Early exercise promotes positive hippocampal plasticity and improves spatial memory in the adult life of rats

There is a great deal of evidence showing the capacity of physical exercise to enhance cognitive function, reduce anxiety and depression, and protect the brain against neurodegenerative disorders. Although the effects of exercise are well documented in the mature brain, the influence of exercise in the developing brain has been poorly explored. Therefore, we investigated the morphological and functional hippocampal changes in adult rats submitted to daily treadmill exercise during the adolescent period. Male Wistar rats aged 21 postnatal days old (P21) were divided into two groups: exercise and control. Animals in the exercise group were submitted to daily exercise on the treadmill between P21 and P60. Running time and speed gradually increased over this period, reaching a maximum of 18 m/min for 60 min. After the aerobic exercise program (P60), histological and behavioral (water maze) analyses were performed. The results show that early-life exercise increased mossy fibers density and hippocampal expression of brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B, improved spatial learning and memory, and enhanced capacity to evoke spatial memories in later stages (when measured at P96). It is important to point out that while physical exercise induces hippocampal plasticity, degenerative effects could appear in undue conditions of physical or psychological stress. In this regard, we also showed that the exercise protocol used here did not induce inflammatory response and degenerating neurons in the hippocampal formation of developing rats. Our findings demonstrate that physical exercise during postnatal development results in positive changes for the hippocampal formation, both in structure and function.     

Aerobic exercise improves hippocampal blood flow for hypertensive Apolipoprotein E4 carriers

Cerebrovascular dysfunction likely contributes causally to Alzheimer’s disease (AD). The strongest genetic risk factor for late-onset AD, Apolipoprotein E4 (APOE4), may act synergistically with vascular risk to cause dementia. Therefore, interventions that improve vascular health, such as exercise, may be particularly beneficial for APOE4 carriers. We assigned cognitively normal adults (65–87 years) to an aerobic exercise intervention or education only. Arterial spin labeling MRI measured hippocampal blood flow (HBF) before and after the 52-week intervention. We selected participants with hypertension at enrollment (n = 44). For APOE4 carriers, change in HBF (ΔHBF) was significantly (p = 0.006) higher for participants in the exercise intervention (4.09 mL/100g/min) than the control group (−2.08 mL/100g/min). There was no difference in ΔHBF between the control (−0.32 mL/100g/min) and exercise (−0.54 mL/100g/min) groups for non-carriers (p = 0.918). Additionally, a multiple regression showed an interaction between change in systolic blood pressure (ΔSBP) and APOE4 carrier status on ΔHBF (p = 0.035), with reductions in SBP increasing HBF for APOE4 carriers only. Aerobic exercise improved HBF for hypertensive APOE4 carriers only. Additionally, only APOE4 carriers exhibited an inverse relationship between ΔSBP and ΔHBF. This suggests exercise interventions, particularly those that lower SBP, may be beneficial for individuals at highest genetic risk of AD.ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02000583","term_id":"NCT02000583"}}NCT02000583     

Effects of age on prefrontal subregions and hippocampal volumes in young and middle‐aged healthy humans

There are limited data available regarding the effects of age and sex on discrete prefrontal gray and white matter volumes or posterior and anterior hippocampal volumes in healthy humans. Volumes of the superior frontal gyrus, anterior cingulate gyrus, and orbital frontal lobe were computed manually from contiguous magnetic resonance (MR) images in 83 (39M/44F) healthy humans (age range = 16–40) and segmented into gray and white matter. Volumes of the posterior and anterior hippocampal formation were also computed with reliable separation of the anterior hippocampal formation from the amygdala. There were significant age‐by‐tissue type interactions for the superior frontal gyrus and orbital frontal lobe such that gray matter within these regions correlated significantly and inversely with age. In contrast, no significant age effects were evident within regional white matter volumes. Analysis of hippocampal volumes indicated that men had larger volumes of the anterior, but not posterior hippocampal formation compared to women even following correction for total brain size. These data highlight age effects within discrete prefrontal cortical gray matter regions in young and middle aged healthy humans and suggest that the white matter comprising these regions may be more resistant to age effects. Furthermore, understanding the potential role of sex and age in mediating prefrontal cortical and hippocampal volumes may have strong relevance for psychiatric disorders such as schizophrenia that have implicated neurodevelopmental abnormalities within frontotemporal circuits in their pathogenesis. Hum Brain Mapp 34:2129–2140, 2013. © 2012 Wiley Periodicals, Inc.     

