NADPH Oxidase and Neurodegeneration

NADPH oxidase (Nox) is a unique, multi-protein, electron transport system that produces large amounts of superoxide via the reduction of molecular oxygen. Nox-derived reactive oxygen species (ROS) are known to be involved in a variety of physiological processes, including host defense and signal transduction. However, over the past decade, the involvement of (Nox)-dependent oxidative stress in the pathophysiology of several neurodegenerative diseases has been increasingly recognized. ROS produced by Nox proteins contribute to neurodegenerative diseases through distinct mechanisms, such as oxidation of DNA, proteins, lipids, amino acids and metals, in addition to activation of redox-sensitive signaling pathways. In this review, we discuss the recent literature on Nox involvement in neurodegeneration, focusing on Parkinson and Alzheimer diseases.

Different approaches, one target: understanding cellular mechanisms of Parkinson's and Alzheimer's diseases

Neurodegenerative disorders are undoubtedly an increasing problem in the health sciences, given the increase of life expectancy and occasional vicious life style. Despite the fact that the mechanisms of such diseases are far from being completely understood, a large number of studies; that derive from both the basic science and clinical approaches have contributed substantial data in that direction. In this review, it is discussed several frontiers of basic research on Parkinson's and Alzheimer's diseases, in which research groups from three departments of the Institute of Biomedical Sciences of the University of Sao Paulo have been involved in a multidisciplinary effort. The main focus of the review involves the animal models that have been developed to study cellular and molecular aspects of those neurodegenerative diseases, including oxidative stress, insulin signaling and proteomic analyses, among others. We anticipate that this review will help the group determine future directions of joint research in the field and, more importantly, set the level of cooperation we plan to develop in collaboration with colleagues of the Nucleus for Applied Neuroscience Research that are mostly involved with clinical research in the same field.

Microglial cells are involved in the susceptibility of NADPH oxidase knockout mice to 6-hydroxy-dopamine-induced neurodegeneration

We explored the impact of Nox-2 in modulating inflammatory-mediated microglial responses in the 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD) model. Nox1 and Nox2 gene expression were found to increase in striatum, whereas a marked increase of Nox2 expression was observed in substantia nigra (SN) of wild-type (wt) mice after PD induction. Gp91phox-/- 6-OHDA-lesioned mice exhibited a significant reduction in the apomorphine-induced rotational behavior, when compared to wt mice. Immunolabeling assays indicated that striatal 6-OHDA injections reduced the number of dopaminergic (DA) neurons in the SN of wt mice. In gp91phox-/- 6-OHDA-lesioned mice the DA degeneration was negligible, suggesting an involvement of Nox in 6-OHDA-mediated SN degeneration. Gp91phox-/- 6-OHDA-lesioned mice treated with minocycline, a tetracycline derivative that exerts multiple anti-inflammatory effects, including microglial inhibition, exhibited increased apomorphine-induced rotational behavior and degeneration of DA neurons after 6-OHDA injections. The same treatment also increased TNF-α release and potentiated NF-κB activation in the SN of gp91phox-/--lesioned mice. Our results demonstrate for the first time that inhibition of microglial cells increases the susceptibility of gp91phox-/- 6-OHDA lesioned mice to develop PD. Blockade of microglia leads to NF-κB activation and TNF-α release into the SN of gp91phox-/- 6-OHDA lesioned mice, a likely mechanism whereby gp91phox-/- 6-OHDA lesioned mice may be more susceptible to develop PD after microglial cell inhibition. Nox2 adds an essential level of regulation to signaling pathways underlying the inflammatory response after PD induction

Effect of Nintendo Wii (TM)-based motor and cognitive training on activities of daily living in patients with Parkinson's disease: A randomised clinical trial

