Alterations of Regional Homogeneity in Parkinson's Disease with Rapid Eye Movement Sleep Behavior Disorder.

Objective: Patients with rapid eye movement (REM) sleep behavior disorder (RBD) in Parkinson's disease (PD-RBD) tend to have poor cognitive performance and faster cognitive deterioration, and the potential mechanism is still ambiguous. Therefore, this study aimed to detect the alterations in local brain function in PD-RBD. Methods: Fifty patients, including 23 patients with PD-RBD and 27 patients with PD without RBD (PD-nRBD), and 26 healthy controls were enrolled. All subjects were subjected to one-night polysomnography and underwent resting-state functional magnetic resonance imaging (rs-fMRI). The fMRI images of the three groups were analyzed by regional homogeneity (ReHo) to observe the local neural activity. Correlations between altered ReHo values and chin electromyographic (EMG) density scores and cognitive scores in the PD subgroups were assessed. Results: Compared with the patients with PD-nRBD, the patients with PD-RBD had higher ReHo values in the frontal cortex (the right superior frontal gyrus, the right middle frontal gyrus and the left medial superior frontal gyrus), the right caudate nucleus and the right anterior cingulate gyrus, and compared with the HCs, the patients with PD-RBD had lower ReHo values in the bilateral cuneus, the bilateral precuneus, the left inferior temporal gyrus and the left inferior occipital gyrus. For the patients with PD-RBD, the phasic chin EMG density scores were positively correlated with the ReHo values in the left medial superior frontal gyrus, and the tonic chin EMG density scores were positively correlated with the ReHo values in the right anterior cingulate gyrus. Conclusion: This study indicates that increased ReHo in the frontal cortex, the caudate nucleus and the anterior cingulate gyrus may be linked with the abnormal motor behaviors during REM sleep and that decreased ReHo in the posterior regions may be related to the visuospatial-executive function in patients with PD-RBD.

Factors Contributing to Malnutrition in Parkinson's Disease Patients With Freezing of Gait.

Background and Purpose: Little is known about the nutritional status and clinical characteristics of patients with Parkinson's disease with freezing of gait (PDFOG). The purpose of this study was to describe the relationship between nutritional status and characteristics of patients with PDFOG. Methods: In this cross-sectional study, 178 PDFOG patients were recruited and classified as nutritionally normal or at risk of malnutrition/already malnourished based on their Mini Nutritional Assessment (MNA) scores. Each participant underwent a structured questionnaire, physical examination and routine serum biochemical tests. Results: We found that 44.4 and 37.1% of PDFOG patients were malnourished [mini nutritional assessment (MNA) score <17] and at risk of malnutrition (17 ≤ MNA score ≤ 23.5), respectively. Compared to patients with normal nutrition, PDFOG patients with malnutrition and at risk of malnutrition had longer duration of Parkinson's disease (PD) and freezing of gait (FOG), more levodopa equivalent daily doses (LEDD), lower body mass index (BMI), more motor symptoms according to the Unified PD Rating Scale-III (UPDRS-III) and non-motor symptoms according to the PD Non-motor Symptoms Questionnaire (PD-NMS) (P < 0.05). Uric acid, albumin, prealbumin, and total cholesterol (TC) differed between the two groups (P < 0.05). High Hoehn and Yahr (H-Y) stage, high Freezing of Gait Questionnaire (FOGQ) scores, low TC and low uric acid were risk factors for malnutrition in patients with PDFOG. Conclusion: Our results showed disease severity, motor symptoms, TC levels and uric acid levels were all associated with nutritional status in patients with PDFOG. This study suggest early discovery of the nutritional status of PDFOG patients is important.

The Association Between Clinical Characteristics and Motor Symptom Laterality in Patients With Parkinson's Disease.