GluR6-containing KA receptor mediates the activation of p38 MAP kinase in rat hippocampal CA1 region during brain ischemia injury

Our previous study showed that kainate (KA) receptor subunit GluR6 played an important role in ischemia-induced MLK3 and JNK activation and neuronal degeneration through the GluR6-PSD95-MLK3 signaling module. However, whether the KA receptors subunit GluR6 is involved in the activation of p38 MAP kinase during the transient brain ischemia/reperfusion (I/R) in the rat hippocampal CA1 subfield is still unknown. In this present study, we first evaluated the time-course of phospho-p38 MAP kinase at various time-points after 15 min of ischemia and then observed the effects of antagonist of KA receptor subunit GluR6, GluR6 antisence oligodeoxynucleotides on the phosphorylation of p38 MAP kinase induced by I/R. Results showed that inhibiting KA receptor GluR6 or suppressing the expression of KA receptor GluR6 could down-regulate the elevation of phospho-p38 MAP kinase induced by I/R. These drugs also reduced the phosphorylation of MLK3, MKK3/MKK6, MKK4, and MAPKAPK2. Additionally, our results indicated administration of three drugs, including p38 MAP kinase inhibitor before brain ischemia significantly decreased the number of TUNEL-positive cells detected at 3 days of reperfusion and increased the number of the surviving CA1 pyramidal cells at 5 days of reperfusion after 15 min of ischemia. Taken together, we suggest that GluR6-contained KA receptors can mediate p38 MAP kinase activation through a kinase cascade, including MLK3, MKK3/MKK6, and MKK4 and then induce increased phosphorylation of MAPKAPK-2 during ischemia injury and ultimately result in neuronal cell death in the rat hippocampal CA1 region.     

The hippocampal physiology of approaching middle‐age: Early indicators of change

Age‐related cognitive decline presents serious lifestyle challenges, and anatomical changes to the hippocampus are often implicated in clinical conditions later in life. However, relatively little is known about how hippocampal physiology is altered in the transition to middle‐age, when early detection may offer the best opportunity for successful treatment. High‐yield extracellular recording is a powerful tool for understanding brain function in freely moving animals at single‐cell resolution and with millisecond precision. We used this technique to characterize changes to hippocampal physiology associated with maturation in 35‐week‐old rats. Combining a series of behavioral tasks with recordings of large numbers of neurons, local field potentials (LFP), and network patterns of activation, we were able to generate a comprehensive picture based on more than 25 different assays for each subject. Notable changes associated with aging included increased firing rates in interneurons, reduced LFP power but increased frequency in the 4–12 Hz theta band, and impairment in hippocampal pattern‐separation for different environments. General properties of pyramidal cell firing and spatial map integrity were preserved. There was no impairment in theta phase‐precession, experience‐dependent place field expansion, or sleep reactivation of waking network patterns. There were however changes in foraging strategy and behavioral responses to the introduction of a novel environment. Taken together the results reveal a diverse pattern of changes which are of increasing relevance in an aging population. They also highlight areas where high‐yield electrophysiological assays can be used to provide the sensitivity and throughput required for pre‐clinical drug‐discovery programs. © 2012 Wiley Periodicals, Inc.     

Aerobic exercise modulates anticipatory reward processing via the μ‐opioid receptor system

