Pycnogenol Protects Against Rotenone-Induced Neurotoxicity in PC12 Cells Through Regulating NF-κB-iNOS Signaling Pathway.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neurons degeneration and oxidative damage may underlie this process. However, there are still no efficient drugs to cure the disease. Pycnogenol (PYC) isolated from the procyanidin-rich French maritime pine (Pinus maritime) bark has shown various antioxidant activities in previous studies. In this study, we explored its effect against rotenone (Rot)-induced neurotoxicity and the underlying mechanisms in PC12 cells. Using Rot-induced cell model of PD, we found that PYC treatment significantly increased cell viability and decreased cell apoptosis in Rot-treated PC12 cells in a dose-dependent manner. Furthermore, data showed that PYC markedly reduced inducible nitric oxide synthase (iNOS)-nitric oxide (NO) signaling in Rot-treated PC12 cells. Pretreatment with the iNOS-specific inhibitor significantly attenuated Rot-induced neurotoxicity. Moreover, PYC was found to be capable of reducing Rot-induced NF-κB activation. Blocking NF-κB signaling with its inhibitor mimicked the biological effect of PYC on Rot-induced iNOS and NO expression levels, as well as neurotoxicity in PC12 cells, suggesting that the NF-κB-iNOS signaling pathway was likely to participate in the PYC-mediated protective progress. Our results suggest that PYC protects against Rot-induced neurotoxicity in PC12 cells, and the mechanism may be associated with the downregulation of NF-κB-iNOS signaling pathway.

Long-Term Changes in Drug Craving and Nutritional Status of Opioid Addicts with Nucleus Accumbens Ablative Stereotactic Neurosurgery at Five Years Postoperatively.

BACKGROUND: The nucleus accumbens (NAcc) has been proven to be associated with drug and food craving. NAcc ablative neurosurgery has been suggested to modulate the balance of the brain reward system and thus alleviate drug dependence in patients. It has been hypothesized that it would also alleviate food craving in patients as well as altering their nutritional status. AIMS: This study aimed to estimate the effect of NAcc neurosurgery on drug craving and nutritional status in patients with drug dependence at 5 years postoperatively. METHODS: The study included 100 patients with NAcc surgery and 92 patients without surgery. Body mass index (BMI) and body fat percentage (BF%) were examined to assess nutritional status, and questionnaires were administered to assess drug craving. RESULTS: Compared with the nonsurgery group and the relapse patients from the surgery group, the nonrelapse patients from the surgery group had higher BMI and BF% but lower drug craving. There were no significant differences between the nonsurgery group and the relapse patients in BMI, but the relapse patients had higher drug craving than the nonsurgery group. CONCLUSIONS: Long-term follow-up suggested that NAcc ablative neurosurgery would alleviate drug craving and yield a better nutritional status if individuals sustained abstinence. It would increase drug craving but would not ruin the nutritional status of patients even when individuals relapsed postoperatively.

Treatment of intractable anorexia nervosa with inactivation of the nucleus accumbens using stereotactic surgery.

BACKGROUND: For 30% of anorexia nervosa (AN) patients, conventional treatments are unsuccessful; this is termed intractable AN. OBJECTIVES: This study investigates whether ablation of the nucleus accumbens (NAc) using stereotactic surgery can arouse the physiological drive to eat in intractable AN patients. METHODS: Eight patients with intractable AN were included: 6 patients underwent bilateral stereotactic radio frequency ablation in the NAc and 2 patients received bilateral NAc deep brain stimulation (DBS). Observations were made for basic vital signs, body mass index (BMI), menstruation, depression, anxiety, obsessive-compulsive disorder, personality, intelligence, memory, quality of life, social functioning, as well as complications and adverse events associated with the treatment. RESULTS: Basic vital signs, BMI and menstruation had recovered 1 year after the operation. Depression, anxiety and obsessive-compulsive disorder were improved 1 year postoperatively. There were changes in personality scores for psychoticism, neuroticism and lie tendencies that seemed to be helpful to the recovery from AN. Intelligence and memory improved after 6 months postoperatively. Quality of life and social functioning were dramatically improved at 1 year postoperatively. CONCLUSIONS: The results of this study reveal that ablation of the NAc can increase the AN patients' physiological drive to eat. Furthermore, there were no severe and/or life-influencing complications associated with the treatment.

Exosomes of BV-2 cells induced by alpha-synuclein: important mediator of neurodegeneration in PD.

