Arbutin reduces cognitive deficit and oxidative stress in animal model of Alzheimer's disease.

Objectives: Recent evidences have shown the beneficial effects of natural products for treating of Alzheimer's disease (AD). Arbutin is derived from Pyrus biossieriana and exerts a wide range of pharmacological activities including anti-inflammatory and anti-oxidant effects. The present study was designed to examine the protective effects of arbutin on streptozotocin (STZ)-induced neurotoxicity in rats. Materials and methods: The spatial memory impairment was induced by intracerebroventricular (i.c.v) microinjection of STZ (3 mg/kg, 10 µL). Animals received the pretreatment of arbutin (50 mg/kg) for 21 days before STZ injection. The Morris Water maze (MWM) task was used to study the spatial learning and memory. The levels of oxidative stress markers including malondialdehyde (MDA), nitrite and carbonyl were measured in serum and hippocampus samples. In addition, antioxidant level was assessed by ferric reducing antioxidant power (FRAP) test. Results: The obtained result indicated that administration of STZ is led to memory impairment and increases the levels of oxidative stress markers in the hippocampus tissues. Conversely, arbutin improves spatial memory and reduces oxidative and nitrosative stress, as evidenced by a significant decrease in the amount of MDA and nitrite in the serum and hippocampus. In addition, an increase in FRAP levels of hippocampus was observed in arbutin receiving animals. The protein carbonyl content was not reduced in arbutin receiving animals. Conclusion: It could be concluded that arbutin protects the brain against STZ-induced memory impairment and oxidative damage in the hippocampus. The neuroprotective effect of arbutin might be mediated through its antioxidant and free radical scavenging effects.

Efficacy of spinal cord stimulation as an adjunctive therapy in heart failure: A systematic review.

Neuromodulation therapy, like spinal cord stimulation (SCS), benefits individuals with chronic diseases, improving outcomes of patients with heart failure (HF). This systematic review aims to investigate the efficacy of SCS when used as an adjunctive therapy in HF. A systematic analysis of all studies that included SCS therapy in human participants with HF was conducted. After excluding studies not meeting specific criteria, 4 studies involving a total of 125 participants were selected. All participants had heart failure with the New York Heart Association (NYHA) classification ranging from 2.2 ± 0.4 to 3. The primary endpoints for assessment included the impact of SCS in HF-related symptoms, Left ventricular function, VO2 max, and NT-proBNP. All the studies could demonstrate safety and feasibility of SCS therapy, although the outcomes varied. Two studies reported improvement in NYHA classification, MLHFQ and QoL parameters after SCS. Concerning LVEF and VO2 max, only one study indicated positive changes. None of the studies found a significant change of NT-proBNP following SCS therapy. Given methodological variation, discrepancies in the results could be attributed to the diversity of the induction technique. Further studies are needed to develop a solid approach for employing SCS in human patients with HF.

Myristica Fragrans Houtt Extract Attenuates Neuronal Loss and Glial Activation in Pentylenetetrazol-Induced Kindling Model.

Inflammatory reactions are closely associated with the development and progression of epilepsy. It has been shown that inhibition of pro-inflammatory cytokines, which are released from activated astrocytes and microglia, are considered to be an effective therapeutic approach for the treatment of epileptic disorders. Regarding the anti-inflammatory effects of nutmeg (Myristica fragrans Houtt), the present study was designed to investigate whether the nutmeg ethanolic extract could exert anticonvulsant and inhibitory effects on glial activation in pentylenetetrazol (PTZ)-induced mice model of kindling. Ethanolic extract of nutmeg was administrated intraperitoneally (i.p.) 1 hour before PTZ injection or one week before PTZ as a separate group, to become fully-kindled. The chemical components of nutmeg extract were analyzed by gas chromatography mass spectrometry (GC-MS). Immunostaining against neuronal and glial markers was performed on hippocampus sections. GC-MS data indicated that the main components of nutmeg extract are myristic acid (39.93%), elemicin (22.16%) and myristicin (11.17%). Behavioral studies showed that pre-treatment of nutmeg extract effectively reduced seizures behavior, decreased cell death, and ameliorated glial activation that is followed by PTZ administration. In conclusion, nutmeg extract might be regarded as a useful supplementary agent in epilepsy treatment through its attenuation of neuronal loss and glial activation.

Adenosine A2A receptor blockade attenuates spatial memory deficit and extent of demyelination areas in lyolecithin-induced demyelination model.