Physical exercise modulates food reward and helps control body weight. The endogenous µ‐opioid receptor (MOR) system is involved in rewarding aspects of both food and physical exercise, yet interaction between endogenous opioid release following exercise and anticipatory food reward remains unresolved. Here we tested whether exercise‐induced opioid release correlates with increased anticipatory reward processing in humans. We scanned 24 healthy lean men after rest and after a 1 h session of aerobic exercise with positron emission tomography (PET) using MOR‐selective radioligand [¹¹C]carfentanil. After both PET scans, the subjects underwent a functional magnetic resonance imaging (fMRI) experiment where they viewed pictures of palatable versus nonpalatable foods to trigger anticipatory food reward responses. Exercise‐induced changes in MOR binding in key regions of reward circuit (amygdala, thalamus, ventral and dorsal striatum, and orbitofrontal and cingulate cortices) were used to predict the changes in anticipatory reward responses in fMRI. Exercise‐induced changes in MOR binding correlated negatively with the exercise‐induced changes in neural anticipatory food reward responses in orbitofrontal and cingulate cortices, insula, ventral striatum, amygdala, and thalamus: higher exercise‐induced opioid release predicted higher brain responses to palatable versus nonpalatable foods. We conclude that MOR activation following exercise may contribute to the considerable interindividual variation in food craving and consumption after exercise, which might promote compensatory eating and compromise weight control.     

Electroacupuncture reduces apoptotic index and inhibits p38 mitogen-activated protein kinase signaling pathway in the hippocampus of rats with cerebral ischemia/reperfusion injury

Electroacupuncture attenuates cerebral hypoxia and neuronal apoptosis induced by cerebral ischemia/reperfusion injury. To further iden-tify the involved mechanisms, we assumed that electroacupuncture used to treat cerebral ischemia/reperfusion injury was associated with the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We established rat models of cerebral ischemia/reperfusion injury using the modified Zea-Longa's method. At 30 minutes before model establishment, p38 MAPK blocker SB20358 was injected into the left lateral ventricles. At 1.5 hours after model establishment, electroacupuncture was administered at acupoints of Chize (LU5), Hegu (LI4), Zusanli (ST36), and Sanyinjiao (SP6) for 20 minutes in the affected side. Results showed that the combination of EA and SB20358 injec-tion significantly decreased neurologic impairment scores, but no significant differences were determined among different interventional groups. Hematoxylin-eosin staining also showed reduced brain tissue injuries. Compared with the SB20358 group, the cells were regularly arranged, the structures were complete, and the number of viable neurons was higher in the SB20358 + electroacupuncture group. Termi-nal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling assay showed a decreased apoptotic index in each group, with a significant decrease in the SB20358 + electroacupuncture group. Immunohistochemistry revealed reduced phosphorylated p38 expression at 3 days in the electroacupuncture group and SB20358 + electroacupuncture group compared with the ischemia/reperfusion group. There was no significant difference in phosphorylated p38 expression between the ischemia/reperfusion group and SB20358 group. These find-ings confirmed that the electroacupuncture effects on mitigating cerebral ischemia/reperfusion injury are possibly associated with the p38 MAPK signaling pathway. A time period of 3 days could promote the repair of ischemic cerebral nerves.     

Fasting-induced activation of mitogen-activated protein kinases (ERK/p38) in the mouse hypothalamus

Activity-dependent changes in neuronal plasticity depend critically on gene regulation. To understand how fasting-induced stimulation leads to gene regulation through intracellular signalling pathways, we investigated the effect of fasting on activation of the mitogen-activated protein kinase (MAPK) family, the extracellular signal-regulated kinase (ERK) and the p38 MAPK (p38) in mouse hypothalamus. In the hypothalamic arcuate nucleus, phosphorylation of ERK significantly increased during fasting, spatially coincident with phosphorylation of cAMP response element binding protein (CREB), induction of c-Fos, and expression of neuropeptide Y (NPY). In the paraventricular nucleus (PVN) of fasted mice, activation of p38 in addition to ERK was also observed. In the arcuate nucleus of ob/ob mice, phosphorylations of ERK and CREB were decreased during fasting, whereas the expression of NPY was increased. In the PVN, increased activation of p38 was observed in spite of decreased activation of ERK. These results suggest that ERK and p38 are differentially activated by fasting in distinct regions of the hypothalamus depending on the condition of energy balance.     