Background and Purpose: The unilateral onset and persistent asymmetry of motor symptoms are important characteristics of Parkinson's disease (PD). By using scales and wearable sensors, this study explored whether motor symptom laterality could affect non-motor symptom and gait performance. Methods: A total of 130 right-handed patients with PD were enrolled in our study and were divided into two groups according to the side of predominant motor symptom presentation by using the Unified Parkinson's Disease Rating Scale part III. We measured the non-motor symptoms with the Non-motor symptoms Scale, sleep quality with the Parkinson's Disease Sleep Scale and Pittsburgh sleep quality index, cognitive function with the Mini-mental State Examination and Montreal Cognitive Assessment, quality of life with the Parkinson's Disease Questionnaire-39, and the severity of anxiety and depression with the Hamilton Anxiety Scale and Hamilton Depression Scale, respectively. All participants underwent the instrumented stand and walk test, and gait data were collected using a set of JiBuEn gait analysis system. Results: We observed that left-dominant symptom PD patients (LPD) were associated with a greater impairment of sleep quality than right-dominant symptom PD patients (RPD). We found no difference between LPD and RPD in terms of gait performance. However, compared with the severe asymmetry RPD patients (RPD-S), severe asymmetry LPD patients (LPD-S) showed a shorter stride length and decreased range of motion of hip joints. Conclusions: In this study, LPD was associated with a more severe sleep-related dysfunction than RPD. In addition, LPD-S exhibited more gait impairments than RPD-S. Considering that motor symptom laterality may affect the non-motor symptom and gait performance, it should be taken into account when evaluating and treating PD patients.

Mild Gait Impairment and Its Potential Diagnostic Value in Patients with Early-Stage Parkinson's Disease.

METHODS: 32 patients with early-stage PD and 30 healthy control subjects (HC) were enrolled. All participants completed the instrumented stand and walk test, and gait data was collected using wearable sensors. RESULTS: We observed increased variability of stride length (SL) (P < 0.001), stance phase time (StPT) (P = 0.004), and swing phase time (SwPT) (P = 0.011) in PD. There were decreased heel strike (HS) (P = 0.001), range of motion of knee (P = 0.036), and hip joints (P < 0.001) in PD. In symmetry analysis, no difference was found in any of the assessed gait parameters between HC and PD. Only total steps (AUC = 0.763, P < 0.001), SL (AUC = 0.701, P = 0.007), SL variability (AUC = 0.769, P < 0.001), StPT variability (AUC = 0.712, P = 0.004), and SwPT variability (AUC = 0.688, P = 0.011) had potential diagnostic value. When these five gait parameters were combined, the predictive power was found to increase, with the highest AUC of 0.802 (P < 0.001). CONCLUSIONS: Patients with early-stage PD presented increased variability but still symmetrical gait pattern. Some specific gait parameters can be applied to diagnose early-stage PD which may increase diagnosis accuracy. Our findings are helpful to improve patient's quality of life.

Gait Analysis of Old Individuals with Mild Parkinsonian Signs and Those Individuals' Gait Performance Benefits Little from Levodopa.

BACKGROUND AND PURPOSE: Gait analysis and the effects of levodopa on the gait characteristics in Mild parkinsonian signs (MPS) are rarely published. The present research aimed to (1) analyze the gait characteristics in MPS; (2) explore the effects of levodopa on the gait performance of MPS. METHODS: We enrolled 22 inpatients with MPS and 20 healthy control subjects (HC) from Nanjing Brain Hospital. The Unified Parkinson's Disease Rating Scale was used to evaluate motor symptoms. Acute levodopa challenge test was performed to explore the effects of levodopa on the gait performance of MPS. The instrumented stand and walk test was conducted for each participant and the JiBuEn gait analysis system was used to collect gait data. RESULTS: For spatiotemporal parameters: Compared with HC, the state before taking levodopa/benserazide in MPS group (meds-off) demonstrated a decrease in stride length (SL) (p≤0.001), an increase in SL variability (p≤0.001), and swing phase time variability (p=0.016). Compared with meds-off, the state after 1 hour of taking levodopa/benserazide in MPS group (meds-on) exhibited an increase in SL (p≤0.001), a decrease in SL variability (p≤0.001). For kinematic parameters: Compared with HC, meds-off demonstrated a decrease in heel strike angle (p=0.008), range of motion (ROM) of knee joint (p=0.011) and ROM of hip joint (p=0.007). Compared with meds-off, meds-on exhibited an increase in HS (p≤0.001). Bradykinesia and rigidity scores were significantly correlated with gait parameters. CONCLUSION: Although the clinical symptoms of the MPS group are mild, their gait damage is obvious and they exhibited a decreased SL and joints movement, and a more variable gait pattern. Levodopa had little effect on the gait performance of those individuals.

