neurodegeneration and Cognitive Deficits Caused by Intracerebroventricular-Streptozotocin in Rats: An In Vitro and In Vivo Study

Pinus roxburghii Sarg. is traditionally used as a nerve tonic, hemostatic and anticonvulsant. The present study was aimed to investigate the neuroprotective activity of Pinus roxburghiiSarg. stem bark for memory and cognition using in vitro and in vivo methods. Plant drug was extracted with methanol using Soxhlet extraction. In vitro cell viability activity of Pinus roxburghiiSarg. was assessed using PC-12 cell lines. The in vivo neuroprotective activity of Pinus roxburghii Sarg. was tested on Wistar albino rats (either sex) and intracerebroventricular streptozotocin (3 mg/kg, bilateral) was given to cause memory deficits. High-performance thin layer chromatography fingerprinting was performed for the presence of quercetin and gallic acid in the plant extract. The phytochemical testing of extract revealed the presence of flavonoids, alkaloids, steroids, and tannins. Pinus roxburghii Sarg. showed significant cell viability at 10, 50 and 100 μg/ml in an in vitro test on PC-12 cell lines. In the in vivo activity, intracerebroventricular streptozotocin caused significant deterioration in memory and cognition, tissue oxidative stress and acetylcholinesterase activity. Pinus roxburghiiSarg. 100, 200 and 300 mg/kg, per os and donepezil (3 mg/kg, per os) significantly (p<0.05) reversed the behavioral changes in rats when tested on morris water maze and elevated plus maze. Increased levels of lipid peroxidation, acetylcholinesterase activity and decreased the level of glutathione were significantly (p<0.05) antagonized by Pinus roxburghii Sarg., similar to donepezil in rat brain. Quercetin and gallic acid were identified quantitatively in the plant extract in High-performance thin layer chromatography study. The methanolic extract of Pinus roxburghii Sarg. ameliorated intracerebroventricular streptozotocin induced cognitive deficits and memory impairment possibly due to the presence of quercetin and gallic acid.

Possible role of ghrelin in neuronal conduction in improved memory cognition

Background Ghrelin, an appetite stimulator, functions through IP3-DAG signaling. It has been found to increase food related memory retention in rodents. Objective The study aims to investigate the role of Ghrelin signaling in memory cognition and retention using intracerebroventricular streptozotocin (ICV-STZ) model in Wistar rats. Methods Male Wistar rats (250-280 g) were employed into the study with sample size n=6. Streptozotocin (STZ) 3 mg/kg was administered on day one through intra-cerebroventricular route. n-Octanoic acid, a Ghrelin activator was given in two doses 50 and 100uL for 21 daysby dissolving in polyethylene glycol 600whereas Nifedipine, Ca++ channel blocker was given at 10 mg/kg, i.p. to one group underwent to administration of n-octanoic acid high dose.Impairments in cognition, memory consolidation and retention were assessed using Morris water maze, Y maze, balance beam, open field test and photoactometer test. The biochemical estimations for oxidative stress i.e. lipid peroxidation, glutathione, and acetylcholinesterase activity were done in rat brain homogenate. Statistical analysis was carried out using graph pad prism 5. Results ICV-STZ treated animals exhibited memory deficits in Morris water maze, Y maze, balance beam test. Administration of low and high doses of n-Octanoic acid produced significant restoration of memory retention. However, nifedipine abolished the memory improvement produced by n-octanoic acid. The level of oxidative stress and AChE activity observed in rat brain was also reversed. Conclusion The finding may reveal that ghrelin plays pivotal role in improving cognition, retentionand working memory possible through Ca signaling.

Sinapic acid mitigates intracerebroventricular streptozotocin induced oxidative stress and neuro-inflammatory changes in rats

Oxidative stress and inflammatory cytokines play an important role in progression of Alzheimer’s disease (AD). Sinapic acid, a natural phenolic compound has shown neuro-protection by amelioration of oxidative stress and neuro-inflammation. Here, we evaluated the effect of sinapic acid on oxidative stress and inflammatory cytokines in intracerebroventricular streptozotocin (ICV-STZ) sporadic model of AD in rats. Male Wistar rats (260 ± 20g), were administered ICV-STZ (3 mg/kg) and sinapic acid (10 and 20 mg/kg, orally) was administered for 21 days. Morris water maze and passive avoidance paradigm test was carried out on 0 and 21st days. On 21st day rats were sacrificed, levels of MDA, GSH, TNF-α and IL-1β were estimated in cortex and hippocampus. The expression of choline acetyltransferase (ChAT) was also assessed by western blot. On day 21, STZ produced memory impairment as evidenced by increased escape latency (p < 0.001), decreased time spent in target zone in Morris water maze. Sinapic acid attenuated the increased escape latency and improved the time spent in target quadrant at 20 mg/kg on 21st day (p < 0.05). STZ induced decreased transfer latency in passive avoidance paradigm was also significantly increased. STZ induced changes in levels of GSH and MDA were significantly normalised by sinapic acid. STZ induced levels of TNF-α and IL-1β were significantly (p < 0.05) attenuated by sinapic acid 20 mg/kg. Moreover, sinapic acid ameliorated the STZ induced decreased expression of ChAT in hippocampus. The results suggest that sinapic acid improves STZ-induced cognitive impairment by ameliorating oxidative stress and neuro inflammation in cortex and hippocampus.