Chronic nicotine improves working and reference memory performance and reduces hippocampal NGF in aged female rats

The cholinergic system is involved in cognition and several forms of dementia, including Alzheimer's disease, and nicotine administration has been shown to improve cognitive performance in both humans and rodents. While experiments with humans have shown that nicotine improves the ability to handle an increasing working memory load, little work has been done in animal models evaluating nicotine effects on performance as working memory load increases. In this report, we demonstrate that in aged rats nicotine improved the ability to handle an increasing working memory load as well as enhanced performance on the reference memory component of the water radial arm maze task. The dose required to exert these effects (0.3mg/kg/day) was much lower than doses shown to be effective in young rats and appears to be a lower maintenance dose than is seen in light to moderate smokers. In addition, our study reports a nicotine-induced reduction in nerve growth factor (NGF) protein levels in the hippocampus of the aged rat. The effects of nicotine on hippocampal NGF levels are discussed as a potential mechanism of nicotine-induced improvements in working and reference memory.     

Intrathecal MK-801 inhibits formalin-induced activation of spinal p38-MAPK in rats

BACKGROUND: p38 mitogen-activated protein kinase (MAPK) plays an instrumental role in signal transduction from the cell surface to the nucleus, while subcutaneous injection of formalin can induce increased activation of spinal p38 MAPK. However, the mechanisms underlying the formalin-induced activation of spinal p38 MAPK in rats are unclear. OBJECTIVE: To observe the effects of N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 on the formalin-induced activation of spinal p38 MAPK in rats. DESIGN, TIME AND SETTING: This randomized grouping, controlled animal experiment was performed at the Department of Physiology and Neurobiology, Shanxi Medical University between May and November 2007. MATERIALS: Forty eight healthy, adult Wistar rats were randomly divided into two groups: formalin + normal saline (n = 12) and formalin + MK-801 (n = 36). The formalin + MK-801 group was further divided into three subgroups according to the dosage of MK-801 (10, 50, and 100 nmol/L, 12 rats for each subgroup) METHODS: Following anesthesia, polyethylene tubing filled with sterile normal saline was implanted into the subarachnoid cavity. On postoperative days 5-8, rats received a 15 minute perfusion of normal saline or MK-801 (10, 50, and 100 nmol/L) in the formalin + normal saline and formalin + MK-801 groups, respectively, followed by formalin injection for the induction of nociceptive behavior. MAIN OUTCOME MEASURES: Detection of total p38 MAPK and of phosphorylated p38 MAPK by western Blot analysis; observation of nociceptive behaviors in the 1 hour after formalin injection. RESULTS: Western Blot analysis revealed that injection of formalin had no effect on total p38 MAPK expression but resulted in increased phosphorylation of p38 MAPK in the spinal cord. This increase was apparent after 5 minutes, peaked at 20 minutes, and thereafter descended and reached control levels after 45 minutes. Pretreatment with MK-801 (10, 50, 100 nmol/L) resulted in a dose-dependent reduction of p38 MAPK phosphorylation in the spinal cord, 20 minutes after formalin injection. Injection of 50 and 100 nmol/L MK-801 produced a suppression of the first phase of nociceptive behaviors, and all three doses of MK-801 resulted in dose-dependent inhibition of the second phase of nociceptive behaviors. CONCLUSION: The NMDA receptor participates in formalin-induced activation of p38 MAPK in the rat spinal cord.     

Intrathecal MK-801 inhibits formalin-induced activation of spinal p38-MAPK in rats**★

BACKGROUND： p38 mitogen-activated protein kinase （MAPK） plays an instrumental role in signal transduction from the cell surface to the nucleus, while subcutaneous injection of formalin can induce increased activation of spinal p38 MAPK. However, the mechanisms underlying the formalin-induced activation of spinal p38 MAPK in rats are unclear. OBJECTIVE： To observe the effects of N-methyl-D-aspartic acid （NMDA） receptor antagonist MK-801 on the formalin-induced activation of spinal p38 MAPK in rats. DESIGN, TIME AND SETTING： This randomized grouping, controlled animal experiment was performed at the Department of Physiology and Neurobiology, Shanxi Medical University between May and November 2007. MATERIALS： Forty eight healthy, adult Wistar rats were randomly divided into two groups： formalin ＋ normal saline （n = 12） and formalin ＋ MK-801 （n = 36）. The formalin ＋ MK-801 group was further divided into three subgroups according to the dosage of MK-801 （10, 50, and 100 nmol/L, 12 rats for each subgroup） METHODS： Following anesthesia, polyethylene tubing filled with sterile normal saline was implanted into the subarachnoid cavity. On postoperative days 5-8, rats received a 15 minute perfusion of normal saline or MK-801 （10, 50, and 100 nmol/L） in the formalin ＋ normal saline and formalin ＋ MK-801 groups, respectively, followed by formalin injection for the induction of nociceptive behavior. MAIN OUTCOME MEASURES： Detection of total p38 MAPK and of phosphorylated p38 MAPK by western Blot analysis; observation of nociceptive behaviors in the 1 hour after formalin injection. RESULTS： Western Blot analysis revealed that injection of formalin had no effect on total p38 MAPK expression but resulted in increased phosphorylation of p38 MAPK in the spinal cord. This increase was apparent after 5 minutes, peaked at 20 minutes, and thereafter descended and reached control levels after 45 minutes. Pretreatment with MK-801 （10, 50, 100 nmol/L） resulted in a dose-dependent reduc     