Increased rapid eye movement density in Chinese patients with Parkinson's disease and RBD.

OBJECTIVE: Impaired rapid eye movement sleep is common among patients with Parkinson's disease (PD). However, information on rapid eye movement density (REM) among PD patients is currently lacking. The current study sought to characterize REM density in PD patients and to examine the associations between REM density sleep parameters and clinical manifestations. PARTICIPANTS AND METHODS: We retrospectively recruited 172 PD patients. All participants were assessed with a two-night polysomnography, and REM density was calculated. Clinical assessments were completed in PD patients before polysomnography. RESULTS: Rapid eye movement sleep behavior disorder (RBD) was observed in 93 patients (54.1%). The disease duration, UPDRS part III score, Hoehn and Yahr (H-Y) stage, and HAMA, HAMD, PDQ-39 scores, and REM density in the Parkinson's disease patients with rapid eye movement sleep behavior disorder (RBD) were significantly higher than in the patients without RBD (P < 0.05). However, NREM sleep stage 3 time (N3 time) and percentage of N3 time of total sleep time (N3%) were significantly lower in the RBD patients than in the patients without RBD (P < 0.05). The forward binary logistic regression model showed that REM density, UPDRS-III score, and N3 sleep time were associated with RBD in the PD patients. CONCLUSIONS: Our results confirm the high prevalence of RBD in patients with PD. Increased REM density was the main risk factor of RBD.

Prevalence and Risk Factors for Malnutrition in Patients With Parkinson's Disease.

Objectives: This study aimed to investigate the relationship between nutritional status and Parkinson's disease (PD) features. Methods: The cohort was composed of 556 Parkinson's patients who were admitted to the hospital. Patients were categorized as normal nutrition or at risk of malnutrition/already malnourished. Questionnaires, physical examinations, and biochemical tests were conducted. The relationship between nutrition status and PD was analyzed using t-tests, χ2-tests, and logistic regression models. Results: The prevalence of malnutrition [defined as a Mini Nutritional Assessment (MNA) score <17] was 39.2%, and 30.3% of patients were at risk of malnutrition (17 ≤ MNA score ≤ 23.5). There was no difference in gender and age between the different nutrition groups (P < 0.05). Patients at risk of malnutrition and those who were malnourished had a longer course of disease, more severe motor symptoms, a higher stage of PD according to the Hoehn and Yahr (H-Y) classification, a lower body mass index (BMI) index, a lower cognitive score, higher levels of depression and anxiety, and more serious non-motor symptoms (P < 0.05) than patients with normal nutrition. There were differences in adenosine deaminase, albumin, phosphorus, chlorine, total protein, and uric acid between the two groups (P < 0.05). High Unified PD Rating Scale (UPDRS-III) scores, high H-Y stages, and dyskinesia were risk factors for malnutrition in PD patients, while high levels of total protein, uric acid, and chlorine were protective factors that led to good nutrition (P < 0.05). Conclusions: Our results showed that dyskinesia, disease severity, total protein levels, uric acid levels, and chlorine levels were associated with nutritional status among Chinese PD patients. The findings of this study indicate the significance of the early detection and prevention of malnutrition to improve the quality of life of PD patients.

Can Quantitative Gait Analysis Be Used to Guide Treatment of Patients with Different Subtypes of Parkinson's Disease?

