Improve Motor Impairment Research Articles

Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways

Phytochemical investigation of the butanol fraction (BUF) derived from the 70% aqueous methanolic leaf extract of Barnebydendron riedelii led to the isolation of three flavonoid glycosides; kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside, quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-galactopyranoside and quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside. Docking studies were fulfilled to validate the possible bio-properties of BUF toward nuclear factorkappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). The protective role of BUF against behavioral, biochemical, molecular, histopathological and immunohistochemical alterations in thioacetamide (TAA)-induced hepatic encephalopathy in rats was investigated. The toxicological studies indicated that BUF was safe up to 2000 mg/kg bw. Prior to TAA intoxication, rats were orally treated with either BUF at multiple doses (70, 140 and 280 mg/kg bw) or lactulose (8 mL/kg bw) for 14 consecutive days. On the 13th and the 14th day, TAA (200 mg/kg bw/day) was intraperitoneally injected. The BUF significantly improved motor impairment, ameliorated cognitive deficits and attenuated TAA-induced hepatotoxicity. Moreover, BUF controlled the inflammatory processes by suppressing the hepatic inflammatory cytokine; interleukin-6 (IL-6) as well as its pro-inflammatory mediator; NF-κB supporting the molecular docking assessment. The brain neurotransmitters; dopamine, serotonin and noradrenaline, as well as ammonia levels were improved in BUF-treated TAA-intoxicated animals in a dose-dependent manner. Furthermore, BUF administration to TAA-intoxicated rats modulated the Nrf2 and heme oxygenase 1 (HO-1) genes expression in liver and brain tissues. The histological evaluation showed that pretreatment of TAA-intoxicated rats with BUF ameliorated the degenerative effects of TAA on liver and brain tissues as well as reduced the activation of cellular apoptotic marker; caspase-3 and glial fibrillary acidic protein (GFAP+) astrocytes. In conclusion, the observed hepato-neuroprotective effect of BUF is attributed to its flavonoidal content through its modulatory effects on of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways.

Neuroprotective effect of rhaponticin against Parkinson disease: Insights from in vitro BV-2 model and in vivo MPTP-induced mice model.

Parkinson's disease (PD) is a complex neurodegenerative illness associatedwith the loss or damage to neurons of the dopaminergic system in the brain. Few therapeutic approaches and considerable side effects of conventional drugs necessitatea new therapeutic agent to treat patients with PD. Rhaponticin is a natural hydroxystilbene, found in herbal plants such as Rheum rhaponticum, and known to have desirable biological activity including anti-inflammatory properties. However, the neuroinflammation on rhaponticin levels has only been investigated partially so far. So, the current study explored whether rhaponticin could ameliorate the pathophysiology observed in both the in vitro microglial BV-2 cells and thein vivo (1-methyl-4-phenyl-1,2,3,5-tetrahydropyridine [MPTP])-mediated PD model. The results show rhaponticin significantly attenuated lipopolysaccharide (LPS)-mediated microglial activation by suppressing nitric oxidesynthase in conjunction with abridged reactive oxygen species production together with proinflammatory mediator reduction. In vivorhaponticin treatment improves motor impairments as well as the loss of dopaminergic neurons in MPTP-treated mice possibly through suppression via mediators of inflammation. Taken together, these results offer evidence that rhaponticin exerts anti-inflammatory effects and neuroprotection in an LPS-induced microglial model and the MPTP-induced mouse models of PD.

Protective effect of Indole-3-carbinol, an NF-κB inhibitor in experimental paradigm of Parkinson’s disease: In silico and in vivo studies