In recent years, inactivation of A2A adenosine receptors has been emerged as a novel strategy for treatment of several neurodegenerative diseases. Although numerous studies have shown the beneficial effects of A2A receptors blockade on spatial memory, the impacts of selective adenosine A2A receptors on memory performance has not yet been examined in the context of demyelination. In the present study, we evaluated the effect of A2A receptor antagonist SCH58261 on spatial memory and myelination in an experimental model of focal demyelination in rat fimbria. Demyelination was induced by local injection of lysolecithin (LPC) 1% (2 µl) into the hippocampus fimbria. SCH58261 (20 µg/0.5 µl or 40 µg/0.5 µl) was daily injected intracerebroventricularly (i.c.v.) for 10 days post LPC injection. The Morris water maze test was used to assess the spatial learning and memory on day 6 post lesion. Myelin staining and immunostaining against astrocytes/microglia were carried out 10 days post LPC injection. The administration of adenosine A2A receptor antagonist prevented the spatial memory impairment in LPC receiving animals. Myelin staining revealed that application of SCH58261 reduces the extent of demyelination areas in the fimbria. Furthermore, the level of astrocytes and microglia activation was attenuated following administration of A2A receptor antagonist. Collectively, the results of this study suggest that A2A receptor blockade can improve the spatial memory and protect myelin sheath, which might be considered as a novel therapeutic approach for multiple sclerosis disease.

Querectin improves myelin repair of optic chiasm in lyolecithin-induced focal demyelination model.

Although the beneficial effects of quercetin on oligodendrocyte precursor cell (OPCs) population has been evaluated in-vitro, there are few studies about the effects of quercetin on myelin repair in the context of demyelination. The aim of this study was to investigate the effects of querectin on functional recovery and myelin repair of optic chiasm in lysolecithin (LPC)-induced demyelination model. Demyelination was induced by local injection of LPC 1% (2 µl) into rat optic chiasm. Querectin at doses 25 or 50 mg/kg was administrated daily by oral gavage for 7 or 14 days post LPC. Visual evoked potential (VEPs) recordings were used to assess the functional property of the optic pathway. Immunostaining and myelin staining were performed on brain sections 7 or 14 days post lesion. Electrophysiological data indicated that LPC injection increased the latency of VEPs waves and quercetin effectively reduced the delay of visual signals. The level of glial activation was alleviated in animals under treatment of quercetin compared to vehicle group. Furthermore, quercetin treatment decreased the extent of demyelination areas and increased the remyelination process following LPC injection. Overall, our findings indicate that quercetin could remarkably improve the functional recovery of the optic pathway by its protective effects on myelin sheath and attenuation of glial activation.

Arbutin attenuates behavioral impairment and oxidative stress in an animal model of Parkinson's disease.

OBJECTIVE: Arbutin has been shown to have antioxidant and free-radical scavenging properties. The aim of this study was to investigate the effects of arbutin administration on behavioral impairment, and oxidative and nitrosative stress in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of Parkinson's disease (PD). MATERIALS AND METHODS: PD model was developed by 4 intraperitoneal (i.p.) injections of MPTP (20 mg/kg) with 2 h intervals in mice. Experimental groups received once daily injection of saline as vehicle (control group) or arbutin (50 mg/kg, i.p.) one week before MPTP injections and this protocol was continued seven days post lesion. Behavioral deficits were evaluated using locomotion test, hanging wire test and forepaw stride length. Parameters indicating the oxidation levels including lipid peroxidation marker (TBARS), nitrite, protein carbonyl levels and antioxidant activity including ferric reducing antioxidant power (FRAP) were assessed in serum and midbrain samples. RESULTS: Treatment with arbutin improved motor functions in an MPTP-induced PD model compared to control group (p<0.001). Mice treated with MPTP showed reduced levels of FRAP (p<0.001) and increased levels of TBARS (p<0.001), nitrite (p<0.001) and protein carbonyl (p<0.01), compared to the control group. In contrast to the MPTP group, arbutin treatment decreased the levels of TBARS (p<0.05), nitrite (p<0.05), protein carbonyl (p<0.05), and increased FRAP levels (p<0.05) in mice with PD. CONCLUSION: These findings suggest that arbutin attenuates the behavioral impairment and oxidative stress in a PD animal model.

Curcumin-loaded nanoparticles ameliorate glial activation and improve myelin repair in lyolecithin-induced focal demyelination model of rat corpus callosum.