PURPOSE: Gait impairment is a common clinical symptom of patients with Parkinson's disease (PD). Detecting specific gait parameters' changes in order to guide clinical intervention is at present lacking. The present study aimed to (1) quantify gait impairments in different PD subtypes and (2) explore whether the results of quantitative gait analysis are beneficial to clinical treatment. PATIENTS AND METHODS: We enrolled 86 patients with PD (48 men, and 38 women) from the Department of Geriatrics of the Affiliated Brain Hospital of Nanjing Medical University. Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn-Yahr Scale were used to evaluate the motor symptoms of PD. All patients stopped anti-Parkinsonian medication for 24 hours (72 hours for controlled release medicine). The patients were divided into two subtypes, namely, postural instability gait difficulty (PIGD; n=56) and tremor dominant (TD; n=30) subtypes according to UPDRS. All patients completed the instrumented stand and walk test, and a set of JiBuEn gait analysis system was used in gait data collection. RESULTS: We observed a shorter stride length (p=0.021), a longer stride time (p=0.036), a faster cadence (p=0.036), and a more variable stride length (p=0.012) in the PIGD group compared with the TD group. In addition, compared with the TD group, we found that the toe-off angle (p=0.005) and the range of motion of ankle joint (p=0.009) decreased in the PIGD group. CONCLUSION: Our study demonstrated that the gait performance of patients with PIGD is worse than those with TD from the perspective of quantitative gait analysis. We extended previous research and found the PIGD group exhibited severe gait impairments in some specific spatiotemporal and kinematic gait parameters. The different manifestations of these gait impairments may guide in choosing appropriate treatment of patients with different PD subtypes.

COX-2-PGE2 signaling pathway contributes to hippocampal neuronal injury and cognitive impairment in PTZ-kindled epilepsy mice.

Epilepsy is one of the most common neurological diseases. It adversely affects cognitive function. Neuroinflammation has been widely recognized as an important factor involved in the pathophysiology of epilepsy. Cyclooxygenase (COX) is a type of oxidoreductase enzyme that acts in the metabolic pathway converting arachidonic acid to prostaglandins, which mediate inflammatory reactions. The activation of inducible cyclooxygenase-2 (COX-2) is considered to be a precipitating factor of neuroinflammation in the brain. Neuroinflammatory processes in the brain are known to contribute to the cascade of events leading to neuronal injury, which may consequently cause cognitive decline. Here in this study, we showed that pentylenetetrazole (PTZ)-kindled mice exhibited an increased level of COX-2 and its main product prostaglandin E2 (PGE2) along with neuroinflammation and neuronal injury in the hippocampus. Pharmacological inhibition of COX-2 by celecoxib, however, significantly reduced hippocampal neuroinflammation and neuronal injury. Furthermore, inhibition of COX-2 by celecoxib attenuated cognitive impairment in the PTZ-kindled mice, suggesting that COX-2-PGE2 signaling pathway mediated neuroinflammation and neuronal injury contributes to cognitive dysfunction in the PTZ-kindled epilepsy mice. Targeting COX-2-PGE2 signaling pathway in the epileptic brain appears to be a viable strategy for attenuating neuronal injury and preventing cognitive deficits in epilepsy patients.

Depressive symptoms effect subjective sleep quality in Chinese patients with Parkinson's disease.