p38MAPK activation and DUSP10 expression in meningiomas

The mitogen activated protein kinase (MAPK) p38MAPK has been implicated in regulation of cell proliferation and apoptosis. However, expression, activation and regulation has not been studied in meningiomas, to our knowledge. p38MAPK is regulated, in part, by dual specificity phosphatases (DUSP) that inactivate signaling by dephosphorylation. DUSP10 is also a likely participant in regulating meningioma proliferation. Five fetal and an adult human leptomeninges and 37 meningioma cultures (MC) were evaluated for DUSP10 as well as phosphorylation of its substrates p38MAPK and p44/42MAPK by western blot and DUSP10 expression by polymerase chain reaction. Platelet derived growth factor-BB (PDGF-BB), transforming growth factor B1 (TGFB1) and cerebrospinal fluid effects on DUSP10 and signaling were also studied in vitro. DUSP10 and phospho-p38MAPK and phospho-p44/42MAPK were detected in all six leptomeninges. DUSP10 was detected in 13 of 17 World Health Organization grade I, 11 of 14 grade II and four of six grade III meningiomas. Phospho-p38MAPK was detected in nine of 17 grade I, two of six grade II, and four of six grade III meningiomas. In the majority of meningiomas DUSP10 expression correlated inversely with phosphorylation of p38MAPK. PDGF-BB increased DUSP10 in MC2 and MC4 and weakly in MC3. TGFB1 increased phosphorylation of p38MAPK and caspase 3 activation. Thus p38MAPK and DUSP10 likely participate in the pathogenesis of meningiomas.     

Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: Preliminary findings

Multiple sclerosis leads to prominent hippocampal atrophy, which is linked to memory deficits. Indeed, 50% of multiple sclerosis patients suffer memory impairment, with negative consequences for quality of life. There are currently no effective memory treatments for multiple sclerosis either pharmacological or behavioral. Aerobic exercise improves memory and promotes hippocampal neurogenesis in nonhuman animals. Here, we investigate the benefits of aerobic exercise in memory-impaired multiple sclerosis patients. Pilot data were collected from two ambulatory, memory-impaired multiple sclerosis participants randomized to non-aerobic (stretching) and aerobic (stationary cycling) conditions. The following baseline/follow-up measurements were taken: high-resolution MRI (neuroanatomical volumes), fMRI (functional connectivity), and memory assessment. Intervention was 30-minute sessions 3 times per week for 3 months. Aerobic exercise resulted in 16.5% increase in hippocampal volume and 53.7% increase in memory, as well as increased hippocampal resting-state functional connectivity. Improvements were specific, with no comparable changes in overall cerebral gray matter (+2.4%), non-hippocampal deep gray matter structures (thalamus, caudate: ?4.0%), or in non-memory cognitive functioning (executive functions, processing speed, working memory: changes ranged from ?11% to +4%). Non-aerobic exercise resulted in relatively no change in hippocampal volume (2.8%) or memory (0.0%), and no changes in hippocampal functional connectivity. This is the first evidence for aerobic exercise to increase hippocampal volume and connectivity and improve memory in multiple sclerosis. Aerobic exercise represents a cost-effective, widely available, natural, and self-administered treatment with no adverse side effects that may be the first effective memory treatment for multiple sclerosis patients.     