Effect of Epigallocatechin Gallate and Catechin on Overexpression of GSK-3β and IR Genes Induced by Streptozotocin in Rat Brain

Background: Type 2 diabetes mellitus (T2DM) is one of the significant risk factors for Alzheimer disease (AD). Defects in insulin signaling pathway induce AD hallmarks mainly through activation of glycogen synthase kinase-3β (GSK-3β) pathway. Objectives: In this study, we investigated the expression of GSK-3β and insulin receptor (IR) genes in the hippocampi of an animal model of sporadic AD and assessed the preventive effect of Catechin (CAT) and epigallocatechin gallate (EGCG) on their expression. Materials &amp; Methods: Adult male Wistar rats were treated by intracerebroventricular streptozotocin (STZ) injection (3 mg/kg) at day 1 and 3 after cannulation. CAT was administered at a dose of 40 mg/kg for 10 days per gavage, and EGCG was administered at a dose of 3 mg/kg for 14 days into drinking water. Then the animals were decapitated, and their hippocampi were removed. Real-time Polymerase Chain Reaction (PCR) was used to evaluate the alteration in gene expression. Results: There was overexpression in GSK-3β gene in STZ-treated rats (P≤0.05), which was brought back to normalcy by EGCG (P≤0.01). The IR gene also increased after STZ treatment, but CAT reduced IR expression (P≤0.05). However, the suppressive effect of EGCG on IR expression was stronger (P≤0.01). Conclusion: The neuroprotective activity of EGCG might be due to its influence on IR and GSK-3β expression.

Brain targeted alendronate loaded chitosan nanoparticles exerts neuroprotective effect against intracerebroventricular streptozotocin induced Alzheimer’s disease in mice

The growing prevalence of Alzheimer’s disease (AD) throughout the world is one of the major health concerns in todays’ scenario. AD is a complex multifactorial neurodegenerative disease characterized by impaired cognitive abilities, senile plaques, neurofibrillary tangles, synapse and neuronal loss. Though wide range of drugs including acetylcholinesterase inhibitors, NMDA receptor antagonists have been recommended for the treatment of AD, but their limited ability to impart only symptomatic relief and constant failure of translation of therapeutic molecules to clinical trials arises a tremendous need to explore potential targets that could promisingly slow down the progression and development of AD. Alendronate, a nitrogen-containing bisphosphonate, is a FDA approved therapy for osteoporosis but it was cited in in-vivo and clinical studies to attenuate dementia, acetylcholinesterase activity and cholesterol synthesis in brain. Despite of these notions, alendronate face some challenges such as poor bioavailability, brain penetration and gastrointestinal side effects. However, the present study was designed with an aim to overcome these hurdles by developing alendronate-loaded chitosan nanoparticles (ALN-CS-NPs). The optimized and developed ALN-CS-NPs were demonstrated to acquire desired particle size (<200nm) and higher concentration in brain as compared to pure ALN. The ALN-CS-NPs were then evaluated in intracerebroventricular-streptozotocin (ICV-STZ) model of sporadic AD. Subsequently, it was observed that ALN-CS-NPs following intranasal administration for 15 days significantly altered the ICV-STZ induced cognitive functions, amyloid precursor protein, amyloid-β, GSK-3β, neuroinflammation and congophillic plaques in mice hippocampus. These encouraging outcomes support the promising role of ALN-CS-NPs in targeted brain delivery for the treatment of sporadic AD.

Moderate protective effect of Kyotorphin against the late consequences of intracerebroventricular streptozotocin model of Alzheimer's disease.

