Journal of Neural Transmission-supplement最新文献

Neural stem cell (NSC) transplantation has been investigated and developed in areas such as brain injury, stroke and neurodegenerative diseases. Recently, emerging evidence suggest that many of clinical symptoms observed in psychiatric disease are likely related to neural network disruptions including neurogenesis dysfunction. In the present study, we transplanted NSCs into a model of fetal alchol effects (FAE) for the purpose of investigating the possibility of regenerative therapy for the FAE. We labeled NSCs with fluorescent dye and radioisotope which were transplanted into FAE rats by intravenous injection. The transplanted cells were detected in wide areas of brain and were greater in number in the brains of the FAE group compared to the control group. Furthermore NSC transplantation attenuated behavioral abnormalities in FAE animals. These results suggest NSC transplantation as a potental new therapy for human FAE.

The gaseous messenger nitric oxide (NO) has been implicated in a wide range of behaviors, including aggression, anxiety, depression, and cognitive functioning. To further elucidate the physiological role of NO and its down-stream mechanisms, we conducted behavioral and expressional phenotyping of mice lacking the neuronal isoform of nitric oxide synthase (NOS-I), the major source of NO in the central nervous system. No differences were observed in activity-related parameters; in contrast to the a priori hypothesis, derived from pharmacological treatments, depression-related tests (Forced Swim Test, Learned Helplessness) also yielded no significantly different results. A subtle anxiolytic phenotype however was present, with knockdown mice displaying a higher open arm time as compared to their respective wildtypes, yet all other investigated anxiety-related parameters were unchanged. The most prominent feature however was gender-independent cognitive impairment in spatial learning and memory, as assessed by the Water Maze test and an automatized holeboard paradigm. No significant dysregulation of monoamine transporters was evidenced by qRT PCR. To further examine the underlying molecular mechanisms, the transcriptome of knockdown animals was thus examined in the hippocampus, striatum and cerebellum by microarray analysis. A set of >120 differentially expressed genes was identified, whereat the hippocampus and the striatum showed similar expressional profiles as compared to the cerebellum in hierarchical clustering. Among the most significantly up-regulated genes were Peroxiredoxon 3, Atonal homologue 1, Kcnj1, Kcnj8, CCAAT/enhancer binding protein (C/EBP), alpha, 3 genes involved in GABA(B) signalling and, intriguingly, the glucocorticoid receptor GR. While GABAergic genes might underlie reduced anxiety, dysregulation of the glucocorticoid receptor can well contribute to a blunted stress response as found in NOS1 knockdown mice. Furthermore, by CREB inhibition, glucocorticoid receptor upregulation could at least partially explain cognitive deficits in these animals. Taken together, NOS1 knockdown mice display a characteristic behavioural profile consisting of reduced anxiety and impaired learning and memory, paralleled by differential expression of the glucocorticoid receptor and GABAergic genes. Further research has to assess the value of these mice as animal models e.g. for Alzheimer's disease or attention deficit disorder, in order to clarify a possible pathophysiological role of NO therein.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction, increased oxidative stress and elevated apoptosis. Until now, AD cannot be diagnosed by a valid clinical method or a biomarker before the disease has progressed so far that dementia is present. Furthermore, no valid method is available to determine which patient with mild cognitive impairment (MCI) will progress to AD. Therefore, a correct diagnosis in the early stage of AD is not only of importance considering that early drug treatment is more effective but also that the psychological burden of the patients and relatives could be decreased. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as biomarker for AD in a peripheral cell model, the lymphocytes.

Background: High variability of estimates of cognitive decline in patients with Alzheimer's disease (AD) derived from unbalanced longitudinal designs may result as much from the applied statistical model as from true biological variability.

Objective: To compare the accuracy of two statistical models, serial subtraction score (SSA) and mixed-effects regression analysis (MEM), to estimate rates of cognitive decline in patients with amnestic mild cognitive impairment (MCI), a group at risk for AD.

Methods: We recorded serial mini mental state examination (MMSE) scores from 78 MCI patients. Additionally, we derived simulated trajectories of cognitive decline with unequally spaced observation intervals. Rates of change were assessed from clinical and simulated data using SSA and MEM models.