Parkinson's disease (PD) is a progressive neurodegenerative disease. Alpha-synuclein aggregation, which can activate microglia to enhance its dopaminergic neurotoxicity, plays a central role in the progression of PD. However the mechanism is still unclear. To investigate how alpha-synuclein affects the neuron, exosomes were derived from alpha-synuclein treated mouse microglia cell line BV-2 cells by differential centrifugation and ultracentrifugation. We found that alpha-synuclein can induce an increase of exosomal secretion by microglia. These activated exosomes expressed a high level of MHC class II molecules and membrane TNF-α. In addition, the activated exosomes cause increased apoptosis. Exosomes secreted from activated microglias might be important mediator of alpha-synuclein-induced neurodegeneration in PD.

Nucleus accumbens surgery for addiction.

BACKGROUND: Opiate addiction remains intractable in a large percentage of patients, and relapse is the biggest hurdle to recovery because of psychological dependence. Multiple studies identify a central role of the nucleus accumbens (NAc) in addiction; several studies note decreased addictive behavior after interventions in this area. METHODS: Based on animal experiments, our institute started the clinical trial for the treatment of drug addicts' psychological dependence by making lesions in the bilateral NAc with stereotactic surgery from July 2000. RESULTS: The short-term outcomes were encouraging and triggered rapid application of this treatment in China from 2003 to 2004. However, lack of long-term outcomes and controversy eventually led to halting the surgery for addiction by the Ministry of Health of China in November 2004 and a nationwide survey about it later. Our institute had performed this surgery in 272 patients with severe heroin addiction. The follow-up study showed that the 5-year nonrelapse rate was 58% and the quality of life was significantly improved. Patients had several kinds of side effects, but the incidence rate was relatively low. The patients gradually recovered more than 5 years after the surgery. The side effects did not severely influence an individual's life or work. Nationwide surgery showed that the nonrelapse rate was 50% in the sample of 150 cases, from 1167 patients overall who underwent stereotactic surgery in China. CONCLUSIONS: Although sometimes accompanied by neuropsychological adverse events, stereotactic ablation of NAc may effectively treat opiate addiction. Lesion location has a significant impact on treatment efficacy and requires further study. Because ablation is irreversible, the NAc surgery for addiction should be performed with cautiousness, and deep brain stimulation (DBS) is an ideal alternative.

Long-term changes in the personality and psychopathological profile of opiate addicts after nucleus accumbens ablative surgery are associated with treatment outcome.

OBJECTIVE: To investigate the long-term outcome and changes of the personality and psychopathological profile of opiate addicts after bilateral stereotactic nucleus accumbens (NAc) ablative surgery. METHODS: 60 patients were followed up for 5 years and abstinent status and adverse events were evaluated. NAc lesion volumes and locations were obtained by postoperative MRI scans. The Chinese version of the Eysenck Personality Questionnaire (EPQ-RSC), the Symptom Checklist-90-Revised (SCL-90-R), the Beck Depression Inventory (BDI), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the World Health Organization's Quality of Life Questionnaire - Brief Version (WHOQOL-BREF) were administered to the patients before and 5 years after the stereotactic surgery. RESULTS: The total abstinence rate of all patients in their 5th postoperative year was 47.4%. The abstinent patients had a significantly larger lesion volume than the relapsed ones, but a larger lesion volume also increased the risk of adverse events. 5 years after surgery, the abstinent patients showed significant decreases on the Psychoticism (EPQ-P) and Neuroticism (EPQ-N) scores by EPQ-RSC, a significant decline on the Global Severity Index and the subscores in all 10 dimensions by SCL-90-R, significant decreases on the BDI and Y-BOCS scores, and significant improvements on the scores of all domains by WHOQOL-BREF, while for the relapsed patients, only the subscores of obsessive-compulsive by SCL-90-R and the Y-BOCS scores significantly decreased. Postoperative analysis revealed that the abstinent patients had a significantly better score than the relapsed ones by various instruments, and NAc lesion volumes and locations did not correlate with the outcome of any of these instruments. CONCLUSION: The bilateral ablation of NAc by stereotactic neurosurgery was a feasible method for alleviating psychological dependence on opiate drugs and preventing a relapse. Long-term follow-up suggested that surgery can improve the personality and psychopathological profile of opiate addicts with a trend towards normal levels, provided persistent abstinence can be maintained; relapse, on the other hand, may ruin this effect.

Associations between bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and anxiety in Parkinson's disease patients: a controlled study.

