Glimepiride prevents paraquat‐induced Parkinsonism in mice: involvement of oxidative stress and neuroinflammation

There is a growing number of epidemiological and molecular studies which suggest that diabetes is associated with an increased risk of Parkinson's disease (PD). Hence, in this study, the effect of glimepiride (GPD), a sulphonylurea (antidiabetic) on paraquat (PQT)‐induced Parkinsonism was evaluated in mice. Thirty‐six mice were randomly divided into six groups (n = 6) and treated orally for 21 consecutive days as follows: Group 1: vehicle (10 mL/kg), Group 2: PQT (10 mg/kg, i.p., twice per week for 3 weeks), Group 3–5: GPD (1, 2 or 4 mg/kg) + PQT (10 mg/kg, i.p., twice per week for 3 weeks), Group 6: GPD (4 mg/kg, p.o.). The effects of the treatment on motor coordination were evaluated using the rotarod performance, bar and open field tests while working memory was assayed using Y‐maze test. Paraquat injection induced significant decrease in falling time, number of crosses and percentage alternation behaviour with a concomitant increase in the duration of cataleptic behaviour in the rotarod, open field, Y‐maze and bar tests, respectively, which was ameliorated by GPD treatment. PQT also increased lipid peroxidation, peroxynitrite and TNF‐α generations as well as deficit in superoxide dismutase and GSH activities in the midbrain. PQT‐induced oxidative stress and neuroinflammation was attenuated by GPD treatment. Findings from this study showed that GPD prevents PQT‐induced motor dysfunction, memory impairment, oxidative stress and neuroinflammation through enhancement of antioxidant defense system and inhibition of pro‐inflammatory cytokine release. Thus, GPD could be a potential adjunct in the management of Parkinsonism.     

Exendin-4 attenuates pain-induced cognitive impairment by alleviating hippocampal neuroinflammation in a rat model of spinal nerve ligation

Glucagon-like peptide-1 receptor has anti-apoptotic,anti-inflammatory,and neuroprotective effects.It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses;however,it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms.We explored the effects of glucagon-like peptide-1 receptor on nociception,cognition,and neuroinflammation in chronic pain.A rat model of chronic pain was established using left L5 spinal nerve ligation.The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation.Electrophysiological examinations showed that,after treatment with exendin-4,paw withdrawal frequency of the left limb was significantly reduced,and pain was relieved.In addition,in the Morris water maze test,escape latency increased and the time to reach the platform decreased following exendin-4 treatment.Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus,as well as an increase in the expression of tumor necrosis factor alpha,interleukin 1 beta,and interleukin 6.All of these effects could be reversed by exendin-4 treatment.These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China(approval No.WDRM 20171214)on September 22,2017.     

Anxiety‐like behavior in female mice changes by feeding,possible effect of guanylate cyclase C

Anxiety disorders are the most frequent mental disorders and are more prevalent in the female population. Up to date, an involvement of guanylate cyclase A and B in anxiety‐like behavior has been suggested. In this study, we showed an expression of guanylate cyclase C (GC‐C) in the amygdala which is regulated by feeding. Therefore, we further investigated sex differences of GC‐C effects on anxiety levels with special attention to female estrous cycle and feeding. The effects of estrous cycle and feeding were investigated by several behavior tests: elevated plus maze, home cage escape and novelty‐induced hypophagy. Possible changes in GC‐C expression in amygdala and hypothalamus during estrous cycle were established by qPCR. When GC‐C is activated (after a meal), the sex difference in all behavior tests used was abolished. As the expression of mRNA for GC‐C in the amygdala increases 2 hr after a meal only in female animals, the anxiety levels change after a meal again only in female animals. When the anxiety levels are investigated, it is very important to pay attention not only to estrous cycle in female animals but also when animals were fed compared to the time point of the experiments. Concluding from our results, the sex differences in the incidence of anxiety disorders in humans could be GC‐C dependent.     

Hippocampal and prefrontal contributions to memory retrieval: Examination of immediate early gene,NMDA receptor and environmental interactions

Animals can use a range of strategies to recall important locations. These include simple stimulus–response strategies and more complex spatial (place) strategies, which are thought to have distinct neural substrates. The hippocampus—and NMDA receptor activation therein—is considered to be crucial for spatial, but not response strategies. The medial prefrontal cortex has also been implicated in memory retrieval; however, evidence concerning its specific role is equivocal. Both hippocampal and prefrontal regions have been associated with flexible behavioural responding (e.g. when task demands change). Here, we investigated the use of spatial and non‐spatial strategies in the Morris water maze and their associated brain areas in rats using immediate early gene (IEG) imaging of Zif268 and c‐Fos. Specifically, we charted the involvement of hippocampal and prefrontal subregions during retrieval of spatial and non‐spatial memories. Behavioural flexibility was also examined using intact and partial cue configurations during recall. Results indicated that regions of both the hippocampus (area CA3) and prefrontal cortex (anterior cingulate cortex) were preferentially engaged in spatial memory recall compared to response learning. In addition, both spatial and non‐spatial memories were dependent on NMDA receptor activation. MK801 impaired recall performance across all groups and reduced IEG activation across hippocampal and prefrontal regions. Finally, IEG results revealed divergent patterns of Zif268 and c‐Fos activity and support the suggestion that Zif268 plays a functional role in the recall of long‐term memories.     

