CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 14, Issue 10, 2015

Exercise promotes several health benefits, such as cardiovascular, musculoskeletal and cardiorespiratory improvements. It is believed that the practice of exercise in individuals with psychiatric disorders, e.g. schizophrenia, can cause significant changes. Schizophrenic patients have problematic lifestyle habits compared with general population; this may cause a high mortality rate, mainly caused by cardiovascular and metabolic diseases. Thus, the aim of this study is to investigate changes in physical and mental health, cognitive and brain functioning due to the practice of exercise in patients with schizophrenia. Although still little is known about the benefits of exercise on mental health, cognitive and brain functioning of schizophrenic patients, exercise training has been shown to be a beneficial intervention in the control and reduction of disease severity. Type of training, form of execution, duration and intensity need to be better studied as the effects on physical and mental health, cognition and brain activity depend exclusively of interconnected factors, such as the combination of exercise and medication. However, one should understand that exercise is not only an effective nondrug alternative, but also acts as a supporting linking up interventions to promote improvements in process performance optimization. In general, the positive effects on mental health, cognition and brain activity as a result of an exercise program are quite evident. Few studies have been published correlating effects of exercise in patients with schizophrenia, but there is increasing evidence that positive and negative symptoms can be improved. Therefore, it is important that further studies be undertaken to expand the knowledge of physical exercise on mental health in people with schizophrenia, as well as its dose-response and the most effective type of exercise.

Cognitive deficits are observed in a variety of domains in patients with bipolar disorder (BD). These deficits are attributed to neurobiological, functional and structural brain factors, particularly in prefrontal cortex. Furthermore, cortical alterations in each phase (mania/hypomania, euthymia and depression) are also present. A growing basis of evidence supports aerobic exercise as an alternative treatment method for BD symptoms. Its benefits for physical health in healthy subjects and some psychiatric disorders are fairly established; however evidence directly addressed to BD is scant. Lack of methodological consistency, mainly related to exercise, makes it difficult accuracy and extrapolation of the results. Nevertheless, mechanisms related to BD physiopathology, such as hormonal and neurotransmitters alterations and mainly related to brain-derived neurotrophic factors (BDNF) can be explored. BDNF, specially, have a large influence on brain ability and its gene expression is highly responsive to aerobic exercise. Moreover, aerobic exercise trough BDNF may induce chronic stress suppression, commonly observed in patients with BD, and reduce deleterious effects caused by allostatic loads. Therefore, it is prudent to propose that aerobic exercise plays an important role in BD physiopathological mechanisms and it is a new way for the treatment for this and others psychiatric disorders.

Background: Contralaterally controlled functional electrical stimulation (CCFES) is an innovative method to improve upper extremity functions after stroke. Objective: To compare the effects of CCFES versus neuromuscular electrical stimulation (NMES) on the upper extremity functions in patients with stroke. Methods: Sixty patients with stroke were randomly assigned into CCFES group (n=30) or NMES group (n=30). All patients were also treated with conventional medical treatment and rehabilitation training. Patients in CCFES group received CCFES to the affected wrist extensors while the NMES group received NMES. The stimulus current was biphasic wave with a pulse duration of 200μs and a frequency of 60Hz. The electrical stimulation lasted for 20min per session, 5 sessions per week for 3 weeks. The intensity of the CCFES was based on the electromyography (EMG) value of the unaffected side while the subjects voluntarily extended their unaffected wrist slightly (<10% range of motion, ROM), moderately (about 50% ROM) and completely (100% ROM). Fugl-Meyer assessment (FMA), motricity index (MI), the Hong Kong version of functional test for the hemiplegic upper extremity (FTHUE-HK) and active range of motion (AROM) of wrist extension were measured before and after 3 weeks of treatment. Results: Compared with the baseline values, both groups showed significant improvements in all the measurements after treatment (p<0.05). Patients in CCFES group showed significantly higher upper extremity FMA, FTHUE-HK scores and AROM of wrist extension than those in NMES group (p<0.05). Conclusion: Compared with the conventional NMES, CCFES provides better recovery of upper extremity function in patients with stroke.