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, majorly with symptoms of motor dysfunction. Study was performed to explore the effect of nuclear factor κB (NF-κB) inhibitors against neurobehavioral abnormalities and neuroinflammation in PD. Cost effective in silico approaches of docking-based ligand -target complex predictions and optimal physicochemical properties were utilised to identify lead NF-κB inhibitor using database. Our studies revealed the potential hit Indole-3-carbinol (I3C) which was considered for the next phase, pharmacological validations. Intranigral administration of lipopolysaccharide (LPS) in rats is utilized as a neuroinflmmation model of PD. In the present study it caused an impairment in motor functions, its coordination, learning and memory as demonstrated in rotarod apparatus, beam balance test, open field test and Morris water maze test. Chronic administration of I3C for 21 days in intranigral LPS treated rats led to a significant improvement in motor functions, coordination, learning and memory which were associated with a decrease in the activity of inflammatory cytokines such as TNF-α and IL-6. Further, it was found to inhibit NF-κB whose levels increased after LPS administration. Moreover, decreased levels of malondialdehyde and increased levels of reduced glutathione, superoxide dismutase and catalase were observed in cortex and striatum after I3C administration in LPS rats. These results suggest a possible neuroprotective effect of I3C via amelioration of LPS-induced behavioural alterations, oxidative damage and neuroinflammation which in turn is attributed to its potent antioxidant and anti-inflammatory (NF-κB inhibition) property. The effect produced by I3C (50 mg/kg) was found to be comparable with levodopa-carbidopa combination (LD:CD) while, I3C (50 mg/kg) in combination with LD:CD exhibited a potentiating effect in improving motor impairments and cognitive deficit. The results thus depict I3C as a promising agent to delay neurodegeneration of the neurons in PD with improvement in motor functions and cognitive function.

Papaverine inhibits α-synuclein aggregation by modulating neuroinflammation and matrix metalloproteinase-3 expression in the subacute MPTP/P mouse model of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor impairments. Most PD drugs act by improving motor impairments, whereas very few drugs that efficiently recover PD-related neuropathological features, particularly α-synuclein-related toxicity, have been developed. In this study, we found that papaverine (PAP) attenuated behavioral deficits and protected against nigrostriatal dopaminergic degeneration in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P) mouse model of PD. Histological analysis of tissue dissected from mice sacrificed nearly 3 weeks after the completion of treatment revealed that PAP significantly ameliorated microglia/astrocyte activation in the striatum and substantia nigra of MPTP/P-treated mice. In addition, PAP diminished α-synuclein expression and aggregation in this model. Furthermore, PAP inhibited the phosphorylation of α-synuclein at serine 129, which may underlie the observed reduction in α-synuclein aggregation. PAP also reduced the expression of matrix metalloproteinase-3 (MMP-3), and the MMP3-positive area co-labeled with thioflavin-S. Taken together, our data suggest that PAP inhibits dopaminergic neuronal cell death and α-synuclein aggregation by suppressing neuroinflammation and MMP-3 expression in the subacute MPTP/P mouse model of PD. Accordingly, PAP may be a promising drug for the treatment of PD.

The efficacy of dance for improving motor impairments, non-motor symptoms, and quality of life in Parkinson's disease: A systematic review and meta-analysis.

Dance may help individuals living with Parkinson's disease (PD) improve motor and non-motor symptoms that impact quality of life (QOL). The primary aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the efficacy of dance in improving motor and non-motor symptoms of PD and QOL. The secondary aims of this review were to evaluate the methodological quality of included studies by assessing risk of bias across nine categories and to inform the direction of future research. Peer-reviewed RCTs that included people living with PD at all disease stages and ages and measured the effects of a dance intervention longer than one day were included. Sixteen RCTs involving 636 participants with mild to moderate PD were eligible for inclusion in the qualitative synthesis and nine in the meta-analysis. Overall, the reviewed evidence demonstrated that dance can improve motor impairments, specifically balance and motor symptom severity in individuals with mild to moderate PD, and that more research is needed to determine its effects on non-motor symptoms and QOL. RCTs that use a mixed-methods approach and include larger sample sizes will be beneficial in fully characterizing effects and in determining which program elements are most important in bringing about positive, clinically meaningful changes in people with PD.

GLP-1 receptor agonists for Parkinson's disease.