Curcumin has been introduced as effective anti-inflammatory agent in treatment of several inflammatory disorders. Despite the wide range pharmacological activities, clinical application of curcumin is restricted mainly due to the low water solubility of this substance. More recently, we could remarkably improve the aqueous solubility of curcumin by its encapsulation in chitosan-alginate-sodium tripolyphosphate nanoparticles (CS-ALG-STPP NPs). In this study, the anti-inflammatory and myelin protective effects of curcumin-loaded NPs were evaluated in lysolecithin (LPC)-induced focal demyelination model. Pharmacokinetic of curcumin was assessed using high performance liquid chromatography (HPLC). Local demyelination was induced by injection of LPC into corpus callosum of rats. Animals were pre-treated with intraperitoneal (i.p.) injections of curcumin or curcumin-loaded NPs at dose of 12.5 mg/kg, 10 days prior to LPC injection and the injections were continued for 7 or 14 days post lesion. Hematoxylin and eosin (H&E) staining and immunostaining against activated glial cells including astrocytes and microglia were carried out for assessment of inflammation level in lesion site. Myelin specific staining was performed to evaluate the effect of curcumin-loaded NPs on myelination of LPC receiving animals. HPLC results showed the higher plasma concentration of curcumin after administration of NPs. Histological evaluation demonstrated that, the extent of demyelination areas was reduced in animals under treatment of curcumin-loaded NPs. Furthermore, treatment with curcumin-loaded NPs effectively attenuated glial activation and inflammation in LPC-induced demyelination model compared to curcumin receiving animals. Overall; these findings indicate that treatment with curcumin-loaded NPs preserve myelinated axons through amelioration of glial activation and inflammation in demyelination context.

Upregulation of klotho and erythropoietin contributes to the neuroprotection induced by curcumin-loaded nanoparticles in experimental model of chronic epilepsy.

Klotho, which is a life extension factor, and erythropoietin (EPO) have been introduced as effective neuroprotective factors in several neurological disorders. The present study is an attempt to examine the potential role of klotho and EPO in therapeutic effect of curcumin-loaded nanoparticles (NPs) in pentylenetetrazol (PTZ)-induced kindling model. In order to induce the kindling model, PTZ was administrated intraperitoneally (i.p.) at dose of 36.5 mg/kg every other day for 20 days. Male NMRI mice received pre-treatment of free curcumin or curcumin-loaded NPs (12.5 mg/kg, i.p.) 10 days before PTZ injection and this was continued until 1 h before each PTZ injection. Immunostaining against NeuN, as a marker of neuronal maturation, and EPO was performed on hippocampal brain sections. Quantitative real time polymerase chain reaction (qRT-PCR) was conducted to assess the expression levels of tumor necrosis factor-α (TNF-α), klotho and EPO in the hippocampus. Immunostaining data indicated that treatment with curcumin-loaded NPs significantly alleviates the neuronal cell death in PTZ receiving animals. Curcumin-loaded NPs effectively upregulated the levels of EPO and klotho in PTZ receiving animals. Furthermore, mRNA level of TNF-α was considerably reduced in animals undergone curcumin-loaded NPs treatment. Overall, the results of this study suggest that downregulation of TNF-α and consequent upregulation of klotho and EPO might contribute to the neuroprotective effect of curcumin-loaded NPs in experimental model of epilepsy.

Inhibition of GABA A receptor improved spatial memory impairment in the local model of demyelination in rat hippocampus.

Cognitive impairment and memory deficit are common features in multiple Sclerosis patients. The mechanism of memory impairment in MS is unknown, but neuroimaging studies suggest that hippocampal demyelination is involved. Here, we investigate the role of GABA A receptor on spatial memory in the local model of hippocampal demyelination. Demyelination was induced in male Wistar rats by bilaterally injection of lysophosphatidylcholine (LPC) 1% into the CA1 region of the hippocampus. The treatment groups were received daily intraventricular injection of bicuculline (0.025, 0.05µg/2µl/animal) or muscimol (0.1, 0.2µg/2µl/animal) 5days after LPC injection. Morris Water Maze was used to evaluate learning and memory in rats. We used Luxol fast blue staining and qPCR to assess demyelination extention and MBP expression level respectively. Immunohistochemistry (IHC) for CD45 and H&E staining were performed to assess inflammatory cells infiltration. Behavioral study revealed that LPC injection in the hippocampus impaired learning and memory function. Animals treated with both doses of bicuculline improved spatial learning and memory function; however, muscimol treatment had no effect. Histological and MBP expression studies confirmed that demylination in LPC group was maximal. Bicuculline treatment significantly reduced demyelination extension and increased the level of MBP expression. H&E and IHC results showed that bicuculline reduced inflammatory cell infiltration in the lesion site. Bicuculline improved learning and memory and decreased demyelination extention in the LPC-induced hippocampal demyelination model. We conclude that disruption of GABAergic homeostasis in hippocampal demyelination context may be involved in memory impairment with the implications for both pathophysiology and therapy.

