Can overexpression of parkin provide a novel strategy for neuroprotection in Parkinson's disease?

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by selective degeneration of the dopamine producing neurons in the substantia nigra. There is currently no clinically applicable therapy for treating or preventing Parkinsonian neurodegeneration. Great effort is put behind the development of novel therapeutic approaches that aim to alter the natural progression of the disease. For example, a disease-modifying strategy based on the use of glial cell line-derived neurotrophic factor family of ligands have yielded successful results in animal models and later in initial clinical trials. More recently, identification of the gene mutations underlying the familial forms of the disease opened new frontiers in tackling the underlying neuropathological changes seen in PD brains. Overexpression of parkin, in particular, emerged as a powerful approach with complementary effects to those described with use of neurotrophic factors. In light of the fact that the mechanism of disease in the affected patient population might be significantly variable, the ability to intervene the disease process at multiple levels should be seen as a key point in devising effective treatments.     

Estrogen/Huntingtin：a novel pathway involved in neuroprotection

正Neurodegenerative diseases(NDs)include more than 600 disease entities that are characterized by loss of specific neurons located in anatomically related functional areas which progressively lead to motor and cognitive deficits.The pathogenesis of NDs involves mitochondrial dysfunction/oxidative stress,programmed cell death or abnormal protein aggregation,trafficking,and/or degradation.In most cases,the end stage     

ΔN-Bcl-xL,a therapeutic target for neuroprotection

The B-cell lymphoma-extra large(Bcl-x L) is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-x L undergoes caspase-dependent cleavage and produces a fragmented form, ΔN-Bcl-x L. Accumulation of ΔN-Bcl-x L is associated with mitochondrial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of ΔN-Bclx L protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor ABT-737 exerts dose dependent effects in primary neurons. When primary hippocampal neurons were treated with 1 μM ABT-737, glutamate-mediated mitochondrial damage and neuronal death were exacerbated, whereas 10 n M ABT-737, a 100-fold lower concentration, protected mitochondrial function and enhanced neuronal viability against glutamate toxicity. In addition, we suggested acute vs. prolonged formation of ΔN-Bcl-x L may have different effects on mitochondrial or neuronal functions. Unlike acute production of ΔN-Bcl-x L by glutamate, overexpression of ΔN-Bcl-x L did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for ΔN-Bcl-x L-mediated mitochondrial dysfunction. Although the detailed mechanism of ABT-mediated neurotoxicity neuroprotection is still unclear, our study shows that the mitochondrial membrane protein ΔN-Bcl-x L is a central target for interventions.     

Encapsulated cell biodelivery of GDNF: a novel clinical strategy for neuroprotection and neuroregeneration in Parkinson's disease?

The main pathology underlying disease symptoms in Parkinson's disease (PD) is a progressive degeneration of nigrostriatal dopamine (DA) neurons. No effective disease-modifying treatment currently exists. Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective and neuroregenerative effects and it enhances dopaminergic function in animal models of PD. These findings raise the possibility that intrastriatal administration of GDNF might be developed into a new clinical strategy for functional preservation and restoration also in PD patients. Gene therapy is a novel tool to increase local levels of GDNF. Transplantation of encapsulated, GDNF-secreting cells is one strategy for ex vivo cell-based gene delivery which has the advantage to allow for removal of the cells if untoward effects occur. Here we summarize studies with such cells in animals, and discuss the results from previous trials with GDNF in PD patients and their implications for the further development of neuroprotective/neuroregenerative therapies. Finally, we describe the different scientific and regulatory issues that need to be addressed in order to reach the clinic and start the first trial in patients.     

In search for novel strategies towards neuroprotection and neuroregeneration: is PPARα a promising therapeutic target?

<正>Peroxisome proliferator activated receptors:In the early1990s,seminal work on rodent liver demonstrated that the hypolipidemic effect of xenobiotics,referred to as peroxisome proliferators,was mediated by a member of steroid hormone receptor superfamily,thus designated peroxisome proliferator-activated receptors(PPARs)(Issemann and     

PPARα serves as a new receptor of aspirin for neuroprotection

Acetyl salicylic acid, commonly known as aspirin, has been being widely used as an anti-inflammatory drug for almost 100 years. However, there was no receptor known for this popular drug. Recently, we have established that peroxisome proliferator-activated receptor alpha (PPARα) acts as a novel receptor of aspirin. Activation of PPARα by aspirin stimulated a series of downstream signaling pathways that could potentially ameliorate different Alzheimer's disease (AD)-related pathologies. In this mini-review, we have discussed how aspirin–PPARα interaction plays a pivotal role in the amelioration of AD pathology via the stimulation of neurotrophic factors, upregulation of plasticity-associated genes, and removal of plaque burden in hippocampal neurons.     

Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients

Vagus nerve stimulation (VNS) is an established tool in the psychiatric armamentarium for patients with therapy-resistant depression (TRD) with response rates of approximately 60%. So far, VNS is titrated slowly during ambulatory in-office visits. Thus, antidepressive effects can be expected after approximately six months.We report our experiences with a rapid dosing regime (RDR) with titration start shortly after VNS-implantation. We retrospectively analysed data of six patients with TRD who received VNS. Stimulation parameters were evaluated with regard to clinical side effects, heart rates (HR) and blood pressures (BP). Depressive symptoms were measured by Montgomery-Asberg Depression Rating Scale (MADRS) one week before and three months after implantation of the VNS.All patients received first stimulation between one and four days after surgery. We elevated output current using 0.25 mA titration steps. We increased output current between one and four days after the last titration. All patients received 1.0 mA output current after eight to 14 days post-surgery. HR and BP remained stable in all patients. All side effects were mild and temporary. MADRS scores were significantly lower three months after VNS-implantation (24 ± 8) than one week before VNS-implantation (42 ± 4; p = 0.028).The therapeutic range of VNS-parameters for antidepressive effect was reached quicker without finding increased numbers of side effects. Consequently, by using RDR the antidepressive effect of VNS-therapy for patients with TRD could be reached earlier than using slow titration. Our presented RDR might be able to significantly shorten the “clinical effect gap” due to the neurobiological and titration-related latency.     

Becoming kink-aware – a necessity for sexuality professionals

Bondage and discipline (B/D), dominance and submission (D/s), and sadism and masochism (S/M), also known as BDSM/kink, is becoming an increasingly popular topic in both mainstream media and people's sexual lives. As such, it is vital for sexuality professionals to have an understanding of BDSM and training in working with clients, over and above the current requirements. We present a three part training program which utilizes Sexual Attitude Reassessments (SARS), independent reading, and skills development through supervision, which will ensure that sexuality professionals are more than simply “kink-friendly” but are highly trained and able to help clients navigate concerns with kink and BDSM relationships.     

Normative needs for care of schizophrenics: a useful concept for community psychiatric planning?

One step in a public health research project focuses on the analysis of the individual (expert-based) normative needs for mental health care of chronic schizophrenic patients (n = 115) in the Dresden Region during the first year post hospital release and the extent to which this can be met by the current established level of complementary care. It is an exemplary contribution to the evaluation of community psychiatry as restructured in the Free State of Saxony following German reunification. The results of the study can be condensed to the following interpreting essential statements. Schizophrenics' normative needs for care are not a statistical issue. The single case analysis corroborates a high rate of relevant fluctuations, above all within the clinical sector (e.g. concerning "dyskinesias and other side effects"), that pose a particular challenge to the flexibility of a system of community psychiatry. This includes that the consequence for the practice of care implies then that when diagnosing course, attention must be paid to shifts in the content of the needs for mental health care (e.g. increasing importance of factors, which contain impairments of basic social competences) in order to orient to them any health care measures already initiated.--With the aid of the used research instrument (Needs for Care Assessment) deficits in meeting the needs for care can be identified. In the Dresden Region considerable deficits persist apparently in the subsections recreational activities and occupational and communication skills, which can be ascribed to the lack of appropriate institutions of care in the area.--The normative needs for care of schizophrenic patients cannot be determined simply on the basis of a few, quickly identifiable markers. Rather it demands individualized analysis incorporating variables pertaining to psychopathology, subjective coping, social competence and the course of the disorder. The development of the needs for care over the period of one year can apparently be predicted by trends in the social sector that are already visible within the first months. With regard to aspects of care planning this finding illustrates the limited ability of cross-section surveys to make definitive statements, as well as the predominance of social disabilities over the entire spectrum of the normative needs for psychiatric care.     

Exosomes: a novel therapeutic target for Alzheimer's disease?