The authors explored the associations between subthalamic nucleus deep brain stimulation (STN-DBS) and anxiety in Parkinson's disease (PD) patients. Recent research suggests that anxiety may be one of the earliest manifestations of PD; however, the lack of a dopamine-medication control group is a major limitation of these studies. Authors paired a group of 31 bilateral STN-DBS PD patients (STN-DBS group) with 31 dopamine-medicated PD patients (Medication-control group) and used various psychological assessment scales for group evaluations. These were completed 1 month preoperatively, and 3 weeks, 5 weeks, 2 months, 4 months, 7 months, and 13 months postoperatively. As compared with the Medication group, the STN-DBS group improved in motor functioning and general status after 1 week Stimulator Power-On; State-Anxiety improved significantly at 1 week and 1 month after Stimulator Power-On, but was not significant at the subsequent time-points. Anxiety scores remained stable before 3rd-month Stimulator Power-On, but got worse after that time. In the STN-DBS group, S-AI was positively related to motor symptoms and life quality preoperatively and 4 months postoperatively, but, in the Medication group, this correlation existed throughout the study. PD-related anxiety decreased in STN-DBS patients because of the improvement in motor function for a short time; however, as the voltages and pulse-widths grew higher with time, the PD-related anxiety became worse.

Correlation of microRNA-375 downregulation with unfavorable clinical outcome of patients with glioma.

BACKGROUND AND AIM: MicroRNA-375 (miR-375) is frequently demonstrated to be frequently dysregulated and functions as a tumor suppressor or an oncogene in different cancer types. However, its roles in human gliomas have not been reported. The aim of this study was to investigate the expression pattern and clinical significance of miR-375 in patients with gliomas. METHODS: Real-time quantitative RT-PCR assay was performed to detect miR-375 expression in human gliomas and non-neoplastic brain tissues. Then, the association of miR-375 expression with clinicopathological factors and prognosis of glioma patients was also statistically analyzed. RESULTS: miR-375 expression was significantly decreased on average in glioma tissues relative to non-neoplastic brain tissues (P<0.0001) with ascending pathological grade. Then, the low miR-375 expression in glioma tissues was significantly associated with advanced pathological grade (P=0.003) and low Karnofsky performance score (KPS, P=0.01). Moreover, both univariate and multivariate Cox regression analyses determined that loss of miR-375 expression effectively predicted the decreased overall survival in patients with gliomas. CONCLUSIONS: These findings offer the first convinced evidence that the downregulation of miR-375 expression in human gliomas may play an inhibitory role during the tumor development. This miRNA might function as a candidate unfavorable prognostic marker for human gliomas.

Dopamine depletion increases the power and coherence of high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

Studies on patients with Parkinson's disease and in animal models have observed enhanced synchronization of oscillations in several frequency bands within and between the cortical-basal ganglia (BG) structures. Recent research has also shown that synchronization of high-voltage spindles (HVSs) in the cortex, striatum and substantia nigra pars reticulate is increased by dopamine depletion. However, more evidence is needed to determine whether HVS activity in the whole cortex-BG network represents homologous alteration following dopamine depletion. As the globus pallidus (GP) is in a central position to propagate and synchronize oscillations in the cortical-BG circuits, we employed local-field potentials and electrocorticogram to simultaneously record oscillations in the GP and primary (M1) and secondary (M2) motor cortices on freely moving 6-hydroxydopamine (6-OHDA) lesioned and control rats. Results showed that HVS episodes recorded from GP, and M2 and M1 cortex areas were more numerous and longer in 6-OHDA lesioned rats compared to controls. Relative power associated with HVS activity in the GP, and M2 and M1 cortices of 6-OHDA lesioned rats was significantly greater than that for control rats. Coherence values for HVS activity between the GP, and M2 and M1 cortex areas were significantly increased by dopamine depletion. Time lag between the M1 cortex HVS and GP HVS was significantly shorter for dopamine depleted than normal rats. Findings indicate a crucial rule for dopamine in the regulation of HVS activity in the whole cortical-BG circuit, and suggest a close relationship between abnormally synchronized HVS oscillations in the cortex-BG network and Parkinson's disease.

Associations between personality changes and nucleus accumbens ablation in opioid addicts.

