Yaoming Chen

Evidence for a role of GABAA receptor in the acute restraint stress-induced enhancement of spatial memory.

Stress exerts complex effects on learning and memory; however, the understanding of the molecular mechanisms involved in stress effects on brain and behavior is rather limited. In this study, we investigated the regulation of the activation of MAPK (mitogen-activated protein kinase) cascades in the rat brain by GABAA receptor in a learning and memory task under acute restraint stress conditions. We found that the acute restraint stress improved the performance of the rats in the Morris water maze. Furthermore, the acute restraint stress significantly increased the phosphorylation of ERK and JNK in the hippocampus and prefrontal cortex (PFC), but not in the striatum. The increase paralleled the time course of the decrease of the level of GABAA receptor alpha1 subunit. The increase of P-ERK levels was inhibited by the agonist of GABAA receptor, muscimol, and further increased by the antagonist of the receptor, bicuculline. However, neither muscimol nor bicuculline affected the levels of P-JNK and P-p38. Finally, injection of muscimol partly reversed the acute restraint stress-induced enhancement of performance in the Morris water maze, and injection of bicuculline improved it. These results demonstrated that the changes in ERK phosphorylation in hippocampus and PFC were regulated by GABAA receptor in a learning and memory paradigm under acute restraint stress conditions.

The Role of α-synuclein and Tau Hyperphosphorylation-Mediated Autophagy and Apoptosis in Lead-induced Learning and Memory Injury

Lead (Pb) is a well-known heavy metal in nature. Pb can cause pathophysiological changes in several organ systems including central nervous system. Especially, Pb can affect intelligence development and the ability of learning and memory of children. However, the toxic effects and mechanisms of Pb on learning and memory are still unclear. To clarify the mechanisms of Pb-induced neurotoxicity in hippocampus, and its effect on learning and memory, we chose Sprague-Dawley rats (SD-rats) as experimental subjects. We used Morris water maze to verify the ability of learning and memory after Pb treatment. We used immunohistofluorescence and Western blotting to detect the level of tau phosphorylation, accumulation of α-synuclein, autophagy and related signaling molecules in hippocampus. We demonstrated that Pb can cause abnormally hyperphosphorylation of tau and accumulation of α-synuclein, and these can induce hippocampal injury and the ability of learning and memory damage. To provide the new insight into the underlying mechanisms, we showed that Grp78, ATF4, caspase-3, autophagy-related proteins were induced and highly expressed following Pb-exposure. But mTOR signaling pathway was suppressed in Pb-exposed groups. Our results showed that Pb could cause hyperphosphorylation of tau and accumulation of α-synuclein, which could induce ER stress and suppress mTOR signal pathway. These can enhance type II program death (autophgy) and type I program death (apoptosis) in hippocampus, and impair the ability of learning and memory of rats. This is the first evidence showing the novel role of autophagy in the neurotoxicity of Pb.

Effect of Microglia Activation on Dopaminergic Neuronal Injury Induced by Manganese, and Its Possible Mechanism

Manganese (Mn) is an essential trace element. It is known to have various functions, such as participating in enzymatic synthesis, and promoting hematopoiesis. On the other hand, it can cause toxic injury upon excess intake. However, toxic effects and its mechanism on glial cells are unclear. In the present study, we demonstrated that MnCl2 can activate microglia, and that this can cause dopaminergic neuronal injury. Investigation of the underlying mechanisms showed that inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) was induced and highly expressed following Mn treatment. Moreover, pretreatment with S-methylisothiourea (SMT. iNOS inhibitor), Mn-induced iNOS expression and dopaminergic neuronal injury were partly reverse. Pretreatment with minocycline (microglia activation inhibitor), Mn-induced activation of microglia and dopaminergic neuronal injury was partly reverse. Taken together, our results showed that Mn can cause microglia activation, which can up-regulate the level of IL-1β, TNF-α and iNOS, and these inflammatory factors can cause dopaminergic neuronal injury. SMT and minocycline prevent Mn-induced dopaminergic neuronal injury.

