Cognitive effects of vanillic acid against streptozotocin-induced neurodegeneration in mice

Abstract

Context: Vanillic acid (VA), a flavoring agent used in food and drug products, obtained naturally from the plant Angelica sinensis (Oliv.) Diels (Apiaceae), used in the traditional Chinese medicine. It is reported to possess strong antioxidant, anti-inflammatory, and neuroprotective effects. However, the pharmacological effects on oxidative stress-induced neurodegeneration are not well investigated.

Objective: This study investigates the neuroprotective effect of VA on streptozotocin (STZ)-induced neurodegeneration in mice through behavioral and biochemical parameters.

Materials and methods: The behavioral effects were determined using the Y-maze and open-field habituation memory. In biochemical parameters, acetylcholinesterase (AChE), corticosterone, tumor necrosis factor (TNF)-α, and antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase) were measured. Five groups of animals used were of control, negative control, and three separate groups treated with 25, 50, and 100?mg/kg of VA, respectively, for 28?d. Intracerebroventricular (ICV) injections of STZ were performed for all groups except control on 14th and 16th of 28?d of VA treatment.

Results: VA improved spatial learning and memory retention by preventing oxidative stress compared with control animals. VA at 50 and 100?mg/kg dose significantly (p?<?0.001) improved the habituation memory, decreased the AChE, corticosterone, TNF-α, and increased the antioxidants (p?<?0.001). VA (100?mg/kg) exhibited dose-dependent effect in all parameters with p?<?0.001 except antioxidants in which VA showed the significance of p?<?0.01.

Discussion and conclusion: VA exhibited reduction in AChE, TNF-α, and corticosterone with improved antioxidants to contribute neuroprotection and could be an effective therapeutic agent for treating neurodegenerative disorders.     

Possible protective effect of melatonin and/or desferrioxamine against streptozotocin-induced hyperglycaemia in mice.

There is a clear link between diabetes and oxidative stress. Hyperglycaemia leads to free radical generation and alteration of endogenous antioxidants. The present study is an attempt to evaluate the possible protective effect of melatonin (MLT) and/or desferrioxamine (DF) against streptozotocin (STZ)-induced hyperglycaemia in mice. Serum lipid profile, pancreatic tissue contents of glutathione (GSH) and malondialdehyde (MDA) were determined. MLT and/or DF were given p.o. in doses of 5 mg kg(-1)day(-1)and 250 mg kg(-1) day(-1), respectively for 15 consecutive days prior to STZ treatment (60 mg kg(-1) day(-1) i.p.) for 3 consecutive days. Results revealed that STZ induced a marked increase in serum glucose, serum triglycerides (TG), cholesterol (CHO) and LDL-cholesterol. On the contrary HDL-cholesterol was markedly decreased in STZ-treated group. Moreover, STZ induced a significant decrease in the pancreatic content of GSH with concomitant increase in MDA content. Administration of MLT or (MLT+DF) prior to STZ treatment revealed a marked decrease in serum glucose level by 35.6 and 31.6%, respectively as compared to STZ-treated group. Furthermore, MLT pretreatment of STZ-induced hyperglycemic mice, has not only normalized GSH content of pancreatic tissues but also increased its level more than that of control animals by 110%. On the contrary, MDA content of pancreatic tissues was markedly decreased even lower than normal control group. MLT also, induced a marked protection in terms of decreasing serum CHO, LDL, TG by 21.8, 83.8 and 82.2%, respectively, while HDL was increase by 56% as compared to STZ treated group. DF was found to be less effective than MLT in the protection against STZ-induced hyperglycemia. In conclusion, these data suggest that MLT protects against the damaging consequences induced by hyperglycemia either systemically or in the pancreatic tissues.     

TRH protection against memory retrieval deficits is independent of endocrine effects.

An electrobrainshock (EBS)-induced memory retrieval deficit was produced in normal and hypophysectomized mice. In normal mice, thyrotropin-releasing hormone (TRH) (0.1 to 30 mg/kg) protected against this EBS disruption of memory after intraperitoneal but not oral (1.0 to 100 mg/kg) administration. In hypophysectomized mice, TRH (0.3 and 3.0 mg/kg) also protected against the retrieval deficit induced by EBS. The memory protection afforded by TRH was unrelated to its ability to elevate plasma levels of triiodothyronine (T3) and thyroxine (T4), nor was TRH's memory protection mediated through an anticonvulsive mechanism. These results support the notion that TRH may play an important role in memory modulation and may have therapeutic value in certain disease states in humans.     