Parkinson's disease (PD) is a progressive disorder characterised by both motor and non-motor problems. Glucagon-like peptide-1 (GLP-1) receptor agonists, licensed for treatment of type 2 diabetes, work by stimulating GLP-1 receptors in the pancreas, which triggers the release of insulin. GLP-1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic efficacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP-1 receptor agonists in neurodegenerative disorders such as PD. To evaluate the effectiveness and safety of GLP-1 receptor agonists for Parkinson's disease. We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference abstracts. The most recent search was run on 25 June 2020. We included randomised controlled trials (RCTs) of adults with PD that compared GLP-1 receptor agonists with conventional PD treatment, placebo, or no treatment. Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author. Through our searches, we retrieved 99 unique records, of which two met our inclusion criteria. One double-blind study of exenatide versus placebo randomised 62 participants, who self-administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12-week washout. One single-blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self-administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles-Olmos 2013. Exenatide versus placebo Primary outcomes We found low-certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in the off-medication state (mean difference (MD) -3.10, 95% confidence interval (CI) -6.11 to -0.09). The difference in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD -3.5, 95% CI -6.7 to -0.3), exceeding the minimum clinically important difference (MCID). We found low-certainty evidence suggesting that exenatide has little or no effect on health-related quality of life (HRQoL) as assessed by the Parkinson's Disease Questionnaire (PDQ)-39 Summary Index (SI) (MD -1.80, 95% CI -6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI -0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI -3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low-certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76). Exenatide versus no treatment Primary outcomes at 14 months We found very low-certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS-UPDRS Part III off medication (MD -4.50, 95% CI -8.64 to -0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ-39 SI (MD 3.50, 95% CI -2.75 to 9.75; very low-quality evidence). We found very low-certainty evidence suggesting that exenatide has little or no effect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low-certainty evidence suggesting that exenatide may lead to weight loss (MD -2.40 kg, 95% CI -4.56 to -0.24). Primary outcomes at 24 months We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS-UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ-39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8). Low- or very low-certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persist for some time following cessation of exenatide. This raises the possibility that exenatide may have a disease-modifying effect. SAEs were unlikely to be related to treatment. The effectiveness of exenatide for improving HRQoL, non-motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP-1 receptor agonists.

Graded fMRI Neurofeedback Training of Motor Imagery in Middle Cerebral Artery Stroke Patients: A Preregistered Proof-of-Concept Study.

Ischemic stroke of the middle cerebral artery (MCA), a major brain vessel that supplies the primary motor and premotor cortex, is one of the most common causes for severe upper limb impairment. Currently available motor rehabilitation training largely lacks satisfying efficacy with over 70% of stroke survivors showing residual upper limb dysfunction. Motor imagery-based functional magnetic resonance imaging neurofeedback (fMRI-NF) has been suggested as a potential therapeutic technique to improve motor impairment in stroke survivors. In this preregistered proof-of-concept study (https://osf.io/y69jc/), we translated graded fMRI-NF training, a new paradigm that we have previously studied in healthy participants, to first-time MCA stroke survivors with residual mild to severe impairment of upper limb motor function. Neurofeedback was provided from the supplementary motor area (SMA) targeting two different neurofeedback target levels (low and high). We hypothesized that MCA stroke survivors will show (1) sustained SMA-region of interest (ROI) activation and (2) a difference in SMA-ROI activation between low and high neurofeedback conditions during graded fMRI-NF training. At the group level, we found only anecdotal evidence for these preregistered hypotheses. At the individual level, we found anecdotal to moderate evidence for the absence of the hypothesized graded effect for most subjects. These null findings are relevant for future attempts to employ fMRI-NF training in stroke survivors. The study introduces a Bayesian sequential sampling plan, which incorporates prior knowledge, yielding higher sensitivity. The sampling plan was preregistered together with a priori hypotheses and all planned analysis before data collection to address potential publication/researcher biases. Unforeseen difficulties in the translation of our paradigm to a clinical setting required some deviations from the preregistered protocol. We explicitly detail these changes, discuss the accompanied additional challenges that can arise in clinical neurofeedback studies, and formulate recommendations for how these can be addressed. Taken together, this work provides new insights about the feasibility of motor imagery-based graded fMRI-NF training in MCA stroke survivors and serves as a first example for comprehensive study preregistration of an (fMRI) neurofeedback experiment.

The onjisaponin B metabolite tenuifolin ameliorates dopaminergic neurodegeneration in a mouse model of Parkinson's disease.