AIM: It has been reported that nucleus accumbens (NAc) lesions can help to prevent relapse in opioid addicts. This article aimed to investigate associations between personality changes and NAc lesions. METHODS: The surgery group consisted of 78 patients who had received bilateral stereotactic lesions of the NAc to treat opioid addiction. Seventy two non-surgery opioid addicts were appropriately paired with the patients of the surgery group as the non-surgery group. All participants were interviewed in person and received urine tests, naloxone provocative tests and hair tests to determine the prevalence of relapse. Eysenck personality questionnaire (EPQ) and the health survey questionnaire (SF-36) were employed to assess personality and functional health, respectively. RESULTS: In the surgery group, 30 participants relapsed, and the non-relapse rate was 61.5% (48/78). Compared with the Chinese normative data, the neuroticism (N) and psychoticism (P) dimensions of the EPQ in the non-surgery group were significantly higher, whereas the lie (L) dimension was significantly lower. There was no significant difference in all dimensions of the EPQ between the surgery group and the Chinese normative data. The N dimension in the relapse group and the L dimension in the surgery group were significantly lower than those of the non-surgery group. The P dimension in the relapse group was significantly higher than that of the non-relapse group. The extraversion (E) dimension was relatively stable between these groups. CONCLUSION: Although the influence of other factors cannot be excluded, it is apparent that surgically induced NAc lesions are associated with lower P and N dimensions for opioid addicts, and a higher P dimension is associated with a tendency to relapse.

Activation of anterior cingulate cortex produces inhibitory effects on noxious mechanical and electrical stimuli-evoked responses in rat spinal WDR neurons.

In present study, in vivo electrophysiological techniques were applied to examine the effects of anterior cingulate cortex (ACC) activation on mechanical and electrical stimuli-evoked responses in rat spinal cord wide-dynamic-range (WDR) neurons. We found that bilateral ACC electrical stimulation (100Hz, 20V, 20s) had different effects on neuronal responses to brush, pressure and pinch stimuli (10s). The brush-evoked neuronal responses at baseline, post 1min and post 5min were 60.8±15.0, 59.2±15.4 and 60.0±19.3 spikes/10s, respectively (n=10, P>0.05 vs. baseline). The pressure-evoked neuronal responses at baseline, post 1min and post 5min were 77.8±11.9, 38.0±7.8 and 45.8±7.6 spikes/10s, respectively (n=10, P<0.05 vs. baseline). The pinch-evoked neuronal responses at baseline, post 1min and post 5min were 137.6±16.7, 62.6±17.5 and 68.8±15.0 spikes/10s, respectively (n=10, P<0.05 vs. baseline). Furthermore, ACC stimulation generated distinct effects on the different components of wind-up response. The total numbers of late response (LR) and after-discharge (AD), but not early response (ER), significantly decreased. Collectively, the present study demonstrated that short-term ACC activation could generate long-term inhibitory effects on the responses of WDR neurons to noxious mechanical (pressure and pinch) and electrical stimuli. The results indicated that ACC activation could negatively regulate noxious information ascending from spinal cord with long-term effect, providing potential neuronal substrate for the modulation of ACC activation on nociception.

Preliminary findings in ablating the nucleus accumbens using stereotactic surgery for alleviating psychological dependence on alcohol.

We studied the effect of stereotactic surgery in cases of alcohol dependence. Twelve patients with a psychological dependence on alcohol (treated systematically with medication for detoxification 3-8 times in various rehabilitation centers before, but had relapsed within 2 weeks after withdrawal) were treated by ablating the nucleus accumbens (NA(C)) bilaterally using stereotactic surgery. The therapeutic effect and safety evaluation index of the surgery were analyzed. The timing of the conducted evaluations was preoperatively and in the sixth postoperative month. Currently, relapse has not occurred in 9 cases. Relapse occurred in 3 cases after surgery. The prevalence of relapse was 16.7% within 6 months, and 25% within 12 months. Non-specific complications of this type of surgery (e.g., intracranial hematoma, infection) were not observed. One case in 12 patients suffered dysosmia, but he recovered completely 4 months later after surgery. The full-scale intelligence quotient (FSIQ) and memory quotient (MQ) of these patients were significantly improved 6 months postoperatively compared with preoperatively. The severity of alcohol dependence scale and a scale measuring alcohol craving in these patients were significantly decreased. There were also significant changes over time in the Minnesota multiphasic personality inventory (MMPI) profile, suggesting a decrease in depression, irritability, and psychopathy. Ablating specified targets (NA(C)) using stereotactic surgery is a safe method to alleviate alcohol craving, reduce relapse rates and improve quality-of-life in patients with psychological dependence on alcohol.

Correlations between angiotensinase activity asymmetries in the brain and paw preference in rats.