Results: MEM reduced variability of rates of change significantly compared to SSA. In a polynomial model, overall length of observation time explained a significant amount of variance of SSA, but not of MEM estimates. For simulated data, MEM was significantly more accurate in predicting true rates of change compared to SSA (p < 0.001).

Conclusion: MEM yields more accurate estimates of cognitive decline from unbalanced longitudinal data. Simulation studies may be useful to select the appropriate statistical model for a given set of clinical data.

Ideally, animal models of neurodegenerative diseases should reproduce the clinical manifestation of the disease and a selective neuronal loss. In this review we will take as an example Parkinson's disease because its pathophysiology is well known and the neuronal loss well characterized. Indeed, Parkinson's disease is characterized by a loss of some but not all dopaminergic neurons, a loss of some non dopaminergic neurons and alpha-synuclein positive inclusions resembling Lewy bodies. There are at least two ways to develop animal models of PD based on the etiology of the disease and consist in 1) reproducing in animals the mutations seen in inherited forms of PD; 2) intoxicating animals with putative environmental toxins causing PD. In this review we discuss the advantages and the drawbacks in term of neuroproction of the currently used models.

In Parkinson's and other neurodegenerative diseases, a therapeutic strategy has been proposed to halt progressive cell death. Propargylamine derivatives, rasagiline and (-)deprenyl (selegiline), have been confirmed to protect neurons against cell death induced by various insults in cellular and animal models of neurodegenerative disorders. In this paper, the mechanism and the markers of the neuroprotection are reviewed. Propargylamines prevent the mitochondrial permeabilization, membrane potential decline, cytochrome c release, caspase activation and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase. At the same time, rasagiline induces anti-apoptotic pro-survival proteins, Bcl-2 and glial cell-line derived neurotrophic factor, which is mediated by activated ERK-NF-kappaB signal pathway. DNA array studies indicate that rasagiline increases the expression of the genes coding mitochondrial energy synthesis, inhibitors of apoptosis, transcription factors, kinases and ubiquitin-proteasome system, sequentially in a time-dependent way. Products of cell survival-related gene induced by propargylamines may be applied as markers of neuroprotection in clinical samples.

Methylphenidate (MPH) is a centrally acting (psycho)stimulant which reversibly blocks the dopamine re-uptake transporter. At present MPH is one of the most frequently prescribed drugs for the symptomatic treatment of attention deficit hyperactivity disorder (ADHD). Although MPH has been in use for about 50 years, there is no information available concerning the long-term benefits and risks of medication. Based on experiments in rats it has been suggested that MPH treatment may affect the maturation of central dopaminergic systems and may be a risk factor for the development of Parkinson's disease (PD). The aim of the present case-control study was to gain information about (1) ADHD-like symptoms that may precede PD motor symptoms, and (2) the exposure to psychostimulants in childhood. We used a German short version of the Wender Utah Rating Scale (WURS-k, Retz-Junginger et al., 2002) which is a reliable measure for the retrospective diagnosis of childhood ADHD, and another questionnaire including a rating scale for symptoms of ADHD in childhood (Q-ADHD-Child) according to DSM-IV and ICD-10 criteria. A total of 92 patients with PD and 115 control subjects were enrolled in this study. Ninety-six percentage of PD patients (N = 88) completed the two rating scales. The data of these patients and of 88 randomly selected individuals of the controls were included for analysis. In the WURS-k, the PD group showed higher total scores compared to control subjects. In addition, we found increased scores in PD patients regarding the items attention deficit, hyperactivity and anxious and depressive symptoms, but not regarding impulsivity, oppositional behaviour and deficits in social adaptation. The results of the Q-ADHD-Child also showed increased scores in PD patients regarding attention deficit and hyperactivity. However, one cannot conclude that the PD patients enrolled in this study had suffered from childhood ADHD, since the average total WURS-k score of (14.4) was far below the cut-off score of 30 or higher which is considered to identify childhood ADHD. Finally, we found no evidence that PD patients had been exposed to psychostimulants such as MPH and amphetamine.