The activity dependent brain repair mechanism has been widely adopted in many types of neurorehabilitation. The activity leads to target specific and non-specific beneficial effects in different brain regions, such as the releasing of neurotrophic factors, modulation of the cytokines and generation of new neurons in adult hood. However physical exercise program clinically are limited to some of the patients with preserved motor functions; while many patients suffered from paralysis cannot make such efforts. Here the authors proposed the employment of mirror neurons system in promoting brain rehabilitation by “observation based stimulation”. Mirror neuron system has been considered as an important basis for action understanding and learning by mimicking others. During the action observation, mirror neuron system mediated the direct activation of the same group of motor neurons that are responsible for the observed action. The effect is clear, direct, specific and evolutionarily conserved. Moreover, recent evidences hinted for the beneficial effects on stroke patients after mirror neuron system activation therapy. Finally some music-relevant therapies were proposed to be related with mirror neuron system.

Despite the evidence of risks related to the use of anabolic steroids for the improvement of athletic performances, the diffusion of such drugs appears to be increasing. An exploratory study was conducted in Cagliari, Italy, to assess the level of information on this issue, to esteem the use of steroids among athletes, to measure the wellbeing of athletes and the risks related to steroid use. A sample of 192 athletes, including 142 non-agonists and 50 agonists (age range: 18 to 36) was invited to fill in a booklet including several selfreport questionnaires. The questionnaire for the assessment of the beliefs regarding the effects of anabolic steroids was developed and validated for the study, while the Self Reporting Questionnaire was used for the assessment of the mental health aspects. A general lack of information on the specific effects of steroid use on general and psychic health, as well as on sportive performances was found. Athletes were also quite unaware of the diffusion of steroids among them. Since the sportive environment seems to be the main source of information, this channel should be targeted to address the prevention and information campaigns. The use of more specific tools and the investigation of the perception of reliability of the information sources as well as the social desirability issues should be explored in future studies.

Objective: To compare the effect of visual spatial training on the spatial attention to that on motor control and to correlate the improvement of spatial attention to motor control progress after visual spatial training in subjects with unilateral spatial neglect (USN). Method: 9 cases with USN after right cerebral stroke were randomly divided into Conventional treatment group + visual spatial attention and Conventional treatment group. The Conventional treatment group + visual spatial attention received conventional rehabilitation therapy (physical and occupational therapy) and visual spatial attention training (optokinetic stimulation and right half-field eye patching). The Conventional treatment group was only treated with conventional rehabilitation training (physical and occupational therapy). All patients were assessed by behavioral inattention test (BIT), Fugl-Meyer Assessment of motor function (FMA), equilibrium coordination test (ECT) and non-equilibrium coordination test (NCT) before and after 4 weeks treatment. Result: Total scores in both groups (without visual spatial attention/with visual spatial attention) improved significantly (BIT: P=0.021/P=0.000, d=1.667/d=2.116, power=0.69/power=0.98, 95%CI[-0.8839,45.88]/95%CI=[16.96,92.64]; FMA: P=0.002/P=0.000, d=2.521/d=2.700, power=0.93/power=0.98, 95%CI[5.707,30.79]/95%CI=[16.06,53.94]; ECT: P=0.002/ P=0.000, d=2.031/d=1.354, power=0.90/power=0.17, 95%CI[3.380,42.61]/95%CI=[-1.478,39.08]; NCT: P=0.013/P=0.000, d=1.124/d=1.822, power=0.41/power=0.56, 95%CI[-7.980,37.48]/95%CI=[4.798,43.60],) after treatment. Among the 2 groups, the group with visual spatial attention significantly improved in BIT (P=0.003, d=3.103, power=1, 95%CI[15.68,48.92]), FMA of upper extremity (P=0.006, d=2.771, power=1, 95%CI[5.061,20.14]) and NCT (P=0.010, d=2.214, power=0.81-0.90, 95%CI[3.018,15.88]). Correlative analysis shows that the change of BIT scores is positively correlated to the change of FMA total score (r=0.77, P<0.01), FMA of upper extremity (r=0.81, P<0.01), NCT (r=0.78, P<0.01). Conclusion: Four weeks visual spatial training could improve spatial attention as well as motor control functions in hemineglect patients. The improvement of motor function is positively correlated to the progresses of visual spatial functions after visual spatial attention training.