The function of angiotensin peptides is dependent upon the action of several aminopeptidases (APs) termed angiotensinases. Soluble (SOL) and membrane (MEM)-bound alanyl-AP (AlaAP) and cystinyl-AP (CysAP) are involved in the metabolism of angiotensins and related to the modulation of behavior and memory. To study the interactions between angiotensinase activity in the hippocampus and behavioral lateralization, Wistar rats were selected on the basis of their performance in the paw preference test (left-handed, ambidextrous and right-handed) and the activities of SOL-AlaAP/CysAP and MEM-AlaAP/CysAP were measured in the both hippocampuses. We observed that: (1) the left hippocampus had higher activities of SOL-AlaAP/CysAP and MEM-AlaAP/CysAP than the right hippocampus; (2) rats showed significant differences in the activities of SOL-AlaAP/CysAP and MEM-AlaAP/CysAP in the hippocampus depending on the behavioral lateralization detecting by paw preference; (3) in three groups of rats, hemispheric dominance - %R/T [%R/T=right hemisphere/(right hemisphere+left hemisphere)x100] activities of MEM-AlaAP, SOL-CysAP and MEM-CysAP was significantly different whereby %RT was lower in left-handed, higher in ambidextrous and intermediate in right-handed rats; (4) individual %R/T activities of SOL-CysAP and MEM-CysAP in the hippocampus were positively correlated with paw preference scores. Finally, we used the passive avoidance behavior test to demonstrate the differences of long-term memory among the three groups. These results suggested that the asymmetric activity of angiotensinase in the rat hippocampus may be associated with both the direction and the intensity of behavioral lateralization as expressed by paw preference.

Long-term effects of bilateral deep brain stimulation of the subthalamic nucleus on depression in patients with Parkinson's disease.

OBJECTIVE: To study the long-term effects of deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) on depression in patients with Parkinson's disease (PD) and to discuss the mechanism. METHODS: A STN-DBS group (n = 27) and anti-Parkinson's medication control group with paired designing were set up. The evaluation of the depression and motor function was performed a total of six times. Depression was evaluated by the Self-Rating Depression Scale (SDS) and Hamilton Rating Scale for Depression (HAMD). Motor function was evaluated by the third part of the Unified Parkinson's Disease Rating Scale (UPDRS-III). RESULTS: Compared with the preoperative and the medication control group, the UPDRS-III scores of the STN-DBS group decreased remarkably within 18 months postoperatively (P < or = 0.001), and the SDS scores decreased notably within 6 months postoperatively (P < or = 0.05), and the HAMD scores decreased notably within 3 months postoperatively (P < or = 0.05). The UPDRS-III scores were strongly correlated with their SDS scores within 6 months postoperatively (P < or = 0.05), especially at 5 weeks postoperation (P < or = 0.001). UPDRS-III scores were also strongly correlated with HAMD scores at 5 weeks postoperation (P < or = 0.05). The mean value of the bilateral voltages was obviously correlated with SDS and HAMD scores (P < or = 0.05) within 18 months postoperatively. CONCLUSION: The improvement in motor symptoms resulting from STN-DBS can improve depression in PD patients, but its long-term effects were unremarkable. Within the treatment range, the higher the mean value of bilateral voltages then the more severe was the depression in PD patients.

Potentiation of inhibitory amino acid receptors-mediated responses by lanthanum in rat sacral dorsal commissural neurons.

Lanthanum is one of rare earth cations with extremely active chemical property and has been reported to influence neuronal transmitter systems. To date, little attention has been directed towards the sacral dorsal commissural nucleus (SDCN), which serves as a relay of sensory information from the pelvic viscera in the spinal cord. Therefore, the effect of lanthanum on the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and glycine (Gly) responses in neurons acutely dissociated from the rat SDCN was investigated using the nystatin-perforated patch-recording configuration under voltage-clamp conditions. At a holding potential of -40 mV, La(3+) reversibly potentiated GABA (3 microM)-activated currents (I(GABA)) in a concentration-dependent manner over the concentration range of 10 microM to 30 mM, with the EC(50) value of 67.3+/-16.4 microM. Similarly, La(3+) reversibly potentiated glycine (10 microM)-activated currents (I(Gly)) in a concentration-dependent manner over the concentration range of 1 microM to 1 mM, with the EC(50) value of 52.3+/-10.9 microM. The effects of La(3+) on I(GABA) and I(Gly) were voltage-independent. Moreover, both of the potentiations were not use-dependent and were overcome by increasing the concentration of agonist. Our results indicate that La(3+) potentiates the inhibitory amino acid receptors-mediated responses in SDCN, which may reduce the transmission of the pelvic visceral information. The information provided by this work may help to elucidate the mechanisms and effects of lanthanum on brain functions.