Extracellular exosomes are formed inside the cytoplasm of cells in compartments known as multivesicular bodies. Thus, exosomes contain cytoplasmic content. Multivesicular bodies fuse with the plasma membrane and release exosomes into the extracellular environment. Comprehensive research suggests that exosomes act as both inflammatory intermediaries and critical inducers of oxidative stress to drive progression of Alzheimer's disease. An important role of exosomes in Alzheimer's disease includes the formation of neurofibrillary tangles and beta-amyloid production, clearance, and accumulation. In addition, exosomes are involved in neuroinflammation and oxidative stress, which both act as triggers for beta-amyloid pathogenesis and tau hyperphosphorylation. Further, it has been shown that exosomes are strongly associated with beta-amyloid clearance. Thus, effective measures for regulating exosome metabolism may be novel drug targets for Alzheimer's disease.     

Is progesterone a worthy candidate as a novel therapy for traumatic brain injury?

Although progesterone is critical to a healthy pregnancy, it is now known to have other important functions as well. Recent research demonstrates that this hormone is also a potent neurosteroid that can protect damaged cells in the central and peripheral nervous systems and has rapid actions that go well beyond its effects on the classical intranuclear progesterone receptor. Based on years of preclinical research demonstrating its safety and effectiveness in animal models of central nervous system injury the hormone was recently tested in two Phase II clinical trials for traumatic brain injury (TBI). A US National Institutes of Health-sponsored, nationwide Phase III clinical trial is now evaluating progesterone for moderate-to-severe TBI in 1200 patients. An industry-sponsored Phase III international trial is also under way, and planning for a trial using progesterone to treat pediatric brain injury has begun. Preclinical data suggest that progesterone may also be effective in stroke and some neurodegenerative disorders.     

Is the neocortex a novel reservoir for adult mammalian neurogenesis?

A novel population of cells expressing typical markers of immature neurons,such as doublecortin-positive cells,was recently identified.This population was predominantly located in layer II of the adult cerebral cortex of relatively large mammals.These cells appear to maintain an immature phenotype for a protracted time window,suggesting a lifelong role in cortical plasticity under normal physiological conditions,and possibly under pathological conditions as well.This review discusses recent evidence regarding the detailed features of these unique cells,including their distribution,morphology,fate,temporal and spatial origin,as well as their relevance and possible functions in various physiological and pathological conditions.In addition,we review studies that have produced conflicting results,possibly as a result of discrepancies in the methodology used to detect neurogenesis.In theory,the properties of these cells indicate that they might exert a significant impact on neocortical function,informing potential therapeutic strategies designed to induce endogenous neurogenesis in the treatment of neuropathological diseases.     

Neuronal mdr-1 gene expression after experimental focal hypoxia: a new obstacle for neuroprotection?

Neuronal damage after stroke-associated brain hypoxia is a leading cause of long-term disability and death. The refractoriness to therapeutic strategies for neuroprotection after 3 h post brain ischemia is poorly understood. P-glycoprotein (P-gp), the multidrug resistance gene (MDR-1) product is normally expressed at blood-brain-barrier. P-gp neuronal expression has been demonstrated in refractory epilepsy and after brain ischemia. In this report we investigated the hypoxia-induced neuronal P-gp expression after local injection of CoCl(2) (1-200 mM) in the fronto-parietal cortex of male adult rats (Bregma -1.30 mm) by stereotaxic surgery. P-gp immunostaining of brain slides was analyzed using specific monoclonal antibodies and double immunolabeling was done with specific astrocytic and neuronal markers. Five days after injection of 1 mM CoCl(2), P-gp expression surrounding the lesion site was observed in neurons, astrocytic end-foot on capillary blood vessels and endothelial cells on blood vessels. Higher CoCl(2) doses (200 mM) resulted in additional P-gp immunostaining of the entire astrocytic and neuronal cytoplasm. Electron microscopy (EM) studies showed alterations in neurons as early as 6 h after the CoCl(2) injection. P-gp expression in hypoxic neurons and astrocytic end-foot could potentially impair of drugs access to the brain parenchyma thus suggesting the presence of two P-gp-based pumping systems (one in astrocytes and other in the hypoxic neurons) that are able to behave as a previously unnoticed obstacle for pharmacological strategies of neuroprotection.