The purpose of this research was to compare the effects of drug therapy, perceptual motor training and a combination of drug therapy and perceptual motor training on gross and fine motor skills of 6 to 12 year-old Iranian attention deficit hyperactivity disorder children. Thirty-six attention deficit hyperactivity disorder children currently under treatment in three Iranian psychological-neurological clinics participated in this research study. Participants were sampled from the accessible population and randomly assigned to three experimental groups (n = 12 each). The Conners Parent Rating Scale was used to classify the children and the Bruininks-Oseretsky Test of Motor Proficiency was administered before and after a three month treatment/ training session. Participants in the first experimental group received drug therapy (including methylphenidate). In the second group participants took part in 18 sessions of perceptual-motor skill training for six consecutive weeks, and in the third group children received both interventions. The results indicated that interventions using perceptual-motor training alone or in combination with a drug therapy significantly improved both gross and fine motor skills over a period of six weeks. Participants in the drug-only group showed no improvement in motor performance.

To evaluate the effect of moderate intensity of aerobic exercise on elderly people with mild Alzheimer’s disease, we recruited fifty volunteers aged 50 years to 80 years with cognitive impairment. They were randomized into two groups: aerobic group (n=25) or control group (n=25). The aerobic group was treated with cycling training at 70% of maximal intensity for 40 min/d, 3 d/wk for 3 months. The control group was only treated with heath education. Both groups were received cognitive evaluation, laboratory examination before and after 3 months. The results showed that the Minimum Mental State Examination score, Quality of Life Alzheimer’s Disease score and the plasma Apo-a1 level was significantly increased (P<0.05), the Alzheimer’s Disease Assessment Scale-cognition score, Neuropsychiatric Inventory Questionnaire score was significantly decreased(P<0.05) in aerobic group before and after 3 months in aerobic group. For the control group, there was no significant difference in scores of Alzheimer’s Disease Assessment Scale-cognition, Neuropsychiatric Inventory Questionnaire, Quality of Life Alzheimer’s Disease, Apo-a1 (P>0.05), while Minimum Mental State Examination scores decreased significantly after 3 months (P<0.05). In conclusion, moderate intensity of aerobic exercise can improve cognitive function in patients with mild Alzheimer’s disease.

Background: Recently, high-frequency repetitive transcranial magnetic stimulation (rTMS) is reported to evaluating the corticospinal pathway and improving both cortical excitability and motor function significantly in subjects. According to some previous reports, the maximum voluntary muscle contraction (MVC) of target muscle can reinforce the influence by rTMS. The aim of this study was to confirm 5 Hz rTMS with MVC in healthy individuals is an effective method to facilitate motor neuron excitability and the efficiency can last at least 30min post stimulation. Objective: To compare the motor evoked potentials (MEPs) elicited by 5Hz rTMS and 5Hz rTMS combined with MVC. Methods: In this randomized, controlled, assessor-blinded, crossover trial, 40 healthy right-handed subjects were divided into group A (n=20) and group B (n=20). All subjects received rTMS over the primary motor cortex area (M1) in the left hemisphere. The parameters of rTMS were 5 Hz, 90%of the resting motor threshold (RMT), for a total of 500 pulses in100 trains (1-sec inter-stimulus and 8- sec inter-interval). Method 1: All subjects received rTMS over the hand area of left M1. Method 2: All subjects received rTMS at the same stimulated point, combined with maximum voluntary hand griping in each 10 trains. Test 1: group A underwent method 1, while group B underwent method 2. Test 2: A week later, group B underwent method 1, while group A underwent method 2. In each test, the MEP amplitude and latency was measured before (P-rTMS), 5min after (Post 1) and 30min after (Post 2) the rTMS intervention. Results: MEP amplitude increased significantly from baseline at 5 minutes post intervention under both treatment regimes. However for both sequences, it decreased towards baseline under the rTMS intervention at 30 minutes post intervention but remained relatively high when rTMS was combined with MVC. MEP latency decreased significantly from baseline at 5 minutes post intervention under both treatment regimes. For both sequences, it then increased again towards baseline under both treatment regimes at 30 minutes post intervention. Although there was a trend for a less pronounced increase under the combined treatment, this effect was not significant. Conclusion: Both 5Hz rTMS and 5Hz rTMS combined with MVC facilitate motor cortical excitability, but the enhancement in rTMS with MVC is more pronounced and maintained longer than simple rTMS.