OBJECTIVES: The objective of this paper was aimed to estimate the influence of depressive symptoms on subjective sleep quality in Chinese PD patients. PATIENTS AND METHODS: A sample of 491 PD patients was collected and studied in the present study. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAMD). PD severity was assessed using Hoehn and Yahr (H-Y) staging, and motor symptoms were measured with the Unified PD Rating Scale (UPDRS) part III. The Montreal Cognitive Assessment (MOCA) was used to evaluate the global Cognitive status and PD Sleep Scale (PDSS) was used to quantify sleep quality. Three linear regression models were built to check factors associated with caregiver burden, one for the total sample and two for subgroups stratified by the presence of cognitive disturbance. RESULTS: In our sample, 29.9% of patients suffer from sleep disturbance. The most frequent depressive symptoms were helplessness (81.5%), depressed mood (57.8%), and general somatic symptoms (55.4%) for entire sample. Patients with cognitive disturbance (n = 274; 55.8% of sample) presented more depressive symptoms than patients without cognitive disturbance. Patients suffer poorer sleep quality when patients experience depression with cognitive disturbance. On linear regression models, the main determinants of subjective quality for the total sample were NMS-depression/anxiety/anhedonia, HAMD-anxiety/somatization, disease severity, age and HAMD-loss of weight. For patients with cognitive disturbance, the significant determinants were NMS-depression/anxiety/anhedonia, HAMD-anxiety/somatization, motor symptoms, HAMD-loss of weight and gender. For patients without cognitive disturbance, the significant determinants were NMS-depression/anxiety/anhedonia, disease severity and HAMD-anxiety/somatization. CONCLUSION: Depressive symptoms in PD are highly associated with and are determinants of subjective sleep quality, and are more prevalent in patients with cognitive disturbance. Detailed assessment and specific interventions aimed at depression and dementia could alleviate sleep disorder.

Wearable Sensors Measure Ankle Joint Changes of Patients with Parkinson's Disease before and after Acute Levodopa Challenge.

BACKGROUND: Previous studies found levodopa could improve the activity of the ankle joints of patients with Parkinson's disease (PD). But ankle joint movement is composed of four motion ranges. The specific changes of four motion ranges in PD remain unknown. OBJECTIVE: The purpose of this study was to decompose the complex ankle joint movement, measure ankle joint changes before and after the acute levodopa challenge test (ALCT), and investigate the effects of these parameters on gait performance. METHODS: 29 PD patients and 30 healthy control subjects (HC) completed the Instrumented Stand and Walk (ISAW) test and gait parameters were collected by the JiBuEn gait analysis system. The percentage of improvement of gait data and the UPDRS III in the on-drug condition (ON) were determined with respect to the off-drug condition (OFF). RESULTS: We observed a reduction in the heel strike angle (HS), 3-plantarflexion (3-PF) angle, and 4-dorsiflexion (4-DF) angle of ankle joints. We did not find significant difference in the toe-off angle (TO), 1-plantarflexion (1-PF) angle, and 2-dorsiflexion (2-DF) angle among three groups. Stride length improvement rate was significantly correlated with HS (r s = 0.616, P < 0.001) and 3-PF (r s = 0.639, P < 0.001) improvement rates. The improvement in the sum of rigidity items (UPDRS motor subsection item 22) was also correlated with HS (r s = 0.389, P=0.037) and 3-PF (r s = 0.373, P=0.046) improvement rates. CONCLUSIONS: Exogenous levodopa supplementation can significantly reduce the rigidity of patients with PD, improve their 3-PF and 4-DF of ankle joint kinematic parameters, and ultimately enhance their gait.

Nonmotor Symptoms Affect Sleep Quality in Early-Stage Parkinson's Disease Patients With or Without Cognitive Dysfunction.

Purpose: Parkinson's disease (PD) patients frequently present with sleep disorders. This study was designed to assess the impact of nonmotor symptoms (NMSs) on sleep quality in early-stage PD patients with and without cognitive dysfunction. Materials and Methods: A sample of 389 early-stage PD patients (modified Hoehn and Yahr score ≤ 2.5, duration ≤ 5 years) was recruited for the present study. The Non-Motor Symptoms Questionnaire (NMS-Quest) was used to screen for global NMSs. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAMD). PD motor symptoms were measured with the Unified PD Rating Scale (UPDRS), part III. The Montreal Cognitive Assessment (MoCA) was used to evaluate global cognitive status, and the PD Sleep Scale (PDSS) was used to quantify sleep quality. Polysomnography (PSG) was used for objective assessment of sleep. Results: In our sample, approximately one-quarter of the PD patients suffered from sleep disturbances (23.7%). Our results also confirmed the high prevalence of cognitive dysfunction in patients with PD (39.8%). In patients with cognitive dysfunction, higher percentage of sleep disorders (34.8 vs. 16.2%, P < 0.01) was observed. They also with lower PDSS score, sleep efficiency (SE) and longer sleep lantency (SL) and wake after sleep onset (WASO) (All P < 0.05). In total, the patients who suffered from NMSs, such as depressive symptoms, anxiety symptoms, urinary tract symptoms and hallucinations/delusions, had poorer sleep quality. Better cognition may predict better sleep quality. In patients with cognitive dysfunction, the NMS-Hallucinations/delusions score was the most important risk factor for sleep disorders. In patients without cognitive dysfunction, NMSs such as anxiety and cognition and medication were related to sleep disorder. Conclusions: NMSs in early-stage PD are highly associated with and are determinants of subjective sleep quality. Future studies should focus on elucidating the pathophysiology of these symptoms.