Mineralocorticoid receptor antagonist-mediated cognitive improvement in a mouse model of Alzheimer's type: possible involvement of BDNF-H2S-Nrf2 signaling

The present study explored the role and mechanisms of mineralocorticoid receptor antagonists in β-amyloid (Aβ)-induced cognitive impairment. A single intracerebroventricular injection of Aβ_1-42 was given to mice, and after 14 days of injection, memory was evaluated using the Morris water maze test. Spironolactone (25 and 50 mg/kg) and eplerenone (50 and 100 mg/kg) were administered for two days before and for 14 days after Aβ injection. Mineralocorticoid receptor blockers attenuated Aβ-induced cognitive impairment assessed in terms of decrease in day 4 escape latency time (ELT) in comparison to day 1 ELT (suggesting an increase in learning) along with an increase in time spent in target quadrant on day 5 (suggesting the retrieval of learned things). These drugs also increased the expression of BDNF, H₂S, Nrf2, reduced glutathione, and decreased β-amyloid and TNF-α in the frontal cortex and hippocampus. Co-administration of ANA-12, BDNF receptor antagonist (0.25 and 0.5 mg/kg) abolished cognitive improving functions of mineralocorticoid receptor blockers, attenuated H₂S, Nrf2, reduced glutathione, and decreased β-amyloid and TNF-α. It is concluded that spironolactone and eplerenone attenuate cognitive decline of Alzheimer's type, possibly through upregulation of BDNF levels in the frontal cortex and hippocampus, which may increase H₂S, decrease Aβ, activate Nrf2-dependent antioxidant system, and decrease neuroinflammation.     

Turmeric (Curcuma longa L.) extract may prevent the deterioration of spatial memory and the deficit of estimated total number of hippocampal pyramidal cells of trimethyltin-exposed rats

Context: Protection of neurons from degeneration is an important preventive strategy for dementia. Much of the dementia pathology implicates oxidative stress pathways. Turmeric (Curcuma longa L.) contains curcuminoids which has anti-oxidative and neuro-protective effects. These effects are considered to be similar to those of citicoline which has been regularly used as one of standard medications for dementia.

Objective: This study aimed at investigating the effects of turmeric rhizome extract on the hippocampus of trimethyltin (TMT)-treated Sprague-Dawley rats.

Materials and methods: The rats were divided randomly into six groups, i.e., a normal control group (N); Sn group, which was given TMT chloride; Sn-Cit group, which was treated with citicoline and TMT chloride; and three Sn-TE groups, which were treated with three different dosages of turmeric rhizome extract and TMT chloride. Morris water maze test was carried out to examine the spatial memory. The estimated total number of CA1 and CA2–CA3 pyramidal cells was calculated using a stereological method.

Results: The administration of turmeric extract at a dose of 200?mg/kg bw has been shown to prevent the deficits in the spatial memory performance and partially inhibit the reduction of the number of CA2–CA3 regions pyramidal neurons.

Discussion: TMT-induced neurotoxic damage seemed to be mediated by the generation of reactive oxygen species and reactive nitrogen species. Turmeric extract might act as anti inflammatory as well as anti-oxidant agent.

Conclusions: The effects of turmeric extract at a dose of 200?mg/kg bw seem to be comparable to those of citicoline.     

酸枣仁汤对高架十字迷宫所致焦虑大鼠的影响

目的:探讨酸枣仁汤抗焦虑的药理作用机制。方法:建立高架十字迷宫大鼠焦虑模型,观察酸枣仁汤对焦虑大鼠行为的影响,ELISA法检测大鼠脑内海马五羟色胺(5-HT)、五羟吲哚乙酸(5-HIAA)、伽马氨基丁酸(GABA)、谷氨酸(GLU)、去甲肾上腺素(NE)的含量。结果:各给药组开放臂进入次数与进入时间与模型组比较显著提高(P0.05);各给药组进臂总次数与模型组比较差异无统计学意义(P0.05)。酸枣仁汤大、小剂量组5-HT、5-HIAA、GABA、GLU、NE的含量均有一定变化。结论:酸枣仁汤对高架十字迷宫所致的大鼠焦虑有明显的治疗作用,其抗焦虑的机制可能与调节脑内海马神经递质的平衡有关,且酸枣仁汤小剂量组较大剂量组有更好的治疗效果。     