Objectives To investigate the effect of Nintendo Wii (TM)-based motor cognitive training versus balance exercise therapy on activities of daily living in patients with Parkinson's disease. Design Parallel, prospective, single-blind, randomised clinical trial. Setting Brazilian Parkinson Association. Participants Thirty-two patients with Parkinson's disease (Hoehn and Yahr stages 1 and 2). Interventions Fourteen training sessions consisting of 30 minutes of stretching, strengthening and axial mobility exercises, plus 30 minutes of balance training. The control group performed balance exercises without feedback or cognitive stimulation, and the experimental group performed 10 Wii Fit (TM) games. Main outcome measure Section II of the Unified Parkinson's Disease Rating Scale (UPDRS-II). Randomisation Participants were randomised into a control group (n = 16) and an experimental group (n = 16) through blinded drawing of names. Statistical analysis Repeated-measures analysis of variance (RM-ANOVA). Results Both groups showed improvement in the UPDRS-II with assessment effect (RM-ANOVA P < 0.001, observed power = 0.999). There was no difference between the control group and the experimental group before training {8.9 [standard deviation (SD) 2.9] vs 10.1 (SD 3.8)}, after training [7.6 (SD 2.9) vs 8.1 (SD 3.5)] or 60 days after training [8.1 (SD 3.2) vs 8.3 (SD 3.6)]. The mean difference of the whole group between before training and after training was -0.9 (SD 2.3, 95% confidence interval -1.7 to -0.6). Conclusion Patients with Parkinson's disease showed improved performance in activities of daily living after 14 sessions of balance training, with no additional advantages associated with the Wii-based motor and cognitive training. Registered on http://www.clinicaltrials.gov (identifier: NCT01580787). (C) 2012 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

The interaction of postural and voluntary strategies for stability in Parkinson's disease

de Lima-Pardini AC, Papegaaij S, Cohen RG, Teixeira LA, Smith BA, Horak FB. The interaction of postural and voluntary strategies for stability in Parkinson's disease. J Neurophysiol 108: 1244-1252, 2012. First published June 6, 2012; doi:10.1152/jn.00118.2012.-This study assessed the effects of stability constraints of a voluntary task on postural responses to an external perturbation in subjects with Parkinson's disease (PD) and healthy elderly participants. Eleven PD subjects and twelve control subjects were perturbed with backward surface translations while standing and performing two versions of a voluntary task: holding a tray with a cylinder placed with the flat side down [low constraint (LC)] or with the rolling, round side down [high constraint (HC)]. Participants performed alternating blocks of LC and HC trials. PD participants accomplished the voluntary task as well as control subjects, showing slower tray velocity in the HC condition compared with the LC condition. However, the latency of postural responses was longer in the HC condition only for control subjects. Control subjects presented different patterns of hip-shoulder coordination as a function of task constraint, whereas PD subjects had a relatively invariant pattern. Initiating the experiment with the HC task led to 1) decreased postural stability in PD subjects only and 2) reduced peak hip flexion in control subjects only. These results suggest that PD impairs the capacity to adapt postural responses to constraints imposed by a voluntary task.

Subthalamic deep brain stimulation modulates small fiber-dependent sensory thresholds in Parkinson's disease

The effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms of Parkinson's disease (PD) rarely have been investigated. Among these, sensory disturbances, including chronic pain (CP), are frequent in these patients. The aim of this study was to evaluate the changes induced by deep brain stimulation in the perception of sensory stimuli, either noxious or innocuous, mediated by small or large nerve fibers. Sensory detection and pain thresholds were assessed in 25 PD patients all in the off-medication condition with the stimulator turned on or off (on- and off-stimulation conditions, respectively). The relationship between the changes induced by surgery on quantitative sensory testing, spontaneous CP, and motor abilities were studied. Quantitative sensory test results obtained in PD patients were compared with those of age-matched healthy subjects. Chronic pain was present in 72% of patients before vs 36% after surgery (P = .019). Compared with healthy subjects, PD patients had an increased sensitivity to innocuous thermal stimuli and mechanical pain, but a reduced sensitivity to innocuous mechanical stimuli. In addition, they had an increased pain rating when painful thermal stimuli were applied, particularly in the off-stimulation condition. In the on-stimulation condition, there was an increased sensitivity to innocuous thermal stimuli but a reduced sensitivity to mechanical or thermal pain. Pain provoked by thermal stimuli was reduced when the stimulator was turned on. Motor improvement positively correlated with changes in warm detection and heat pain thresholds. Subthalamic nucleus deep brain stimulation contributes to relieve pain associated with PD and specifically modulates small fiber-mediated sensations. (C) 2012 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.