Physical exercise is responsible for different metabolic and hemodynamic changes, including increased cerebral blood flow and perfusion. It is known that running increases vascular endothelial growth factor expression in the brain, which is critical for the anti-depressive effects of adult neurogenesis induced by physical exercise. Both animal and human studies revealed that neurovascular responses to physical exercise are well correlated to adult hippocampal neurogenesis and cognition improvement. Yet it is unknown if the increased blood perfusion to hippocampus is affecting the adult neurogenesis. Manipulating systemic blood pressure, or stimulating the cerebral blood flow with alternative measures, might provide useful tools to understand how much neurovascular plasticity contributes to the brain cognition enhancement by physical exercise. In addition, it will be interesting to examine the responses of brain cells (including neuron, glia and endothelia cells) to increased shear stress and oxygen load, to investigate the underlying molecular mechanisms.

Depression is associated with decreased serotonin metabolism and functioning in the central nervous system, evidenced by both animal models of depression and clinical patient studies. Depression is also accompanied by decreased hippocampal neurogenesis in diverse animal models. Neurogenesis is mainly defined in dentate gyrus of hippocampus as well as subventricular zone. Moreover, hypothalamus, amygdala, olfactory tubercle, and piriform cortex are reported with evidences of adult neurogenesis. Physical exercise is found to modulate adult neurogenesis significantly, and results in mood improvement. The cellular mechanism such as adult neurogenesis upregulation was considered as one major mood regulator following exercise. The recent advances in molecular mechanisms underlying exercise-regulated neurogenesis have widen our understanding in brain plasticity in physiological and pathological conditions, and therefore better management of different psychiatric disorders.

Microbiota is a set of microorganisms resident in gut ecosystem that reacts to psychological stressful stimuli, and is involved in depressed or anxious status in both animals and human being. Interestingly, a series of studies have shown the effects of physical exercise on gut microbiota dynamics, suggesting that gut microbiota regulation might act as one mediator for the effects of exercise on the brain. Recent studies found that gut microbiota dynamics are also regulated by metabolism changes, such as through physical exercise or diet change. Interestingly, physical exercise modulates different population of gut bacteria in compared to food restriction or rich diet, and alleviates gut syndromes to toxin intake. Gut microbiota could as well contribute to the beneficial effects of exercise on cognition and emotion, either directly through serotonin signaling or indirectly by modulating metabolism and exercise performance.

Neuroscience is an emergent research field that comprises many multidisciplinary investigations, searches for explanations about the relationship between the body and the brain. Here, we will give a little summary of this field showing the main current findings. We discuss the lack of consistent data about the relationship among exercise for neurodegenerative diseases and psychiatric disorders, sports performance and rehabilitation, and therefore, the difficult to describe cause-effect associations or to describe in detail the neurobiological mechanisms underlying these associations.

The delivery of drugs to brain is a daunting task due to the presence of multiple protective barriers. Nanoparticles (NPs), due to their ability to deliver and accumulate drugs in brain by crossing the blood brain barrier, have emerged as effective brain targeting drug delivery system. The major drawback of NPs obstructing their application in brain related diseases is neurotoxicity which leads to memory deficit, behavioural changes, changes in the structure and membrane potential of the neurons. An understanding of the molecular mechanisms associated with nanoparticle induced neurotoxicity is essential to solve the problem. NPs induce cytotoxicity, genotoxicity and epigenetic changes. This review focuses on nanoparticles, their physicochemical characteristics, manifestations of neurotoxicity and the mechanisms through which neurotoxicity is induced. This review may help in improving the understanding of the mechanisms associated with nanoparticle induced neurotoxicity so as to devise ways to overcome the associated neurotoxicity.