Protective effects of Polygala paniculata extract against methylmercury-induced neurotoxicity in mice

We have examined the possible protective effects of Polygala paniculata extract against methylmercury (MeHg)-induced neurotoxicity in adult mice. MeHg was diluted in drinking water (40 mg L(-1), freely available) and the hydroalcoholic Polygala extract was diluted in a 150 mM NaCl solution and administered by gavage (100 mg kg(-1) b.w., twice a day). After a two-week treatment, MeHg exposure significantly inhibited glutathione peroxidase and increased glutathione reductase activity, while the levels of thiobarbituric acid reactive substances were increased in the cerebral cortex and cerebellum. These alterations were prevented by administration of Polygala extract, except for glutathione reductase activity, which remained elevated in the cerebral cortex. Behavioural interference in the MeHg-exposed animals was evident through a marked deficit in the motor performance in the rotarod task, which was completely recovered to control levels by Polygala extract co-administration. This study has shown, for the first time, the in-vivo protective effects of Polygala extract against MeHg-induced neurotoxicity. In addition, our findings encourage studies concerning the beneficial effects of P. paniculata on neurological conditions related to excitotoxicity and oxidative stress.     

Protective effects of icariin against learning and memory deficits induced by aluminium in rats

1. The present study examined the protective effects of icariin against the learning and memory deficits in aluminium-treated rats and its potential mechanisms of action. 2. Qualified rats were treated with 1600 p.p.m. AlCl(3) in drinking water for 8 months and the ability of spatial learning and memory was tested by the Morris water maze. In the place navigation test, aluminium administration significantly increased the mean escape latency and searching distance. In space probing test, aluminium markedly decreased the searching time and searching distance in the quadrant where the platform was originally located. All tests indicated deficits in rat spatial learning and memory induced by aluminium. Icariin treatment (60 and 120 mg/kg, by gavage for 3 months) dose-dependently protected against the development of aluminium-induced spatial learning and memory deficits. 3. To examine the mechanisms responsible for the protection afforded by icariin, the superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in the hippocampus were assayed biochemically and the level of Abeta(1-40) in the hippocampus was determined immunohistochemically. Icariin treatment significantly increased SOD activity and decreased MDA and Abeta(1-40) content in the hippocampus of aluminium-intoxicated rats. 4. In conclusion, the present study demonstrates that icariin is effective in improving the spatial learning and memory of aluminium-intoxicated rats. The mechanisms responsible appear to be due, at least in part, to an increased anti-oxidant capacity and decreased lipid peroxidation and Abeta(1-40) levels in the rat hippocampus.     

葛根素D—半乳糖诱导的小鼠记忆障碍的影响

目的:探讨葛根素对D-半乳糖致衰老小鼠学习记忆的影响及其作用机制。方法:用开场行为和Y-迷宫分别检测腹腔注射葛根素后D-半乳糖衰老模型小鼠自发活动和学习记忆行为的变化,然后用紫外分光光度计和荧光分光光度计分别检测衰老小鼠脑组织SOD、MDA以及脂褐素等生化指标。结果:葛根素60mg/kg可显著增加D-半乳糖致衰老小鼠在新异环境中的自发活动和探究行为,显著提高其学习记忆能力(记忆保持率从69％±9％提高到79％±6％);葛根素60mg/kg和30mg/kg均可以显著提高脑组织SOD的活性,从(12.1±2.9)提高到(14.9±2.1)和(15.5±2.7)U/g脑湿重,并使衰老小鼠脑内脂褐素含量明显下降,从(27±5)降到(20±4)和(20±4)μ/g脑湿重。结论:葛根素对D-半乳糖致衰老小鼠学习记忆减退有改善作用,这可能与其提高衰老小鼠脑组织抗氧化能力有关。     

Effects of Coeloglossum. viride var. bracteatum extract on memory deficits and pathological changes in senescent mice