The role of p38MAPK activation in spinal dorsal horn in remifentanil-induced postoperative hyperalgesia in rats

Objectives: Remifentanil may induce hyperalgesia. Recent studies implicate a close relationship between post-surgical hyperalgesia and phosphorylation and activation of p38 mitogen-activated protein kinase (p38MAPK) in the spinal microglia. This study aimed to investigate whether the combination of post-surgical and remifentanil-induced hyperalgesia worsens post-operative pain and whether phosphorylated p38MAPK (phospho-p38MAPK) in the spinal dorsal horn in rats is involved in remifentanil-induced postoperative hyperalgesia.

Methods: Sprague-Dawley rats were randomly divided into six groups: control, incision only, remifentanil only, remifentanil + incision, remifentanil + incision + SB203580, and remifentanil + incision + DMSO. The p38MAPK inhibitor SB203580 and DMSO were injected intrathecally. A right plantar surgical incision was performed in the incision groups, and remifentanil was infused for 60 min in the remifentanil groups. Mechanical paw withdrawal threshold (PWT) and thermal paw withdrawal latency (PWL) of the bilateral hind paws were measured and the number of phospho-p38MAPK-positive cells in rat spinal dorsal horn sections was counted.

Results: Intravenous remifentanil infusion decreased bilateral plantar PWL values from 1 h to 3 days after surgery, however there was no additive effect with incision-induced values. There was a significant increase in the number of dorsal horn phospho-p38MAPK-positive cells in the remifentanil + incision group compared to the incision group, but no increase in the number of these cells when remifentanil was given alone. Intrathecal pretreatment with SB203580 attenuated remifentanil + incision–induced postoperative hyperalgesia and significantly reduced activation of phospho-p38MAPK in spinal dorsal horn.

Conclusions: Incision-induced and remifentanil-induced increases in hyperalgesia were not additive when incision and remifentanil were used together. Data on phospho-38MAPK activation in remifenanil-induced hyperalgesia were contradictory and need further clarification.     

抑制p38 MAPK信号通路对海马神经元毒性损伤的保护作用

目的通过观察细胞表面形态的三维构像变化,探讨抑制p38 MAPK通路对减轻红藻氨酸(KA)毒性作用引起大鼠海马神经元所造成损害的作用和机制。方法原代培养10 d的海马神经元给予SB203580(0.2μmol/L),p38MAPK特异性抑制剂)预处理.30min后再予不同浓度(0μmol/L,25μmol/L和250μmol/L)KA分别作用10 min和100 min,利用原子力显微镜(AFM)对细胞表面结构进行纳米级水平扫描和观测。结果正常海马神经元表面光滑,起伏均匀、规律;KA作用后神经元呈退行性改变,表现为胞体肿胀,胞膜表面粗糙,出现隆起和“孔洞”样胞膜破裂结构,并且其变化程度分别与作用时间和KA浓度呈量-效关系;预先给予SB203580处理,以上变化有所减轻。结论KA毒性作用后海马神经元胞膜表面超微结构所产生明显变化;p38MAPK信号通路参与这种损害过程;抑制该信号转导通路,对海马神经元的毒性损害起一定保护作用。     

Combining restricted diet with forced or voluntary exercises improves hippocampal BDNF and cognitive function in rats

Dietary restriction (RDt) and exercise (Ex) enhances cognitive function due, at least in part, levels of neurotrophins such as brain-derived neurotrophic factor (BDNF). This study examined changes in BDNF levels and data acquisition and retention following every-other-day RDt alone, and combined with either voluntary wheel (VxRDt) or forced swimming Exs (FxRDt) in rats. Hippocampal BDNF was measured using ELISA while learning and memory formation were assessed with the radial arm water maze (RAWM) paradigm. After 6 weeks, VxRDt and FxRDt enhanced BDNF levels, and short- and long-term memories (p < 0.05). The magnitude of the increase in BDNF was significantly higher in VxRDt group than in other groups (p < 0.05). However, no differences were found in learning and memory formation between the Ex regiments (VxRDt versus FxRDt). Additionally, RDt alone neither modulated BDNF level nor enhanced learning and memory formation (p > 0.05). These results suggest more important role of Ex, as opposed to RDt, in enhancing learning and memory formation. In addition, VxRDt appears to be more potent in enhancing brain BDNF levels than FxRDt, when combined with RDt in rats.     