The established decrease in the level of endogenous kyotorphin (KTP) into the cerebrospinal fluid of patients with an advanced stage of Alzheimer's disease (AD) and the found neuroprotective activity of KTP suggested its participation in the pathophysiology of the disease. We aimed to study the effects of subchronic intracerebroventricular (ICV) treatment (14days) with KTP on the behavioral, biochemical and histological changes in rats with streptozotocin (STZ-ICV)-induced model of sporadic AD (sAD). Three months after the administration of STZ-ICV, rats developed increased locomotor activity, decreased level of anxiety, impaired spatial and working memory. Histological data from the STZ-ICV group demonstrated decreased number of neurons in the CA1 and CA3 subfields of the hippocampus. The STZ-ICV group was characterized with a decrease of total protein content in the hippocampus and the prefrontal cortex as well as increased levels of the carbonylated proteins in the hippocampus. KTP treatment of STZ-ICV rats normalized anxiety level and regained object recognition memory. KTP abolished the protein loss in prefrontal cortex and decrease the neuronal loss in the CA3 subfield of the hippocampus. STZ-ICV rats, treated with KTP, did not show significant changes in the levels of the carbonylated proteins in specific brain structures or in motor activity and spatial memory compared to the saline-treated STZ-ICV group. Our data show a moderate and selective protective effect of a subchronic ICV administration of the dipeptide KTP on the pathological changes induced by an experimental model of sAD in rats.

Calcineurin-Mediated Hippocampal Inflammatory Alterations in Streptozotocin-Induced Model of Dementia.

Although the pathogenesis of Alzheimer's disease (AD) remains unclear, some molecular aspects that precede or accompany the deposit of β-amyloid in senile plaques attract attention, such as calcium dysregulation and neuroinflammation. It has been suggested that the Ca2+/calmodulin-dependent protein phosphatase, calcineurin (CaN), plays an important role in AD pathogenesis. We hypothesized that CaN activation is involved in the inflammatory changes observed in the streptozotocin (STZ)-induced model of AD. We investigated hippocampal inflammatory and CaN changes in Wistar rats in two moments after intracerebroventricular STZ administration: in the first week (early) and fourth week (later on). We found an early (at 1week) and persistent (at fourth week) increment in the subunit A of CaN, as well as an increase in the major 48kDa fragment of this subunit. Glial and inflammatory activation were confirmed by changes of IBA-1, TLR-4, glial fibrillary acidic protein (GFAP), and S100B in the hippocampus. Augmented CaN activity was accompanied by reduced phosphorylation of the pro-apoptotic protein BAD, at Ser 136. Importantly, we found an increase in the nuclear translocation of NFAT4 (more associated to astroglial reactivity) in the hippocampus at 1 and 4weeks in this model. NFAT3 (more associated with neuronal activation) exhibited an early increase, but decreased later on. Taken together, these data contribute to the understanding of neurochemical changes in the STZ model of sporadic AD, and may explain the persistent inflammatory response in AD, which might occur via the proteolytic activation of CaN, and signaling of NFAT mediated by isoform 4, in activated astrocytes.

Inhibition of PDE5 attenuates streptozotocin-induced neuroinflammation and tau hyperphosphorylation in a streptozotocin-treated rat model

Intracerebroventricular (icv) streptozotocin (STZ) injection decreases cerebral insulin signal pathway function and produces multiple effects that resemble the molecular, pathological, and behavioural features of Sporadic Alzheimer’s disease (SAD). We previously reported that yonkenafil (yonk), the analogue of sildenafil and a novel PDE5 inhibitor exerts an anti-amyloidogenesis effect by regulating the Aβ level and inhibiting the expression of β-amyloid precursor protein in the APP/PS1 transgenic mice model. In this study, the effects of yonk on cognitive behaviors as well as the pathological features in streptozotocin-induced SAD rat model were investigated. The results demonstrated that administration of yonk at doses of 3 and 10 mg/kg for three weeks significantly improved cognitive deficits, attenuated STZ-induced neuronal death, inhibited the over-activation of microglia and astrocytes and the levels of pro-inflammatory markers, as well as decreased PDE5 protein expression in the hippocampus. Furthermore, yonk (3 mg/kg) notably prevented changes in tau hyperphosphorylation, decreased IRS-1and JNK phosphorylation and increased the GSK3β (ser9) phosphorylation induced by STZ. In summary, these data suggested that yonk significantly reversed STZ-induced memory deficits by inhibiting the over-activation of microglia and astrocytes, as well as ameliorated the levels of pro-inflammatory makers and tau hyperphosphorylation through regulating GSK3β signalling pathway.