The neuroprotection of Rattin against amyloid β peptide in spatial memory and synaptic plasticity of rats

Rattin, a specific derivative of humanin in rats, shares the ability with HN to protect neurons against amyloid β (Aβ) peptide‐induced cellular toxicity. However, it is still unclear whether Rattin can protect against Aβ‐induced deficits in cognition and synaptic plasticity in rats. In the present study, we observed the effects of Rattin and Aβ31–35 on the spatial reference memory and in vivo hippocampal Long‐term potentiation of rats by using Morris water maze test and hippocampal field potential recording. Furthermore, the probable molecular mechanism underlying the neuroprotective roles of Rattin was investigated. We showed that intra‐hippocampal injection of Rattin effectively prevented the Aβ31–35‐induced spatial memory deficits and hippocampal LTP suppression in rats; the Aβ31–35‐induced activation of Caspase‐3 and inhibition of STAT3 in the hippocampus were also prevented by Rattin treatment. These findings indicate that Rattin treatment can protect spatial memory and synaptic plasticity of rats against Aβ31–35‐induced impairments, and the underlying protective mechanism of Rattin may be involved in STAT3 and Caspases‐3 pathways. Therefore, application of Rattin or activation of its signaling pathways in the brain might be beneficial to the prevention of Aβ‐related cognitive deficits. © 2013 Wiley Periodicals, Inc.     

Increase in hippocampal theta oscillations during spatial decision making

The processing of spatial and mnemonic information is believed to depend on hippocampal theta oscillations (5–12 Hz). However, in rats both the power and the frequency of the theta rhythm are modulated by locomotor activity, which is a major confounding factor when estimating its cognitive correlates. Previous studies have suggested that hippocampal theta oscillations support decision‐making processes. In this study, we investigated to what extent spatial decision making modulates hippocampal theta oscillations when controlling for variations in locomotion speed. We recorded local field potentials from the CA1 region of rats while animals had to choose one arm to enter for reward (goal) in a four‐arm radial maze. We observed prominent theta oscillations during the decision‐making period of the task, which occurred in the center of the maze before animals deliberately ran through an arm toward goal location. In speed‐controlled analyses, theta power and frequency were higher during the decision period when compared to either an intertrial delay period (also at the maze center), or to the period of running toward goal location. In addition, theta activity was higher during decision periods preceding correct choices than during decision periods preceding incorrect choices. Altogether, our data support a cognitive function for the hippocampal theta rhythm in spatial decision making. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Kaolin-induced ventriculomegaly at weaning produces long-term learning,memory, and motor deficits in rats

Ventriculomegaly occurs when there is imbalance between creation and absorption of cerebrospinal fluid (CSF); even when treated, long-term behavioral changes occur. Kaolin injection in the cisterna magna of rats produces an obstruction of CSF outflow and models one type of hydrocephalus. Previous research with this model shows that neonatal onset has mixed effects on Morris water maze (MWM) and motoric performance; we hypothesized that this might be because the severity of ventricular enlargement was not taken into consideration. In the present experiment, rats were injected with kaolin or saline on postnatal day (P)21 and analyzed in subgroups based on Evan's ratios (ERs) of the severity of ventricular enlargement at the end of testing to create 4 subgroups from least to most severe: ER0.4–0.5, ER0.51–0.6, ER0.61–0.7, and ER0.71–0.82, respectively. Locomotor activity (dry land and swimming), acoustic startle with prepulse inhibition (PPI), and MWM performance were tested starting on P28 (122 cm maze) and again on P42 (244 cm maze). Kaolin-treated animals weighed significantly less than controls at all times. Differences in locomotor activity were seen at P42 but not P28. On P28 there was an increase in PPI for all but the least severe kaolin-treated group, but no difference at P42 compared with controls. In the MWM at P28, all kaolin-treated groups had longer path lengths than controls, but comparable swim speeds. With the exception of the least severe group, probe trial performance was worse in the kaolin-treated animals. On P42, only the most severely affected kaolin-treated group showed deficits compared with control animals. This group showed no MWM learning and no memory for the platform position during probe trial testing. Swim speed was unaffected, indicating motor deficits were not responsible for impaired learning and memory. These findings indicate that kaolin-induced ventriculomegaly in rats interferes with cognition regardless of the final enlargement of the cerebral ventricles, but final size critically determines whether lasting locomotor, learning, and memory impairments occur.