Reperfusion combined with intraarterial administration of resveratrol-loaded nanoparticles improved cerebral ischemia-reperfusion injury in rats.

Endovascular thrombectomy (EVT) has been recommended as the first line therapy for large artery occlusion (LAO) stroke. However, abrupt recovery of blood flow induces oxidative stress which breaks down the blood-brain barrier (BBB), activates apoptosis and inhibits neurogenesis. Supplement of exogenous antioxidants to relieve the injuries related to oxidative stress is a rational treatment combined to EVT for acute LAO therapy. Resveratrol (RES), an antioxidant, was encapsulated into polymeric nanoparticles (RES-NPs). In transient middle cerebral artery occlusion (tMCAO) rats, intraarterial administration of RES-NPs demonstrated significant protection against cerebral ischemia/reperfusion (I/R) injuries. RES-NPs attenuated the oxidative stress induced by I/R, prevented brain edema, protected neurons from undergoing apoptosis, and contributed to neurogenesis through enhanced expression of brain-derived neurotrophic factor (BDNF). These results suggested that intra-arterial infusion of RES-NPs in conjunction with EVT could be a potential strategy for the LAO stroke therapy.

Altered putamen and cerebellum connectivity among different subtypes of Parkinson's disease.

OBJECTIVE: Impairment of basal ganglia (BG)-thalamo-cortical circuit causes various symptoms of Parkinson's disease (PD). We investigated the functional connectivity (FC) patterns of putamen among PD subtypes and healthy control (HC) and explored their clinical significance. METHODS: A total of 16 patients with tremor-dominant (TD) PD, 23 patients with postural instability and gait difficulty-dominant (PIGD) PD, and 31 HC that underwent functional magnetic resonance imaging were observed. Voxel-wise FC analysis was performed by computing correlation between bilateral putamen and other voxels within the brain. Correlation analysis was performed between FC strength and clinical symptoms. RESULTS: Compared with PIGD group, TD group showed increased FC between left putamen and right cerebellum lobule VI and cerebellum crus I, then we compared the cerebellum FC difference among the three groups. The cerebellum lobule VI FC difference was mainly involved in motor related cortex, and the cerebellum crus I FC difference was related to cognition areas. While compared with HC, TD and PIGD groups both had significant FC difference brain areas correlated with motor and cognition symptoms. The connectively of putamen and right cerebellum lobules VI and I showed positive correlation with tremor and Montreal Cognitive Assessment degree of scores, respectively. The connectivity of putamen and sensorimotor cortex had negative correlation with PIGD scores. CONCLUSIONS: The altered connectivity of BG-cortical circuit in patients with PD was related to PIGD symptoms. Motor and cognitive impairments declined slower in patients with TD PD, which may be related to increased functional connectivity between putamen and cerebellum.