Glutathione S-transferase pi (GSTP1) is a crucial enzyme in detoxification of electrophilic compounds and organic peroxides. Together with Se-dependent glutathione peroxidase (Se-GSHPx) it protects cells against oxidative stress which may be a primary factor implicated in motor neuron disease (MND) pathogenesis. We investigated GSTP1 polymorphisms and their relationship with GST and Se-GSTPx activities in a cohort of Polish patients with MND. Results were correlated with clinical phenotypes. The frequency of genetic variants for GSTP1 exon 5 (I105V) and exon 6 (A114V) was studied in 104 patients and 100 healthy controls using real-time polymerase chain reaction. GST transferase activity was determined in serum with 1-chloro-2,4-dinitrobenzene, its peroxidase activity with cumene hydroperoxide, and Se-GSHPx activity with hydrogen peroxide. There were no differences in the prevalence of GSTP1 polymorphism I105V and A114V between MND and controls, however the occurrence of CT variant in codon 114 was associated with a higher risk for MND. GSTP1 polymorphisms were less frequent in classic ALS than in progressive bulbar palsy. In classic ALS C* (heterozygous I /V and A /V) all studied activities were significantly lower than in classic ALS A* (homozygous I /I and A/A). GST peroxidase activity and Se-GSHPx activity were lower in classic ALS C* than in control C*, but in classic ALS A* Se-GSHPx activity was significantly higher than in control A*. It can be concluded that the presence of GSTP1 A114V but not I105V variant increases the risk of MND, and combined GSTP1 polymorphisms in codon 105 and 114 may result in lower protection of MND patients against the toxicity of electrophilic compounds, organic and inorganic hydroperoxides.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by deposit of amyloid plaques and neurofibrillary tangles and oxidative stress plays an essential role in the pathogenesis of AD. Jatrorrhizine (JAT), a Coptidis Rhizome, has multiple biological functions such as anti-oxidation and anti-inflammation. Herein, we investigated the neuroprotective effects of JAT on okadaic acid (OA)- induced cytotoxicity and apoptosis in HT22 cells. Following the exposure to 80nmol/L OA for 12h, the reduction in cell survival, activities of superoxide dismutase, glutathione peroxidase and mitochondria membrane potential has been shown in HT22 cells. In contrast, OA increased levels of lactate dehydrogenase, malondialdehyde production and intracellular reactive oxygen species. OA also enhanced the expression of Bax but decreased the levels of Bcl-2, OA also upregulated the expression of cleaved caspase-3, phosphorylated extracellular signal-regulated kinases 1/2, phosphorylated c-Jun Nterminal kinases, phosphorylated p38 and NF-kappa B p65 subunit in HT22 cells and this up-regulation was attenuated by JAT which was pre-incubated for 12h in the cells prior to OA exposure. In conclusion, our data present the protective role of JAT in OA induced cytotoxicity, via its antioxidant and anti-apoptotic properties by inhibiting the mitogen-activated protein kinases pathways in HT22 hippocampal neurons. These results indicate that JAT may be the potential target to treat AD induced by oxidative stress and apoptosis.

Ouabain stimulates activation of various signaling cascades such as protein kinase B (Akt) and Extracellular-signaling-regulated kinase 1/2 (ERK 1/2) in various cell lines. Retinoic acid (RA) is commonly used to induce neuroblastoma differentiation in cultures. Upon RA administration, human neuroblastoma cell line, SK-N-SH demonstrated neurite extensions, which is an indicator of neuronal cell differentiation. Here we report that ouabaininduced signaling is altered under the action of 1 μM RA in human neuroblastoma SK-N-SH cells. RA increased the expression of p110α subunit of phosphoinositide 3-kinase (PI3K), Akt and β1 subunit of Na+/K+-ATPase. Ouabain activated Akt and ERK 1/2 in differentiated SK-N-SH cells; this effect was not observed in non-differentiated SK-N-SH cells. Long-term incubation of non-differentiated SK-N-SH with 1 μM ouabain led to a decrease in the number of cells; this effect was reduced in differentiated SK-N-SH cells. Taken together, these results suggest that ouabain leads to cell death in neuroblastoma cells rather than neuronal cells due to the different response to ouabain manifested by activation of Akt and ERK 1/2. Highlights RA increases the expression of p110α subunit of PI3K, Akt and β1 subunit of Na+/K+-ATPase Ouabain induces activation of Akt and ERK 1/2 in differentiated SK-N-SH cells but not in non-differentiated cells 1 μM ouabain leads to a decrease in the number of cells in non-differentiated SK-N-SH Reduction of ouabain-induced cell death in differentiated SK-N-SH