Onjisaponin B (OB) is the main active ingredient of the traditional Chinese medicinal herb polygala, which is effective against neurodegenerative disorders. However, the target of OB is currently unknown. Neuroinflammation and oxidative stress are both risk factors for the pathogenesis and progression of Parkinson's disease (PD). Here, we used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced subacute mouse model of PD to explore the efficacy and neuroprotective mechanism of OB in PD. Immunohistochemistry was used to mark dopaminergic (DA) neurons and microglia in the substantia nigra pars compact. Administration of OB (20 and 40 mg/kg) prevented the degeneration of DA neurons and improved motor impairment in the rotarod test. Furthermore, OB attenuated microglia over-activation and reduced the secretion of inflammatory factors including tumor necrosis factor-alpha, interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), as determined by ELISA. Meanwhile, the activities of superoxide dismutase and malondialdehyde were used to measure the level of oxidative stress in brain homogenates and suppression of excessive lipid epoxidation and increased antioxidant enzyme activity were found in OB-treated PD mice. Finally, OB inhibits the expression of the p65 subunit of NF-κB in the nucleus and attenuated expression of the RhoA and ROCK2 proteins in PD mice. Consequently, our results show that OB ameliorates DA neurodegeneration in a MPTP-induced mouse model of PD through anti-oxidant and anti-inflammatory activities mediated via the RhoA/ROCK2 signaling pathway. This finding demonstrates that OB may be a promising drug for DA neuron degeneration, which may provide a new therapeutic agent for future discovery of drugs for PD.See video abstract: http://links.lww.com/WNR/A580.

Combination therapy with astaxanthin and epidermal neural crest stem cells improves motor impairments and activates mitochondrial biogenesis in a rat model of spinal cord injury

Spinal cord injury (SCI), a multifactorial disease, can lead to irreversible motor and sensory disabilities. Cell therapy in combination with pharmacological agents can be a promising approach to attenuate SCI damages. Epidermal neural crest stem cells (EPI-NCSCs) extracted from bulge hair follicle in adults are attractive candidates due to the possibility of autologous transplantation. This study evaluated the effect of EPI-NCSCs combined with astaxanthin (Ast), a potent antioxidant, on damages induced by SCI.Male rats were treated with Ast (0.2 mM) and EPI-NCSCs (106/10 μl PBS) alone and combined together after SCI contusion. Motor function was assessed by Basso, Beattie and Bresnahan (BBB) test on days 1, 3, 7, 14, 21, 28, 35 and 42 post-injury. Motor neurons number and myelin level were evaluated on days 14 and 42 using Nissl and Luxol Fast Blue staining. The gene expression of mitochondrial biogenesis involved factors (PGC1α, NRF1 and TFAM) was measured by qPCR.All treatments improved motor function, with the highest BBB score in Ast + Cell compared to Ast and Cell. Decreased motor neurons number and myelin level following SCI, were increased by Ast, Cell and Ast + Cell, but combination therapy significantly had a better effect. We observed reduction in PGC1α, NRF1, and TFAM expression in spinal tissue after SCI, and treatment with Cell and Ast + Cell significantly restored NRF1 and TFAM mRNA levels.These results suggested that Ast in combination with EPI-NCSCs has better effects on behavioral dysfunction, motor neuron loss and demyelination after SCI. These protective effects may be attributed to mitochondrial biogenesis activation.

Unraveling the Role of Astrocytes in Subthalamic Nucleus Deep Brain Stimulation in a Parkinson\u2019s Disease Rat Model