Streptozotocin causes acute responses on hippocampal S100B and BDNF proteins linked to glucose metabolism alterations

Streptozotocin (STZ) is a glucosamine-nitrosourea commonly used to induce long-lasting models of diabetes mellitus and Alzheimer's disease. Direct toxicity of STZ on the pancreas and kidneys has been well characterized, but the acute effect of this compound on brain tissue has received less attention. Herein, we investigated the acute and direct toxicity of STZ on fresh hippocampal slices, measuring changes in BDNF and S100B secretion (two widely-used peripheral markers of brain injury), as well as glucose metabolism. Moreover, we investigated in vivo changes of these proteins in the hippocampus, 48 h after intracerebroventricular STZ administration. Transverse hippocampal slices (0.3 mm thick) were obtained using a McIlwain tissue chopper and target proteins were measured in the incubation medium by ELISA. STZ decreased S100B secretion, but increased BDNF secretion as well as causing impairment in glucose uptake in hippocampal slices, measured using [3H] deoxy-glucose. Glucose levels and glucose metabolism differentially modulated S100B secretion in astrocytes and BDNF secretion in neurons, when evaluated under specific conditions (high-potassium medium, presence of tetrodotoxin or fluorocitrate). Moreover, at 48 h after intracerebroventricular STZ, hippocampal BDNF content, but not S100B, was reduced. Our results indicate that BDNF and S100B are useful and sensitive markers of glucose metabolism disturbance and reinforce these proteins as general acute markers of brain disorders.

Isoflurane‐Induced Hypothermia Does Not Aggravate Memory Impairment in A Sporadic Alzheimer's Disease Rat Model Produced by Intracerebroventricular Streptozotocin

Several studies have shown that hypothermia and anesthesia are risk factors for Alzheimer's disease. Most of them were performed on healthy elderly rodents. However, the effect of anesthesia‐induced hypothermia in memory in a sporadic Alzheimer's disease animal model has never been studied. In this study, Wistar rats (3‐month‐old) were induced to anesthesia with 3% isoflurane and maintained with 1.5–2% isoflurane in 100% oxygen for 3 hours. In the first 30 min of anesthesia, rats were subjected to a single bilateral intracerebroventricular injection of streptozotocin (STZ, 1 mg/kg) to produce the sporadic Alzheimer's disease model, or its vehicle (0.05 mol/L citrate buffer, pH 4.5, 2 μL/ventricle). The rats were either subjected to hypothermia or not, induced by isoflurane (hypothermic and normothermic groups, respectively). In this sense, during anesthesia, normothermic rats were kept on a heating pad, and their rectal temperature was maintained at 37.5 ± 0.5°C. Hypothermic rats were kept without a heating pad. Spatial working memory was evaluated using Morris Water Maze from the 3rd to 28th‐day postsurgery, and by Y‐maze test on the 30th‐day postsurgery. Recognition memory was evaluated on the 31st‐day postsurgery using the Novel Object Recognition Test. All the procedures were approved by and are in accordance with the local ethics committee from St Joseph's Hospital and Medical Center (protocol n° 485). In the Morris water maze test, both hypothermic and normothermic STZ‐injected rats shown similar impairment in spatial working memory compared to their respective controls, i.e., hypothermic and normothermic vehicle‐injected rats, respectively. In the Y‐maze test, normothermic STZ‐injected rats shown a deficit in spatial working memory compared to normothermic vehicle‐injected rats (p = 0.028). However, this effect was missed in hypothermic groups with no difference between STZ‐ and vehicleinjected groups (p = 0.073). Similarly, in the Novel Object Recognition Test, recognition memory was impaired in normothermic STZ‐injected rats compared to normothermic vehicleinjected rats (p = 0.012) and no effect was observed between hypothermic STZ‐ and vehicleinject rats (p = 0.118). In conclusion, isoflurane‐induced hypothermia does not aggravate the STZ‐deleterious effect in recognition memory and spacial work memory in rats.Support or Funding InformationThis work was supported by the Brazilian National Council for Scientific and Technological Development (grant 449102/2014‐9 to D.C.C.) and the São Paulo Research Foundation (grants 2015/02991‐0 to M.C.A., 2015/23426‐9 to D.C.C., and 2016/01836‐3 to R.C.L.V.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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.