MicroRNA-23a contributes to hippocampal neuronal injuries and spatial memory impairment in an experimental model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of epilepsy characterized by spontaneous recurrent seizures. It has been widely accepted that individuals with TLE tend to have neuronal injuries and memory impairment. However, little is known about the underlying molecular mechanisms. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of target genes at the posttranscriptional level. An increasing body of evidence suggests that miRNAs play pivotal roles in the pathogenesis of epilepsy. Here, we sought to determine the role of miR-23a, one of the most common miRNAs involved in various cancer types, in hippocampal neuronal injuries and spatial memory impairment in an experimental model of TLE. We found that miR-23a is upregulated in the hippocampus after status epilepticus (SE) in kanic acid (KA)-induced TLE mice. Furthermore, the upregulation of miR-23a is accompanied by hippocampal oxidative damage, neuronal injuries and spatial memory impairment in TLE mice. Inhibition of miR-23a expression by miR-23a antagomirs reduced hippocampal oxidative stress, neuronal injuries and improved spatial memory, while an increase in miR-23a expression by miR-23a agomir exacerbated hippocampal oxidative stress, neuronal injuries and spatial memory impairment in TLE mice. Our findings suggest that miR-23a contributes to hippocampal oxidative damage and neuronal injuries, which may consequently contribute to spatial memory impairment in TLE mice. Thus, targeting miR-23a in the epileptic brain may provide a novel strategy for protecting against hippocampal neuronal injuries and improving spatial memory in TLE patients.

Alteration of GABAergic signaling is associated with anxiety-like behavior in temporal lobe epilepsy mice.

Temporal lobe epilepsy (TLE), which is one of the most common neurological diseases, is accompanied by a high incidence of psychiatric disorders. Among these psychiatric disorders, anxiety is one of the major psychiatric comorbidities in epilepsy patients. However, anxiety in epilepsy patients often remains unrecognized and untreated. It is believed that the inhibitory networks of γ-aminobutyric acid (GABA) neurotransmission play pivotal roles in the modulation of emotion and mood responses in both physiological and pathological conditions. The impairment of neurotransmission mediated by GABAergic signaling is related to the pathophysiology of anxiety. However, it remains unclear whether and how GABAergic signaling modulates anxiety responses in the context of an epileptic brain. In the present study, we sought to determine the role of inhibitory networks of GABAergic signaling in the anxiety-like behavior of epileptic mice. Our results show epileptic mice exhibited increased anxiety-like behavior, and this increased anxiety-like behavior was accompanied by a decrease in GABAergic interneurons and an increase in GABA type A receptor (GABAAR) ß3 subunit (GABRB3) expression in the hippocampus. Furthermore, the activation of GABAARs produced an anxiolytic-like effect, while the inhibition of GABAARs elicited an anxiogenic-like effect in the epileptic mice, suggesting that the alteration of GABAergic signaling is associated with anxiety-like behavior in epileptic mice. Thus, targeting GABAergic signaling in the epileptic brain may provide an effective anxiolytic treatment in epilepsy patients.

MicroRNA-132 is associated with the cognition improvement following voluntary exercise in SAMP8 mice.

The senescence-accelerated SAMP8 mouse is characterized by progressive cognitive decline and is considered to be a specific model of Alzheimer's disease (AD). A growing body of evidence indicates that physical exercise suppresses age-related cognitive decline. In the current study, we investigated the influence of voluntary wheel running on cognitive function in SAMP8 mice. We found that voluntary physical exercise ameliorated cognition decline and suppressed hippocampal neurodegeneration in SAMP8 mice. MicroRNA-132 (miR-132) is a short non-coding RNA which is enriched in the brain and is implicated in the regulation of neuronal activity and cognitive function. Here we show that miR-132 expression was significantly increased in the hippocampus of SAMP8 mice. Voluntary physical exercise, however, suppressed the increase of miR-132 expression in SAMP8 mice. Furthermore, upregulation of hippocampal miR-132 expression exacerbates cognition decline, while downregulation of hippocampal miR-132 ameliorates cognition deficit in the SAMP8 mice. Taking together, our results suggest that miR-132 is associated with the cognition improvement following voluntary exercise in SAMP8 mice.