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for motor symptoms of Parkinson’s disease (PD) when L-DOPA therapy induces disabling side effects. Classical inflammatory activation of glial cells is well established in PD, contributing to the progressive neurodegenerative state; however, the role of DBS in regulating the inflammatory response remains largely unknown. To understand the involvement of astrocytes in the mechanisms of action of DBS, we evaluated the effect of STN–DBS in regulating motor symptoms, astrocyte reactivity, and cytokine expression in a 6-OHDA-induced PD rat model. To mimic in vivo DBS, we investigate the effect of high-frequency stimulation (HFS) in cultured astrocytes regulating cytokine induction and NF-κB activation. We found that STN-DBS improved motor impairment, induced astrocytic hyperplasia, and reversed increased IFN-γ and IL-10 levels in the globus pallidus (GP) of lesioned rats. Moreover, HFS activated astrocytes and prevented TNF-α-induced increase of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in vitro. Our results indicate that DBS/HFS may act as a regulator of the inflammatory response in PD states, attenuating classical activation of astrocytes and cytokine induction, potentially through its ability to regulate NF-κB activation. These findings may help us understand the role of astrocyte signaling in HFS, highlighting its possible relationship with the effectiveness of DBS in neurodegenerative disorders.

Clinical recommendations to guide physical therapy practice for Huntington disease.

ObjectiveIn the past decade, an increasing number of studies have examined the efficacy of physical therapy interventions in people with Huntington disease (HD).MethodsWe performed a mixed-methods systematic review using Joanna Briggs Institute (JBI) methodology and included experimental and observational study designs. The search resulted in 23 quantitative studies and 3 qualitative studies from which we extracted data using JBI standardized extraction tools. Results of this review suggested that physical therapy interventions may improve motor impairments and activity limitations in people with HD. Here, we expand on the review findings to provide specific recommendations to guide clinical practice.ResultsWe recommend the following specific physical therapy interventions for people with HD: aerobic exercise (grade A evidence), alone or in combination with resistance training to improve fitness and motor function, and supervised gait training (grade A evidence) to improve spatiotemporal features of gait. In addition, there is weak (grade B) evidence that exercise training improves balance but does not show a reduction in the frequency of falls; inspiratory and expiratory training improves breathing function and capacity; and training of transfers, getting up from the floor, and providing strategies to caregivers for involvement in physical activity in the midstages of HD may improve performance. There is expert consensus for the use of positioning devices, seating adaptations, and caregiver training in late stages of HD.ConclusionsThere is strong evidence to support physical therapy interventions to improve fitness, motor function, and gait in persons with HD.

Can dietary fiber influence Parkinson's patients' gut microbiota and short chain fatty acid production – an ex-vivo study, preliminary results

AbstractIntroductionRecent studies demonstrated that the gut microbiome of Parkinson's Disease (PD) patients differs from that of age-matched healthy controls. Notably less butyrate-producing bacteria and low mucosal and fecal short chain fatty acid (SCFA) concentrations were found in PD patients. SCFA play a role in the interplay of health and disease: SCFA butyrate improves colon motility, protects the colonic epithelium and reduces inflammation. Administration of butyrate in animal models of PD improved motor impairment and dopamine deficiency and reduced early mortality. We hypothesize that certain orally supplemented dietary fibers can stimulate butyrate production in the colon of Parkinson's patients, and consequently can improve the motor impairment and their quality of life. This hypothesis still requires a step-wise approach. Our objective is to investigate the effect of different types of dietary fiber on the gut microbiota and SCFA production in PD patients and healthy elderly.Material and methodsPD patients and healthy controls (HC) were selected based on age (55–70 years old) and BMI (18.5 -25 kg/m2). For PD patients the Hoehn and Yahr score (I – III) was added to this selection. The effect of inulin varying in degree of polymerization (DP) (average DP ~10 vs. average DP ~23) on the SCFA production was evaluated by ex vivo fermentation experiments with fecal samples of PD patients and HC. Inulin (1% w/v) was incubated in small-scale batch fermentations for 24 h at 37°C in anaerobic conditions. SCFA production was analyzed by solid phase micro-extraction capillary gas chromatography-mass spectrometry detection (SPME-cGS-MS). The clostridia clusters IV and XIVa were quantified through 16s qPCR.Results and discussionShort chain (Sc) and long chain(Lc) inulin fermentation resulted in a mean total SCFA increase of respectively 490.3 ± 128.2μmol/ml and 384.3 ± 85.9μmol/ml in HC (n = 7) and 453.9 ± 99.2μmol/ml and 402.9μmol/ml ± 84.1μmol/ml in PD patients (n = 3). Sc inulin fermentation increased butyrate production with 200.0μg/ml ± 46.2μmol/ml in HC and 119.8 ± 94.4μg/ml in PD patients (p = 0.09). Lc inulin fermentation increased butyrate production with 174.9μmol/ml ± 82.2μmol/ml and 113.3μmol/ml ± 21.2μmol/ml in HC and PD patients, respectively (p = 0.25). Large variation between samples was observed in PD patients.ConclusionAlthough sample size is relatively small and data is still collected, we can conclude that both Sc and Lc inulin increase total SCFA and butyrate production in HC and PD patients. This ex vivo study shows that stimulation of the butyrate production is still possible in PD patients and could be beneficial.