Piperine restores streptozotocin-induced cognitive impairments: Insights into oxidative balance in cerebrospinal fluid and hippocampus.

Piperine has been shown to have antioxidant activity and a cognitive-enhancing effect following long-term oral administration. In a comparative study of memantine, the current investigation threw light on the cognitive benefits of piperine. Lipid peroxidation and the ferric reducing antioxidant power (FRAP) of cerebrospinal fluid (CSF) and hippocampus in streptozotocin (STZ)-induced experimental dementia of the Alzheimer's type was measured. After reaching a criterion in a memory test, STZ-induced rats received piperine [2.5, 5, and 10mg/kg, intraperitoneally (i.p.)], vehicle, and memantine (10mg/kg, i.p.) for two weeks after the first STZ administration, or two weeks before and one week after, as a preventive approach. After the behavioral studies, samples were taken for biochemical and histological assays. An appropriate concentration of piperine (2.5mg/kg), on a daily basis, effectively increased the number of correct (non-repeated) arm entries and repressed reentry to a previously visited arm, in terms of reference errors as well as memantine (10mg/kg, i.p.), irrespective of the dose administered. The cognitive-enhancing effect induced by piperine at a relevant dose was simultaneous with CSF and hippocampal malonaldehyde decrement, and the redox balance was established to some extent by maintaining the FRAP levels of CSF near to those of the control. Similarly, the neuroprotective properties of piperine are in accordance with histopathological outcomes, which have shown an increased number of live cresyl violet (CV)-positive neurons in a dentate gyrus (DG) subregion. Therefore, the effects of piperine on the redox balance of CSF and hippocampal neurons may certainly contribute to the cognitive-enhancing activity of the drug.

Vitamin D Improves Learning and Memory Impairment in Streptozotocin-Induced Diabetic Mice.

INTRODUCTION: Diabetes mellitus (DM) is associated with memory and learning deficits. Evidence has been provided that vitamin D is involved in brain function. The aim of the present study was to determine the potential effect of vitamin D on acquisition and retention of memory and learning in streptozotocin (STZ)-induced diabetic mice. METHODS: Experiments were performed in four groups of mice (each group; n = 7). Male mice were induced to diabetes by single dose (60 mg/kg, i.p.) injection of freshly prepared STZ dissolved in cold normal saline. Treatment with vitamin D (5µg/kg daily, i.p. dissolved in tween80) was begun at three days after diabetes induction. Passive avoidance (PA) learning method was used four weeks later. Retrieval test was carried out 24 h after training. RESULTS: Our results demonstrate significant impairment in acquisition and retrieval processes of PA learning in STZ- induced diabetic mice. Treatment with vitamin D improved learning and memory compared to the control group, both in acquisition and retrieval stages and reversed learning deficits in diabetic mice. In acquisition test, there were significant differences in the initial latency among the DM+Vit. D treated and control groups (P < 0.05). There was a significant difference in step-through latency between diabetic group treated with vitamin D compared to diabetic non-treated groups (P < 0.05). CONCLUSION: It is possible that the effects of Vitamin D on cognitive deficits in STZ-induced diabetic mice could be mediated through calcium homeostasis modulation. These findings suggest a potential role for vitamin D in the treatment of diabetes-associated cognition deficits. The positive effect of vitamin D on the avoidance task may be attributed to its neuronal protective roles metabolic regulating roles of prolonged vitamin D administration.

Vitamin E protects salivary glands dysfunction induced by ionizing radiation in rats.