Effects of acetazolamide on cognitive performance during high-altitude exposure

High-altitude hypoxia impedes cognitive performance. It is not well known whether the prophylactic use of acetazolamide for altitude sickness can influence cognitive performance at high altitude. When ascending to high altitude locations, one may face medical risks, including cognitive impairment, which may significantly hinder climbing abilities or exploratory behavior. Effective prophylactic drugs have rarely been reported. Because acetazolamide is commonly used to treat acute mountain sickness (AMS), we assessed the potential effects of acetazolamide on cognitive performance during high-altitude exposure. Twenty-one volunteers aged 22-26 years were randomized to receive a 4-day treatment of acetazolamide (125 mg Bid, n=11) or placebo (n=10) before and after air travel from Xianyang (402 m) to Lhasa (3561 m). Neuropsychological performance was assessed using the digit symbol substitution test (DSST), paced auditory serial addition test (PASAT), operation span task, and free recall test at 6, 30, and 54 h after arrival at Lhasa. The Lake Louise Score (LLS) was used to diagnose AMS. At high altitude, acetazolamide impaired rather than improved neuropsychological measures of concentration, cognitive processing speed, reaction time, short-term memory, and working memory, which were assessed by DSST, PASAT, and operation span task at 6 and 30 h after arrival (p<0.05). However, the prophylactic use of acetazolamide was found to reduce the incidence of AMS compared to the placebo (p<0.05). In conclusion, acetazolamide impairs neuropsychological function, at least in part, shortly after the ascent to high altitude.

Manganese induces the overexpression of α-synuclein in PC12 cells via ERK activation

Manganese has been known to induce neurological disorders. In the present study, we determined the effect of manganese on the expression of α-synuclein in PC12 cells and its role in manganese-induced cytotoxicity. We also investigated the relationship between α-synuclein expression and the change of ERK1/2 MAPK activity. In our research, manganese exposure induced the overexpression of α-synuclein, while siRNA knockdown of α-synuclein reversed manganese-induced cytotoxicity. Furthermore, manganese induced the activation of ERK1/2 MAPK. The MEK1 inhibitor PD98059, which inhibits the activation of ERK MAPK, attenuated the overexpression of α-synuclein and the cytotoxicity induced by manganese. In conclusion, our studies show that manganese may induce the overexpression of α-synuclein via ERK1/2 activation, which may play a role in manganese-induced cytotoxicity.

Acute cold exposure and rewarming enhanced spatial memory and activated the MAPK cascades in the rat brain

Cold is a common stressor that is likely to occur in everyday occupational or leisure time activities. Although there is substantial literature on the effects of stress on memory from behavioral and pharmacologic perspectives, the effects of cold stress on learning and memory were little addressed. The aims of the present work were to investigate the effects of acute cold exposure on Y-maze learning and the activation of cerebral MAPK cascades of rats. We found that the 2-hour cold exposure (-15 degrees C) and a subsequent 30-min rewarming significantly increased the performance of the rats in the Y-maze test. Serum corticosterone (CORT) level was increased after the cold exposure. After a transient reduction following the cold exposure, the P-ERK levels in the hippocampus and PFC drastically increased 30 min later. The levels of P-JNK increased gradually after the cold exposure in all the three brain regions we investigated, but the level of P-p38 only increased in the PFC. The levels of GABAA receptor alpha1 subunit remained unchanged after the cold exposure. Furthermore, the performance of rats treated with cold plus muscimol or bicuculline in the Y-maze test was similar to that of the rats treated with those GABAergic agents alone. These results demonstrated that acute cold exposure and the subsequent rewarming could result in enhanced performance of spatial learning and memory, and the activation of MAPKs in the brain. However, GABAA receptor may not be involved in the acute cold exposure-induced enhancement of memory.

Manganese Induces Tau Hyperphosphorylation through the Activation of ERK MAPK Pathway in PC12 Cells

Manganese has long been known to induce neurological degenerative disorders. Emerging evidence indicates that hyperphosphorylated tau is associated with neurodegenerative diseases, but whether such hyperphosphorylation plays a role in manganese-induced neurotoxicity remains unclear. To fill this gap, we investigated the effects of manganese on tau phosphorylation in PC12 cells. In our present research, treatment of cells with manganese increased the phosphorylation of tau at Ser199, Ser202, Ser396, and Ser404 as detected by Western blot. Moreover, this manganese-induced tau phosphorylation paralleled the activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK). The mitogen-activated protein kinase kinase-1 (MEK1) inhibitor PD98059, which inhibits the activation of ERK MAPK, partially attenuated manganese-induced tau hyperphosphorylation and cytotoxicity. Moreover, the activation of ERK MAPK was involved in the activation of glycogen synthase kinase-3β (GSK-3β) kinase, which also contributed to the hyperphosphorylation of tau and the cytotoxicity in PC12 cells induced by manganese. Taken together, we found for the first time that the exposure to manganese can cause the hyperphosphorylation of tau, which may be connected with the activation of ERK MAPK.