Effects of concomitant neuromuscular electrical stimulation during repetitive transcranial magnetic stimulation before repetitive facilitation exercise on the hemiparetic hand.

Repetitive transcranial magnetic stimulation (rTMS) and Repetitive facilitative exercise (RFE) improves motor impairment after stroke. To investigate whether neuromuscular electrical stimulation (NMES) can facilitate the effects of rTMS and RFE on the function of the hemiparetic hand in stroke patients. This randomized double-blinded crossover study divided 20 patients with hemiparesis into two groups and provided treatment for 4 weeks at 5 days/week. NMES-before-sham group and NMES-following-sham group performed NMES sessions and sham NMES sessions for each 2 weeks. Patients received NMES or sham NMES for the affected extensor muscle concurrently with 1 Hz rTMS for the unaffected motor cortex for 10 min and performed RFE for 60 min. The Fugl-Meyer Assessment (FMA), Action Research Arm Test (ARAT), Box and Block Test (BBT) and Modified Ashworth Scale (MAS) were used for evaluation. FMA and ARAT improved significantly during both sessions. The gains in the BBT during an NMES session were significantly greater than those during a sham NMES session. MAS for the wrist and finger significantly decreased only during an NMES session. NMES combined with rTMS might facilitate, at least in part, the beneficial effects of RFE on motor function and spasticity of the affected upper limb.

Exosomal DNA Aptamer Targeting α-Synuclein Aggregates Reduced Neuropathological Deficits in a Mouse Parkinson’s Disease Model

The α-synuclein aggregates are the main component of Lewy bodies in Parkinson’s disease (PD) brain, and they showed immunotherapy could be employed to alleviate α-synuclein aggregate pathology in PD. Recently we have generated DNA aptamers that specifically recognize α-synuclein. In this study, we further investigated the in vivo effect of these aptamers on the neuropathological deficits associated with PD. For efficient delivery of the aptamers into the mouse brain, we employed modified exosomes with the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface. We demonstrated that the aptamers were efficiently packaged into the RVG-exosomes and delivered into neurons in vitro and in vivo. Functionally, the aptamer-loaded RVG-exosomes significantly reduced the α-synuclein preformed fibril (PFF)-induced pathological aggregates, and rescued synaptic protein loss and neuronal death. Moreover, intraperitoneal administration of these exosomes into the mice with intra-striatally injected α-synuclein PFF reduced the pathological α-synuclein aggregates and improved motor impairments. In conclusion, we demonstrated that the aptamers targeting α-synuclein aggregates could be effectively delivered into the mouse brain by the RVG-exosomes and reduce the neuropathological and behavioral deficits in the mouse PD model. This study highlights the therapeutic potential of the RVG-exosome delivery of aptamer to alleviate the brain α-synuclein pathology.

Effects of Boswellia serrata resin extract on motor dysfunction and brain oxidative stress in an experimental model of Parkinson's disease.