Neuronal Nitric Oxide Synthase Contributes to PTZ Kindling Epilepsy-Induced Hippocampal Endoplasmic Reticulum Stress and Oxidative Damage.

Epilepsy is one of the most common chronic neurological disorders which provoke progressive neuronal degeneration. Endoplasmic reticulum (ER) stress has recently been recognized as pivotal etiological factors contributing to epilepsy-induced neuronal damage. However, the specific contribution of epilepsy made to ER stress remains largely elusive. Here we use pentylenetetrazole (PTZ) kindling, a chronic epilepsy model, to identify neuronal nitric oxide synthase (nNOS) as a signaling molecule triggering PTZ kindling epilepsy-induced ER stress and oxidative damage. By genetic deletion of nNOS gene, we further demonstrated that nNOS acts through peroxynitrite, an important member of reactive nitrogen species, to trigger hippocampal ER stress and oxidative damage in the PTZ-kindled mice. Our findings thus define a specific mechanism for chronic epilepsy-induced ER stress and oxidative damage, and identify a potential therapeutic target for neuroprotection in chronic epilepsy patients.

Neuronal Nitric Oxide Synthase Contributes to PTZ Kindling-Induced Cognitive Impairment and Depressive-Like Behavior.

Epilepsy is a chronic neurological disease which is usually associated with psychiatric comorbidities. Depsression and cognition impairment are considered to be the most common psychiatric comorbidities in epilepsy patients. However, the specific contribution of epilepsy made to these psychiatric comorbidities remains largely unknown. Here we use pentylenetetrazole (PTZ) kindling, a chronic epilepsy model, to identify neuronal nitric oxide synthase (nNOS) as a signaling molecule triggering PTZ kindling-induced cognitive impairment and depressive-like behavior. Furthermore, we identified that both hippocampal MAPK and PI3K/AKT signaling pathways were activated in response to PTZ kindling, and the increased MAPK and PI3K/AKT signaling activation was paralleled by increased level of reactive oxygen species (ROS) in the hippocampus. However, the PTZ kindling-induced MAPK, PI3K/AKT signaling activities and the ROS level were attenuated by nNOS gene deficiency, suggesting that nNOS may act through ROS-mediated MAPK and PI3K/AKT signaling pathways to trigger cognition deficit and depressive-like behavior in PTZ-kindled mice. Our findings thus define a specific mechanism for chronic epilepsy-induced cognitive impairment and depressive-like behavior, and identify a potential therapeutic target for psychiatric comorbidities in chronic epilepsy patients.

Repeated restraint stress increases seizure susceptibility by activation of hippocampal endoplasmic reticulum stress.

A growing body of evidence suggests that stress triggers a variety of pathophysiological responses. Recent studies show that stress produces enduring effects on structure and function of hippocampus, which is one of the most important structures involved in epilepsy. In the present study, we determined the effect of repeated restraint stress exposure on the susceptibility of pentylenetetrazole (PTZ)-induced seizures and the possible mechanisms involved using a rodent model. Our results show that mice subjected to repeated restraint stress exhibited shorter latency to PTZ-induced tonic-clonic seizures and higher seizure severity, suggesting chronic restraint stress increases seizure susceptibility. Following repeated restraint stress, we observed an increased level of endoplasmic reticulum (ER) stress as well as oxidative stress in the hippocampus. Moreover, our results show that chronic restraint stress exposure causes neuron loss in the hippocampus. Inhibition of ER stress with chemical chaperone, tauroursodeoxycholic acid (TUDCA), however, protects against chronic restraint stress-induced neuron loss, suggesting repeated restraint stress-induced neuronal degeneration is dependent on ER stress activation. On the other hand, inhibition of ER stress with TUDCA suppresses restraint stress-induced seizure susceptibility. Taken together, these results indicate that repeated restraint stress increases seizure susceptibility by activation of hippocampal ER stress and ER stress mediated oxidative stress and neurodegeneration. Thus, attenuating ER stress may serve as a potential therapeutic strategy targeted to block stress-induced seizure activities.