Motor learning, retention and transfer after virtual-reality-based training in Parkinson's disease - effect of motor and cognitive demands of games: a longitudinal, controlled clinical study

Objectives To evaluate the learning, retention and transfer of performance improvements after Nintendo Wii Fit (TM) training in patients with Parkinson's disease and healthy elderly people. Design Longitudinal, controlled clinical study. Participants Sixteen patients with early-stage Parkinson's disease and 11 healthy elderly people. Interventions Warm-up exercises and Wii Fit training that involved training motor (shifts centre of gravity and step alternation) and cognitive skills. A follow-up evaluative Wii Fit session was held 60 days after the end of training. Participants performed a functional reach test before and after training as a measure of learning transfer. Main outcome measures Learning and retention were determined based on the scores of 10 Wii Fit games over eight sessions. Transfer of learning was assessed after training using the functional reach test. Results Patients with Parkinson's disease showed no deficit in learning or retention on seven of the 10 games, despite showing poorer performance on five games compared with the healthy elderly group. Patients with Parkinson's disease showed marked learning deficits on three other games, independent of poorer initial performance. This deficit appears to be associated with cognitive demands of the games which require decision-making, response inhibition, divided attention and working memory. Finally, patients with Parkinson's disease were able to transfer motor ability trained on the games to a similar untrained task. Conclusions The ability of patients with Parkinson's disease to learn, retain and transfer performance improvements after training on the Nintendo Wii Fit depends largely on the demands, particularly cognitive demands, of the games involved, reiterating the importance of game selection for rehabilitation purposes. (C) 2012 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Early and late neurodegeneration and memory disruption after intracerebroventricular streptozotocin

Glucose metabolism and insulin signaling disruptions in the brain have been proposed as a likely etiology of Alzheimer's disease. The aim of the present study was to investigate the time course of cognitive impairments induced by intracerebroventricular injection of streptozotocin (STZ) in rats and correlate them with the ensuing neurodegenerative process. Early and late effects of STZ were evaluated by using the reference and working memory versions of the Morris' water maze task and the evaluation of neurodegenerative markers by immunoblotting and the Fluoro-jade C histochemistry. The results revealed different types of behavioral and neurodegenerative responses, with distinct time courses. We observed an early disruption on the working memory as early as 3 h after STZ injections, which was followed by degenerative processes in the hippocampus at 1 and 15 days after STZ injections. Memory disruption increases over time and culminates with significant changes in amyloid-beta peptide and hyperphosphorylated Tau protein levels in distinct brain structures. These findings add information on the Alzheimer's disease-like STZ animal model and on the mechanisms underlying neurodegenerative processes. (C) 2012 Elsevier Inc. All rights reserved.

Transcranial sonography in Parkinson's disease

Transcranial sonography has become a useful tool in the differential diagnosis of parkinsonian syndromes. This is a non-invasive, low cost procedure. The main finding on transcranial sonography in patients with idiopathic Parkinson's disease is an increased echogenicity of the mesencephalic substantia nigra region. This hyperechogenicity is present in more than 90% of cases, and reflects a dysfunction in the dopaminergic nigrostriatal pathway. This study discussed how the hyperechogenicity of the substantia nigra may facilitate the differential diagnosis of parkinsonian syndromes.

Temporal changes of CB1 cannabinoid receptor in the basal ganglia as a possible structure-specific plasticity process in 6-OHDA lesioned rats

The endocannabinoid system has been implicated in several neurobiological processes, including neurodegeneration, neuroprotection and neuronal plasticity. The CB1 cannabinoid receptors are abundantly expressed in the basal ganglia, the circuitry that is mostly affected in Parkinson’s Disease (PD). Some studies show variation of CB1 expression in basal ganglia in different animal models of PD, however the results are quite controversial, due to the differences in the procedures employed to induce the parkinsonism and the periods analyzed after the lesion. The present study evaluated the CB1 expression in four basal ganglia structures, namely striatum, external globus pallidus (EGP), internal globus pallidus (IGP) and substantia nigra pars reticulata (SNpr) of rats 1, 5, 10, 20, and 60 days after unilateral intrastriatal 6-hydroxydopamine injections, that causes retrograde dopaminergic degeneration. We also investigated tyrosine hydroxylase (TH), parvalbumin, calbindin and glutamic acid decarboxylase (GAD) expression to verify the status of dopaminergic and GABAergic systems. We observed a structure-specific modulation of CB1 expression at different periods after lesions. In general, there were no changes in the striatum, decreased CB1 in IGP and SNpr and increased CB1 in EGP, but this increase was not sustained over time. No changes in GAD and parvalbumin expression were observed in basal ganglia, whereas TH levels were decreased and the calbindin increased in striatum in short periods after lesion. We believe that the structure-specific variation of CB1 in basal ganglia in the 6-hydroxydopamine PD model could be related to a compensatory process involving the GABAergic transmission, which is impaired due to the lack of dopamine. Our data, therefore, suggest that the changes of CB1 and calbindin expression may represent a plasticity process in this PD model