Boswellia serrata oleo-gum resin (frankincense) exerted antioxidant and anti-inflammatory effects against several diseases, such as; asthma, rheumatoid arthritis and irritable bowel syndrome. In the current study, the influences of B. serrata resin extract on motor dysfunction and oxidative stress markers were investigated in the intrastriatal 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). The animals were randomly assigned to sham, lesion (6-OHDA), and three lesion groups treated with ethyl alcoholic extract of B. serrata at doses of 125, 250 and 500 mg/kg for 3 weeks. The neurotoxin 6-OHDA (12.5 µg) was microinjected into the left striatum to induce PD in male rats. Motor behavior was assessed by rotational and elevated narrow beam tests. Oxidative stress markers were measured in striatal and midbrain homogenates. There was a significant increase in contralateral rotations in 6-OHDA group versus sham group (p<0.001), and treatment with B. serrata resin extract at doses of 125 and 250 mg/kg significantly decreased the rotations in comparison to 6-OHDA group (p<0.001 and p<0.001, respectively). The 6-OHDA group also showed considerable elevation in the latency to initiate crossing (p<0.001) and the total time (p<0.001) on narrow beam test. Moreover, treatment with B. serrata extract at doses of 125, 250 and 500 mg/kg caused a significant reduction in the latency and total time (p<0.001, p<0.001, and p<0.01, respectively). Biochemical analysis showed no significant difference in oxidative stress markers levels among the groups. Our findings suggest that B. serrata resin extract acts as an anti-inflammatory and antioxidant agent that protects nigrostriatal dopaminergic neurons and improve motor impairments in PD.

Inhibition of MPTP-induced α-synuclein oligomerization by fatty acid-binding protein 3 ligand in MPTP-treated mice

Accumulation and aggregation of α-synuclein (αSyn) triggers dopaminergic (DAergic) neuronal loss in Parkinson's disease (PD). This pathological event is partly facilitated by the presence of long-chain polyunsaturated fatty acids (LC-PUFAs), including arachidonic acid. The intracellular transport and metabolism of LC-PUFAs are mediated by fatty acid-binding proteins (FABPs). We previously reported that heart-type FABP (FABP3) interacts with αSyn, thereby promoting αSyn oligomerization in DAergic neurons in the substantia nigra pars compacta (SNpc) following 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. This αSyn oligomerization is prevented in Fabp3 gene knock out mice. We document a novel FABP3 ligand, MF1 (4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy)butanoic acid), that inhibits αSyn accumulation in DA neurons, thereby inhibiting the oligomerization of αSyn, loss of DAergic neurons, and PD-like motor deficits in MPTP-treated mice. Chronic oral administration of MF1 (0.3 or 1.0 mg/kg/day) significantly improved motor impairments and inhibited MPTP-induced accumulation and oligomerization of αSyn in the SNpc, and in turn prevented loss of tyrosine hydroxylase (TH)-positive cells in the SNpc. MF1 administration (0.1, 0.3, or 1.0 mg/kg/day) also restored MPTP-induced cognitive impairments. Although chronic administration of l-DOPA (3,4-dihydroxl-l-phenylalanine; 25 mg/kg/day, i.p.) also improved motor deficits, it failed to improve the cognitive impairments. In addition, l-DOPA failed to inhibit DAergic neuronal loss and αSyn pathologies in the SNpc. In summary, the novel FABP3 ligand MF1 rescues MPTP-induced behavioural and neuropathological features, suggesting that MF1 may be a disease-modifying drug candidate for synucleinopathies.

Aquatic exercise improves motor impairments in people with Parkinson's disease, with similar or greater benefits than land-based exercise: a systematic review.

What are the effects of aquatic exercise on disease severity, (non-)motor impairments, activity performance, fear of falling, and quality of life in people with Parkinson's disease (PD)? Does aquatic exercise have greater effects on these outcomes than other forms of exercise in people with PD? Systematic review and meta-analysis of randomised controlled trials. People with idiopathic PD. Supervised aquatic exercise programs ≥ 2 weeks. The primary outcomes were disease severity, motor impairments, activity performance, and fear of falling. The secondary outcomes were non-motor impairments and quality of life. Of the 129 identified records, seven trials met the inclusion criteria and six were meta-analysed (159 participants). One trial assessed the effect of aquatic exercise compared with control and found a significant improvement in the Unified Parkinson's Disease Rating Scale Part III (MD-4.6, 95% CI-7.5 to-1.7) in favour of aquatic exercise. Six studies compared aquatic exercise with land-based exercise after intervention (mean 7.2 weeks of training (SD 2.2); 159 participants). The effect of aquatic exercise was superior to land-based exercise on the Berg Balance Scale (MD 2.7, 95% CI 1.6 to 3.9), the Falls Efficacy Scale (MD-4.0, 95% CI-6.1 to-1.8) and the 39-item Parkinson's Disease Questionnaire (MD-6.0, 95% CI-11.3 to-0.6), with no other significant effects identified. The significant benefit on the Berg Balance Scale was maintained at the follow-up assessment (MD 6.3, 95% CI 2.1 to 10.5, 54 participants). Aquatic exercise improves motor impairments in people with PD significantly more than no intervention. It also has slightly to moderately greater benefits than land-based exercise on balance capacity, fear of falling, and health-related quality of life. On other outcomes, the benefits of aquatic exercise are similar to those of land-based exercise. PROSPERO CRD42017077370.