Previous studies have shown that injection of D-galactose could result in senescent performances in animals, that injection of NaNO2 could cause ischaemia and hypoxia in many organs, and combined injection of D-galactose and NaNO2 make normal mice taking on senescent performances in a shorter period. The aim of this study was to investigate the effects of CE, an extract from a Tibetan medicinal herb, Coeloglossum. viride (L.) Hartm. var. bracteatum (Willd.), on senescent mice. The step-down test was performed to evaluate the learning and memory function of mice. The activities of superoxide dismutase, adenosine triphosphatase, monoamine oxydase and the content of malondialdehyde were measured to determine the impairment of brain. The expressions of Bcl-2, Bax, and caspase-3 proteins in mouse hippocampus were studied by immunohistochemical staining. The data demonstrated that D-galactose and NaNO2 treated mice had significant deficits in learning and memory function. The reduced activities of superoxide dismutase, adenosine triphosphatase, increased activities of monoamine oxydase and level of malondialdehyde were also found. Bax and caspase-3 positive cells increased while Bcl-2 positive cells decreased remarkably. Treatment of CE (2.5, 5 mg.kg(-1)) ameliorated the memory impairment; rectified the biochemistry and neural system changes in mice. These results suggest that CE offers promise as a tool for treatment of senescence-related diseases.     

HOE-140, an antagonist of B2 receptor,protects against memory deficits and brain damage induced by moderate lateral fluid percussion injury in mice

Rationale

There are evidences indicating the role of kinins in pathophysiology of traumatic brain injury, but little is known about their action on memory deficits.

Objectives

Our aim was to establish the role of bradykinin receptors B₁ (B₁R) and B₂ (B₂R) on the behavioral, biochemical, and histologic features elicited by moderate lateral fluid percussion injury (mLFPI) in mice.

Methods

The role of kinin B₁ and B₂ receptors in brain damage, neuromotor, and cognitive deficits induced by mLFPI, was evaluated by means of subcutaneous injection of B₂R antagonist (HOE-140; 1 or 10 nmol/kg) or B₁R antagonist (des-Arg9-[Leu8]-bradykinin (DAL-Bk; 1 or 10 nmol/kg) 30 min and 24 h after brain injury. Brain damage was evaluated in the cortex, being considered as lesion volume, inflammatory, and oxidative damage. The open field and elevated plus maze tests were performed to exclude the nonspecific effects on object recognition memory test.

Results

Our data revealed that HOE-140 (10 nmol/kg) protected against memory impairment. This treatment attenuated the brain edema, interleukin-1β, tumor necrosis factor-α, and nitric oxide metabolites content elicited by mLFPI. Accordingly, HOE-140 administration protected against the increase of nicotinamide adenine dinucleotide phosphate oxidase activity, thiobarbituric-acid-reactive species, protein carbonylation generation, and Na⁺ K⁺ ATPase inhibition induced by trauma. Histologic analysis showed that HOE-140 reduced lesion volume when analyzed 7 days after brain injury.

Conclusions

This study suggests the involvement of the B₂ receptor in memory deficits and brain damage caused by mLFPI in mice.     

Effects of an extract of Ginkgo biloba on learning and memory in mice

The effects of an extract of Ginkgo biloba (EGb 761) on acquisition, performance, and retention of mice in an appetitive operant conditioning were investigated. The animals were trained for 30 consecutive days to acquire a two-lever response sequence followed by food reward. EGb 761 was administered daily at a dose level of 100 mg/kg PO. Drug treatment started four and eight weeks before the training and was maintained until a retention test 10 weeks after it. The results indicated that EGb 761 facilitated memory processes. EGb 761 quickened the acquisition and improved the performance of the two-response sequence: The number of correct responses was increased and correct responses were performed more frequently in the most effective manner. Besides, incorrect responses were reduced sooner and faster and to a lower level in EGb 761-treated mice. With regard to the retention EGb 761 improved the retrieval of the learned response.     

The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task

The effects of the neurosteroid pregnenolone sulfate (PS) on learning as well as on scopolamine-induced learning deficits were studied in Swiss mice using an appetitively reinforced Go-No Go visual discrimination task. Subcutaneous (SC) administration of scopolamine (0.3–3 mg/kg) after the first session of training dose-dependently impairs learning during the following sessions in this task. Moreover, intracerebroventricular (ICV) administration of PS (0.01–10 nmol) dose-dependently blocks learning deficits induced by scopolamine (3 mg/kg), with the most potent effects at the dose of 0.5 nmol PS. In addition to antagonizing the amnestic effects of scopolamine, PS (0.5 nmol ICV) has a memory-enhancing effect, when administered alone after the first training session. Scopolamine (3 mg/kg SC) also produced substantial deficits on retrieval performance in the Go-No Go visual discrimination task, and caused motor disturbances, when administered 15 min before testing. PS (0.5 nmol ICV) also reduced scopolamine-induced deficits on retrieval but had no effect on scopolamine-induced motor impairments in the traction reflex test. Such a rapid effect of PS on memory processes may be mediated via NMDA and/or GABA_A receptors.     

Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats

Although it is well established that chronic stress impairs spatial learning and memory, few studies have investigated possible ways to prevent its deleterious effects. Here, we investigated the effects of Crocus sativus L., commonly known as saffron, and its active constituent crocin on learning and memory loss and the induction of oxidative stress in the hippocampus by chronic stress. Rats were injected with saffron extract, crocin or vehicle over a period of 21 days while being exposed to chronic restraint stress (6 h/day). After this, they were trained and tested on a water-maze spatial memory task. They performed four trials per day for 5 consecutive days, and this was followed by a probe trial two days later. At the end of the behavioral testing, several parameters of oxidative stress in the hippocampus were measured. Treatment with saffron extract or crocin blocked the ability of chronic stress to impair spatial learning and memory retention. Relative to controls that received vehicle, stressed animals that received saffron extract or crocin had significantly higher levels of lipid peroxidation products, significantly higher activities of antioxidant enzymes including glutathione peroxidase, glutathione reductase and superoxide dismutase and significantly lower total antioxidant reactivity capacity. Finally, crocin significantly decreased plasma levels of corticosterone, as measured after the end of stress. These observations indicate that saffron and its active constituent crocin can prevent the impairment of learning and memory as well as the oxidative stress damage to the hippocampus induced by chronic stress. Thus, using these substances may be useful in pharmacological alleviation of cognitive deficits.     

E838对小鼠骨髓细胞染色体的辐射防护作用

目的探讨E838对γ射线照射小鼠骨髓细胞染色体损伤的防护作用。方法将615小鼠,随机分为对照组、辐射对照组、E838组、炔雌三醇(EE3)组。E838组和EE3组分别腹腔注射E838和EE3,另两组给予等体积茶油,第3次给药24 h后进行剂量为1.5 Gy的137Csγ射线全身照射,观察其骨髓细胞染色体畸变率。结果 E838组、EE3组骨髓细胞染色体畸变与辐射对照组比较差异有统计学意义(P<0.01),E838组畸变细胞与EE3组比较差异有统计学意义(P<0.05)。结论 E838可降低辐射诱发的骨髓细胞染色畸变细胞数,对骨髓细胞染色体具有一定的辐射防护作用。     

黄芩茎叶总黄酮对铝中毒小鼠记忆障碍的作用

目的研究黄芩茎叶总黄酮(TotalflavonoidsfromstemsandleavesofScutellariabaicalensisGeorgi,SSF)对慢性铝中毒小鼠学习记忆运动障碍、神经和肝脏病理改变及自由基不正常变化的作用。方法小鼠腹腔注射(Introperitonealinjection,ip)AlCl350d制备铝中毒模型。通过小鼠学习记忆能力、自主活动、皮层和肝脏病理改变及脑肝脏丙二醛(malondialdehyde,MDA);超氧化物岐化酶(superoxidedismutase,SOD)测定,评价SSF对小鼠慢性铝中毒的作用。结果与空白对照组相比,AlCl3(100mg·kg-1,ip,50d)使小鼠学习记忆能力降低、自主活动次数减少、皮层和肝脏细胞病理改变、脑和肝脏MDA水平增加和SOD活性减低。SSF50、100和200mg·kg-1不同程度的改善铝中毒小鼠上述病理改变。结论SSF能够改善慢性铝中毒小鼠学习记忆运动障碍、神经肝脏病理改变和自由基不正常变化。     

Beneficial effects of an Andrographis paniculata extract and andrographolide on cognitive functions in streptozotocin-induced diabetic rats

Context Andrographolide containing Andrographis paniculata (Burm. F.) Wall. Ex Nees (Acanthaceae) extracts is often used for treatments of diabetes and other inflammatory disorders commonly accompanying cognitive and other psychiatric disorders.

Objective To compare the efficacies of a standardised A. paniculata extract (AP) and pure andrographolide on cognitive functions, oxidative stress and cholinergic function in diabetic rats.