The purpose of this study is to investigate the radioprotective effect of vitamin E as a natural product. Vitamin E protects the salivary glands dysfunction that is induced by ionizing radiation. It was analysed with radioisotope scintigraphy and then salivary gland to background counts ratio was calculated. Histopathological evaluation was performed. The rats were treated with vitamin E at dose of 400IU/kg 48, 24, and 1h before 15Gy gamma rays irradiation. The rats were evaluated for the salivary gland function through nuclear medicine protocol. Radiation causes significant salivary glands dysfunction at the 3rd and the 70th days with a reduction in radioactivity uptake in the salivary glands. Ratios of salivary gland to background radioactivities were 1.99±0.11, 1.58±0.08 and 1.92±0.04 for control, radiation, and vitamin E plus radiation groups, respectively. Vitamin E significantly improved salivary gland dysfunction induced by ionizing radiation in the rats. In conclusion, our results indicate protective effects of vitamin E against salivary gland dysfunction induced by gamma radiation. Thus, vitamin E is a promising radioprotective agent for patients who receive radiation in head and neck cancer therapy.

Effect of milk and yogurt on streptococcus sobrinus counts and caries score in rats.

BACKGROUND: An anti-cariogenic diet containing probiotics can be effective in caries prevention. This animal study compared the effects of milk and yogurt on Streptococcus sobrinus counts and caries score. MATERIALS AND METHODS: A total of 36 male rats were infected with S. sobrinus (27,607) and divided into three groups. Group A and B received 200 mL of milk and 100 g of yogurt per day, respectively, and a control group received 2.5 mL of NCP number 2 diet twice daily for 21 days. After killing the animals, their lower left jaws were removed and sonicated to quantify the colonies of S. sobrinus. Dental caries was scored using Keyes technique. Data were analyzed using ANOVA and Kruskal-Wallis, Mann-Whitney and Wilcoxon-Signed Rank tests. Statistical significance was set at P < 0.05. RESULTS: The mean (±standard error of the mean) of S. sobrinus colonies in the milk, yogurt and control groups were determined at 119666.67 (±20733), 46416.666 (±12846) and 163,250 (±33493), respectively. Microbial counts decreased in the yogurt group compared with the milk and control groups (P = 0.004 and P = 0.000; respectively). There were significant differences between caries scores of smooth surfaces in the milk and yogurt groups compared with the control group (P = 0.000 and P = 0.000, respectively). Both milk and yogurt significantly reduced caries score of fissured surfaces compared with controls (P = 0.004 and P = 0.000, respectively). CONCLUSION: Considering the limitations of this study, yogurt administration reduces S. sobrinus counts. In addition, yogurt and milk regimens reduce the caries scores of smooth and fissured surfaces.

Alprazolam role in the analgesic effect of ibuprofen on postendodontic pain.

BACKGROUND: Postendodontic pain (PEP) has always been a major problem for patients and dentists and NSAIDs are being used to relieve PEP and it is supposed that some benzodiazepines may potentiate facilitate the analgesic effects of the NSAIDs. This study was conducted to evaluate the effect of alprazolam on the analgesic effect of ibuprofen in PEP treatment. METHODS: This randomized double-blind clinical trial was conducted on 45 patients aged 20-45 years who were subjected of root canal treatment. A written informed consent was obtained from each patient. The subjects were randomly divided into three groups; placebo, ibuprofen (400 mg) and alprazolam (0.5) mg + ibuprofen (400 mg). The intensity of pain was recorded using visual analog scale (VAS) at 4, 6, 12, 24, 48 and 72 hours after drug administration. RESULTS: Of the participants, twenty six (57.8%) were males and 19 patients (42.2%) were females. Four hours after starting treatment, the VAS scores in the placebo and ibuprofen -treated groups were significantly higher than ibuprofen and alprazolam+ibuprofen groups (4.93±1.16, 3.67±1.88 and 2.67±1.11, respectively, p<0.0001). The VAS scores in alprazolam + ibuprofen group (2.33±1.05) were significantly lower at 6 hours after treatment when compared to the other groups (Ibuprofen: 3.00±1.36 and placebo: 3.08±1.74, P=0.002). This decrease in VAS score sustained to 12 hours after the start of alprazolam + ibuprofen treatment when compared to ibuprofen or placebo receiving group alone (p<0.003). The average pain score in female patients who received alprazolam + ibuprofen was significantly lower than males at 12 hours (1.3±0.6 v.s 2.14±0.9, P=0.002) and 24 hours after treatment (0.88±0.6 v.s 1.86±0.9, P=0.003). CONCLUSION: According to the results, it can conclude that alprazolam may enhance the analgesic efficacy of ibuprofen in postendodontic pain.