The Use of Noninvasive Brain Stimulation, Specifically Transcranial Direct Current Stimulation After Stroke.

The Use of Noninvasive Brain Stimulation, Specifically Transcranial Direct Current Stimulation After Stroke.

C-Abl Inhibition Exerts Symptomatic Antiparkinsonian Effects Through a Striatal Postsynaptic Mechanism.

Parkinson’s disease (PD) is caused by a progressive degeneration of nigral dopaminergic cells leading to striatal dopamine deficiency. From the perspective of antiparkinsonian drug mechanisms, pharmacologic treatment of PD can be divided into symptomatic and disease-modifying (neuroprotective) therapies. An increase in the level and activity of the Abelson non-receptor tyrosine kinase (c-Abl) has been identified in both human and mouse brains under PD conditions. In the last decade, it has been observed that the inhibition of c-Abl activity holds promise for protection against the degeneration of nigral dopaminergic cells in PD and thereby exerts antiparkinsonian effects. Accordingly, c-Abl inhibitors have been applied clinically as a disease-modifying therapeutic strategy for PD treatment. Moreover, in a series of studies, including that presented here, experimental evidence suggests that in a mouse model of parkinsonism induced by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, c-Abl inhibition exerts an immediate effect improving motor impairments by normalizing altered activity in striatal postsynaptic signaling pathways mediated by Cdk5 (cyclin-dependent kinase 5) and DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein 32 kDa). Based on this, we suggest that c-Abl inhibitors represent an ideal antiparkinsonian agent that has both disease-modifying and symptomatic effects. Future research is required to carefully evaluate the therapeutic efficacy and clinical challenges associated with applying c-Abl inhibitors to the treatment of PD.

Zolpidem ameliorates motor impairments in the unilaterally 6-hydroxydopamine-lesioned rat.

Nuclei within the basal ganglia-such as the globus pallidus external segment, subthalamic nucleus, and substantia nigra pars reticulata-have been shown to exhibit synchronous bursting activity entrained to excessive cortical beta oscillations following dopamine depletion. Zolpidem binds to GABAA receptors with selectivity for those expressing the α1 subunit, potentiating inhibitory postsynaptic currents and increasing the time decay of channel opening. Interestingly, zolpidem-sensitive nuclei within the basal ganglia circuitry are also those that have been shown to exhibit hyperexcitation in a dopamine-depleted state. We hypothesized that a drug with selectivity for these nuclei may improve motor impairments associated with Parkinson's disease. In order to determine the threshold dose at which zolpidem might encumber motor behavior, a dose-response experiment was performed in intact rats using rotarod. Next, we tested whether subthreshold doses (0.1, 0.25, 0.5mg/kg; i.p.) of zolpidem improved volitional motor behavior/coordination using the rotarod balance beam and cylinder/paw preference tests in unilaterally 6-hydroxydopamine-lesioned rats. It was found that 0.1mg/kg zolpidem significantly improved rotarod performance and significantly reduced forelimb use asymmetry compared to undrugged post-lesion conditions. Here, we present the first translational evidence for a role of zolpidem-sensitive GABAA receptors in the treatment of PD motor symptoms. Our data show that zolpidem improves both motor coordination and volitional forelimb use in the unilateral 6-hydroxydopamine lesion model of PD, and thus suggest that zolpidem-sensitive GABAA receptors may represent a novel therapeutic target for the treatment of motor symptoms of Parkinson's disease.