Materials and methods Streptozotocin-induced diabetic Charles Foster albino rats treated orally with a hydro-methanolic A. paniculata leaf extract (50, 100 and 200?mg/kg/day), or with pure andrographolide (15, 30 and 60?mg/kg/day) for 10 consecutive days, were subjected to Morris water maze test. After the test, acetylcholinesterase, superoxide dismutase (SOD), and catalase (CAT) activities and lipid peroxidation (LPO) in brain tissues were assessed.

Results Acetylcholinesterase activity in pre-frontal cortex and hippocampus of diabetic rats was 2.1 and 2.6 times higher compared to nondiabetic rats. LPO was 1.6 times higher and decreased SOD (56.3%) and CAT (44.9%) activities in pre-frontal cortex of diabetic rats compared to nondiabetic rats. AP or andrographolide treatments dose dependently attenuated cognitive deficits, reduced acetylcholinesterase activity, oxidative stress, improved diabetic hyperglycemia and insulin deficiency. All observed effects of AP were quantitatively almost equal to those expected from its analytically quantified andrographolide content.

Discussion and conclusion Reported observations are the very first ones suggesting beneficial effects of andrographolide against diabetes associated cognitive deficits, increased acetylcholinesterase activity and deteriorated antioxidative status. Efforts to exploit A. paniculata extracts enriched in andrographolide as preventive measures against such disorders can be warranted.     

Potential of ezetimibe in memory deficits associated with dementia of Alzheimer's type in mice

Background:

High cholesterol levels have been positively correlated with a higher incidence of memory impairment and dementia.

Aim:

The study was undertaken to investigate the potential of the lipid-lowering drug, ezetimibe, in memory deficits associated with dementia of Alzheimer''s (AD) type in mice.

Methods:

Dementia was induced with chronic administration of a high-fat diet (HFD) or intracebroventricular streptozotocin (ICV STZ, two doses of 3 mg/kg) in separate groups of animals. The memory of the animals was assessed by employing a Morris water maze. Brain thio barbituric acid-reactive species and reduced glutathione levels were measured to assess the total oxidative stress. Brain acetyl cholinesterase (AChE) activity and total serum cholesterol levels were also measured.

Results:

STZ/HFD produced a significant impairment of memory along with an increase in brain AChE activity and oxidative stress. HFD mice also showed an increase in cholesterol levels. Ezetimibe (10 mg/kg, orally for 15 days) significantly attenuated STZ/HFD-induced memory deficits and biochemical changes. It also prevented HFD-induced rise in the cholesterol level.

Conclusions:

The memory-restorative effect of ezetimibe can be attributed to its cholesterol-dependent as well as cholesterol-independent effects. The study highlights the potential of ezetimibe in memory dysfunctions associated with dementia of AD.     

Protective role of Dodonaea viscosa extract against streptozotocin-induced hepatotoxicity and nephrotoxicity in rats

Previous investigations have shown that D. viscosa herbal extract is often used to treat a variety of diseases. Therefore, the purpose of this study was to investigate any additional potential impacts on rat liver and kidney damage induced by diabetes. Streptozotocin (STZ) (60 mg/kg/day) was given as a single dosage to cause type 1 diabetes. After then, diabetic rats received oral doses of D. viscosa for four weeks at 150 and 300 mg/kg/day. Blood, liver, and kidney tissues were collected at the end of the treatment and examined. Analysis was made of the serum lipid profile, liver, and kidney functions, as well as blood biochemistry. Moreover, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), prostaglandin E-2 (PGE-2), and nitric oxide (NO) were estimated in serum. In liver and kidney samples, thiobarbituric acid reactive substances (TBARs) and reduced glutathione (GSH), as well as the pro-inflammatory cytokines and enzymatic activities of glutathione peroxidase (GPx), glutathione reeducates (GR), glutathione-S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) were analyzed. Histological changes in liver and kidney cross-sections were also observed. Our findings demonstrated that D. viscosa dramatically decreased pro-inflammatory indicators in blood, kidney, and liver tissues as well as blood glucose, and restored insulin levels, and lipid profiles. Additionally, it significantly raises the antioxidant enzyme activity SOD, CAT, GPx, and GST, while significantly lowering TBARs levels. The above-mentioned biochemical changes that took place in tissues were further supported by histological alterations. These findings imply that D. viscosa protects against STZ-induced hyperglycemia, aberrant lipid synthesis, and oxidative stress and that these benefits may be mediated by interacting with various targets to increase the levels of antioxidant enzymes in the liver and kidneys. Its mode of action and safety for use as medicine against various metabolic problems caused by diabetes require more research.