Proteasome inhibition is associated with manganese-induced oxidative injury in PC12 cells

Manganese has been known to induce neurological disorders similar to Parkinsons disease. The dysfunction of ubiquitin-proteasome system, a pathway involved in detoxification and targeting of damaged proteins, is connected with Parkinsons disease pathogenesis. Oxidative stress may be involved in Parkinsons disease, and may also be associated with manganese-induced neurotoxicity. In the present study, we determined the effects of manganese chloride on proteasome activity in PC12 cells. Furthermore, we investigated the relationship between oxidative stress and the change of proteasome activity. The proteasome activity of PC12 cells was measured by an ELISA method. Selective oxidative stress parameters, including malondialdehyde and protein carbonyl, were measured in PC12 cells treated with manganese chloride. Cell survival and apoptosis were measured by methyl thiazolyl tetrazolium and terminal transferase-mediated dUTP nick end-labeling. In our research, manganese chloride exposure inhibited the activity of proteasome and induced oxidative stress. Both can be reversed by antioxidant agent N-acetylcysteine. N-acetylcysteine also inhibited the cytotoxicity induced by manganese chloride. In conclusion, our results imply that proteasome inhibition may be associated with manganese-induced cytotoxicity in dopaminergic neurons, which may be connected with oxidative damage.

The effect of sodium selenite on lead induced cognitive dysfunction

The effect of lead (Pb) on spatial memory and hippocampal long-term potentiation (LTP) as a key risk factor has been widely recognized and the oxidative damage has been proposed as a possible mechanism of lead neurotoxicity. Selenium (Se) is a nutritionally essential trace element with known antioxidant potential. In this study we investigated the effect and the underlying mechanisms of Se supplementary on Pb induced cognition and synaptic plasticity impairment. Lactating Sprague-Dawley rats (SD rats) were randomly divided to four groups: 0ppm lead acetate (Pb); 0ppm Pb and 0.2ppm sodium selenite (Se); 100ppm Pb; 100ppm Pb and 0.2ppm Se. Lactating rats were treated with or without Pb and/or Se throughout lactation until weaning. The levels of hippocampal LTP, the spatial memory, the apoptosis of hippocampal neurons, the levels of lactate dehydrogenase (LDH) release, and the serum level of superoxide dismutase (SOD) and malondialdehyde (MDA) were assayed. It had been observed that in Pb group the spatial memory, the induce level of LTP, the serum SOD level decreased, the LDH release level, the neurons apoptosis level, the serum MDA level increased, while in the Se supplements groups, the spatial memory, the induce level of LTP increased significantly. Compared with the Pb group, Se supplements shown down regulated the level of LDH, the neurons apoptosis and the serum MDA, and up regulated the level of serum SOD. We could draw the conclusion that Se supplements could alleviate toxic effect of lead on hippocampal LTP and spatial memory. The treated with selenium around 0.2ppm may protect against spatial memory dysfunction induced by lead exposure.

Effect of acetazolamide and gingko biloba on the human pulmonary vascular response to an acute altitude ascent

Acetazolamide and gingko biloba are the two most investigated drugs for the prevention of acute mountain sickness (AMS). Evidence suggests that they may also reduce pulmonary artery systolic pressure (PASP). To investigate whether these two drugs for AMS prevention also reduce PASP with rapid airlift ascent to high altitude, a randomized controlled trial was conducted on 28 healthy young men with acetazolamide (125 mg bid), gingko biloba (120 mg bid), or placebo for 3 days prior to airlift ascent (397 m) and for the first 3 days at high altitude (3658 m). PASP, AMS, arterial oxygen saturation (Sao2), mean arterial pressure (MAP), heart rate (HR), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF) were assessed both at 397 m and 3658 m. HR, PEF, and PASP increased with altitude exposure (p<0.05), and SaO2 decreased (p<0.05). PASP with acetazolamide (mean at 3658 m, 26.2 mm Hg; incremental change, 4.7 mm Hg, 95% CI., 2.6-6.9 mm Hg) was lower than that with ginkgo biloba (mean at 3658 m, 33.7 mm Hg, p=0.001; incremental change, 13.1 mm Hg, 95%CI., 9.6-16.5 mm Hg, p=0.002), and with placebo (mean at 3658 m, 34.7 mm Hg, p<0.001; 14.4 mm Hg, 95% CI., 8.8-20.0 mm Hg, p=0.001). The data show that a low prophylactic dosage of acetazolamide, but not gingko biloba, mitigates the early increase of PASP in a quick ascent profile.