Treadmill exercise attenuates 3,4‐methylenedioxymethamphetamine‐induced memory impairment through a decrease apoptosis in male rat hippocampus

3,4‐methylenedioxymethamphetamine (MDMA) leads to apoptosis in the hippocampus with consequent induction of learning and memory impairment. In this study, we have investigated the effects of treadmill exercise on memory in relation to apoptosis and oxidative stress in the hippocampi of MDMA‐treated rats. Male Wistar rats received multiple intraperitoneal (IP) injections of MDMA (10 mg/kg) and exercised for one month on a treadmill (simultaneously or asynchronously with MDMA). We assessed memory function with the Morris water maze (MWM) test. Lipid peroxidation (LPO) and expression of caspase 3, Bax, and Bcl‐2 were examined by the thiobarbituric acid assay (TBA) and western blot, respectively. Our results showed that asynchronous treadmill exercise could significantly improve MDMA‐induced memory impairment in the MWM test. Caspase 3 expression decreased in the exercise group compared to the MDMA group. Although MDMA treatment caused an increase in the Bax/Bcl‐2 ratio, the treadmill exercise reduced this ratio. Simultaneous exercise caused a reduction in lipid peroxidation in the hippocampus. This data suggests that treadmill exercise can be a useful strategy for treating memory impairment in persons with neurodegenerative disease and stimulant drug users. © 2017 Wiley Periodicals, Inc.     

Exogenous nitric oxide negatively regulates the S‐nitrosylation p38 mitogen‐activated protein kinase activation during cerebral ischaemia and reperfusion

S. H. Qi, L. Y. Hao, J. Yue, Y. Y. Zong and G. Y. Zhang (2013) Neuropathology and Applied Neurobiology 39, 284–297 Exogenous nitric oxide negatively regulates the S‐nitrosylation p38 mitogen‐activated protein kinase activation during cerebral ischaemia and reperfusion Aims: A number of studies have suggested that nitric oxide (NO) plays an important role in the reactive phosphorylation of p38MAPKα (p38). However, whether S‐nitrosylation of p38 is activated by NO and the details remain unclear. The aim of the present work was to assess the activation of p38, the S‐nitrosylation site and the p38 signalling pathway in rat hippocampus and in HEK293 cell induced by exogenous NO. Methods: Primary hippocampal cultures, HEK293 cells and rat model of cerebral ischaemia/reperfusion (brain ischaemia was induced by four‐vessel occlusion procedure) were used in this study. Biotin‐switch method and immunoblotting were performed to study the S‐nitrosylation and phosphorylation of p38, and neuronal loss was observed by histology. Results: Endogenous NO increased p38 phosphorylation and S‐nitrosylation, and the activation of p38 was dependent on the S‐nitrosylation of Cys‐211, which was critical for the NO‐mediated activation of p38. The exogenous NO donor sodium nitroprusside, S‐nitrosoglutathione, 7‐nitroindazole, the inhibitor of the neuronal nitric oxide synthase, inhibited the activation of p38 signal pathway induced by cerebral ischaemia/reperfusion and attenuated the damage in rat hippocampal neurones. Moreover, the N‐methyl‐D‐aspartate receptor (NMDAR) is probably involved in the p38 activation process of S‐nitrosylation and phosphorylation. Conclusion: Endogenous NO induces the S‐nitrosylation and phosphorylation of p38 and mediates p38 signalling pathway by NMDAR, and as exogenous NO inhibits this process and is neuroprotective in rat cerebral ischaemia/reperfusion, it may make a contribution to stroke therapy.     

Exercise boosts hippocampal volume by preventing early age‐related gray matter loss

Recently, a larger hippocampus was found in exercising mice and men. Here we studied the morphological underpinnings in wheel running mice by longitudinal magnetic resonance imaging. Voxel‐based morphometry revealed that running increases hippocampal volume by inhibiting an early age‐related gray matter loss. Disruption of neurogenesis‐related neuroplasticity by focalized irradiation is sufficient to block positive effects of exercise on macroscopic brain morphology. © 2013 Wiley Periodicals, Inc.