A retrospective study of a 50-year autopsy series of 900 patients with the clinical diagnosis of parkinsonism (31.2% with dementia) revealed pure Lewy body disease (LBD) in 84.9%, but only 44.7% with idiopathic Parkinson disease (PD); 16% were associated with cerebrovascular lesions, 14.8% with Alzheimer pathology; 8.9% were classified dementia with Lewy bodies (DLB), 9.4% showed other degenerative disorders, and 5.6% other/ secondary parkinsonian syndromes. The frequency of LBD during different periods was fairly stable, with increase of DLB and PD plus Alzheimer changes, but decrease of associated cerebrovascular lesions during the last decades. Using variable clinical diagnostic criteria not only by specified neurologists, the misdiagnosis rate ranged from 11.5 to 23% and was similar to that in most previous clinico-pathological studies. The majority of cases with false clinical diagnosis of PD had a final pathological diagnosis of DLB with or without Alzheimer lesions. A postmortem series of 330 elderly patients clinically diagnosed as parkinsonism with (37.6%) and without dementia showed that IPD, Braak stages 3-5 were rarely associated with cognitive impairment, which was frequently seen in IPD with associated Alzheimer pathology (35.5%), DLB (33.9%), and in Alzheimer disease (AD) or mixed dementia (17%), whereas it almost never was associated with minor cerebrovascular lesions. Clinico-pathological studies in DBL, demented and nondemented PD, and AD cases showed a negative relation between cognitive impairment and Alzheimer changes, suggesting that these either alone or in combination with cortical Lewy body pathologies are major causes of cognitive dysfunction. Further prospective clinico-pathological studies are needed to validate the currently used clinical criteria for PD, to increase the diagnostic accuracy until effective biomarkers are available, and to clarify the impact of structural and functional changes on cognitive function in parkinsonism as an ultimate goal of early disease detection and effective treatment.

In Parkinson's disease clinical and experimental evidence suggest that neuroinflammatory changes in cytokines caused by microglial activation contribute to neuronal death. Experimentally, neuroinflammation of dopaminergic neurons can be evoked by lipopolysaccharide (LPS) exposure. In mesencephalic primary cultures LPS (100 microg/ml) resulted in 30-50% loss of dendritic processes, changes in the perikarya, cellular atrophy and neuronal cell loss of TH-immunoreactive (TH+) cells. iNOS activity was increased dose dependently as well as prostaglandin E2 concentrations. Ginsenosides, as the active compounds responsible for ginseng action, are reported to have antioxidant and anti-inflammatory effects. Here ginsenoside Rd was used to counteract LPS neurodegeneration. Partial reduction of LPS neurotoxic action was seen in dopaminergic neurons. Cell death by LPS as well as neuroprotective action by ginsenoside Rd was not selective for dopaminergic neurons. Neuronal losses as well as cytoprotective effects were similar when counting NeuN identified neurons. The anti-inflammatory effect of ginsenoside Rd could equally be demonstrated by a reduction of NO-formation and PGE2 synthesis. Thus, protective mechanisms of ginsenoside Rd may involve interference with iNOS and COX-2 expression.

Abnormal glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. In the present study we investigated two potential neuronal glutamatergic markers, the Excitatory Amino Acid Transporter 3 (EAAT3) and the Vesicular Glutamate Transporter 1 (VGluT1), in post-mortem striatal tissue from control subjects and from subjects with schizophrenia (n = 15 per group). We also investigated the possible influence of chronic antipsychotic administration (typical and atypical) on striatal VGluT1 expression in the rat brain. We found deficits in EAAT3 in all striatal regions examined in schizophrenia when compared to controls. Following correction for confounding factors (post-mortem interval), these deficits only remained significant in the caudate nucleus (p = 0.019). We also found significant deficits in VGluT1 in the caudate nucleus (p = 0.009) in schizophrenia. There were no significant differences in VGluT1 in the striatum of antipsychotic treated rats when compared to their vehicle treated controls. The data provides additional evidence for a glutamatergic synaptic pathology in the caudate nucleus in schizophrenia and may reflect a loss of glutamatergic cortico-striatal pathways. The absence of an effect of antipsychotic administration on VGluT1 indicates that the deficits in schizophrenia are unlikely to be a consequence of pharmacotherapy and thus likely to be a correlate of the disease process.