Aegle marmelos leaf extract ameliorates the cognitive impairment and oxidative stress induced by intracerebroventricular streptozotocin in male rats

AimsAegle marmelos (L.) Correa (A. marmelos) has been used in Ayurvedic medicine as a brain tonic however its neuroprotective effect against streptozotocin (STZ) induced cognitive impairment and oxidative stress has not been reported yet in vivo. Therefore, the present study was attempted to investigate the neuroprotective potential of ethanolic extract of A. marmelos leaves (AME) on STZ induced memory impairment in male rats. Main methodsAlbino Wistar rats were pre-treated orally with AME at the doses 200 and 400 mg/kg for two weeks, followed by intracerebroventricular (i.c.v.) injection of STZ (3 mg/kg) on day 1 and 3. Two weeks after STZ administration, behavioural parameters were monitored using Morris water maze task. Biochemical and histopathological studies were carried out after three weeks of STZ administration. The levels of oxidative stress markers (malondialdehyde (MDA), glutathione, nitrite, catalase) neuroinflammatory mediators; tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and acetylcholinesterase (AChE) activity were estimated in hippocampus of rat brain. Donepezil (5 mg/kg) was taken as a standard drug. Key findingsThe levels of MDA, nitrite, TNF-α and IL-6 were significantly increased while glutathione levels were significantly decreased in hippocampus of STZ-treated rats. Further, a significant decrease in the activity of catalase and increase in AChE activity was observed indicating cholinergic hypofunction and neuronal damage in STZ-treated animals. All these alterations were significantly ameliorated by AME in a dose dependent manner. SignificanceThe neuroprotective potential of A. marmelos against STZ induced oxidative stress and cognitive deficit in rats indicates its therapeutic value in Alzheimer's disease (AD).

Cannabinoid Receptor Type 1 Agonist ACEA Improves Cognitive Deficit on STZ-Induced Neurotoxicity Through Apoptosis Pathway and NO Modulation.

The cannabinoid system has the ability to modulate cellular and molecular mechanisms, including excitotoxicity, oxidative stress, apoptosis, and inflammation, acting as a neuroprotective agent, by its relationship with signaling pathways associated to the control of cell proliferation, differentiation, and survival. Recent reports have raised new perspectives on the possible role of cannabinoid system in neurodegenerative diseases like Alzheimer disease's (AD). AD is a neurodegenerative disorder characterized by the presence of amyloid plaques, neurofibrillary tangles, neuronal death, and progressive cognitive loss, which could be caused by energy metabolism impairment, changes in insulin signaling, chronic oxidative stress, neuroinflammation, Tau hyperphosphorylation, and Aβ deposition in the brain. Thus, we investigated the presumptive protective effect of the cannabinoid type 1 (CB1)-selective receptor agonist arachidonyl-2'-chloroethylamide (ACEA) against streptozotocin (STZ) exposure stimuli in an in vitro neuronal model (Neuro-2a neuroblastoma cells) and in vivo model (intracerebroventricular STZ injection), experimental models of sporadic AD. Our results demonstrated that ACEA treatment reversed cognitive impairment and increased activity of Akt and ERK triggered by STZ, and increased IR expression and increased the anti-apoptotic proteins levels, Bcl-2. In the in vitro model, ACEA was able to rescue cells from STZ-triggered death and modulated the NO release by STZ. Our study has demonstrated a participation of the cannabinoid system in cellular survival, involving the CB1 receptor, which occurs by positive regulation of the anti-apoptotic proteins, suggesting the participation of this system in neurodegenerative processes. Our data suggest that the cannabinoid system is an interesting therapeutic target for the treatment of neurodegenerative diseases.

Alteration in memory cognition due to activation of caveolin-1 and oxidative damage in a model of dementia of Alzheimer's type.

OBJECTIVE:The present study aims to investigate the role of caveolin-1 in dementia of Alzheimer's type using intracerebroventricular streptozotocin (ICV-STZ)-induced neurodegeneration model in rats.MATERIALS AND METHODS:Male Wistar rats (220–260 g) were employed. STZ 3 mg/kg via ICV route was given once to cause neuronal injury. Daidzein – a caveolin inhibitor at 0.2, 0.4, and 0.6 mg/kg s.c. were given daily whereas minoxidil – a caveolin activator was given at 0.45 mg/kg, i.p. on alternate days for 28 days. STZ was also given at its submaximal dose 1.5 mg/kg to minoxidil group only.RESULTS:ICV-STZ control animals exhibited cognitive and neurological deficits on the Morris water maze, elevated plus maze, and balance beam tests (P < 0.0001). Treatment with daidzein significantly restored memory impairments and decreased oxidative damage whereas minoxidil potentiates the effect of STZ causing significant impairment in memory. Significant oxidative stress such as lipid peroxidation and glutathione (P < 0.0001) were also observed due to ICV-STZ administration resulting in neuronal damage which was significantly prevented by treatment with daidzein in brain tissues.CONCLUSION:The findings from the present investigation may conclude that the caveolin-1 from caveolae at the cell membrane induces memory deficits and oxidative stress phenotype that resemble the neurological phenotype of Alzheimer's disease. Further studies are warranted to gauge the effect of caveolin dyshomeostasis on the amyloidogenic cascade.