Patient selected goals and satisfaction after bilateral subthalamic nucleus deep brain stimulation in Parkinson's disease.

Assessing patient goals is crucial in understanding patient centered outcomes and satisfaction. However, patient goals may change throughout treatment. Our objective is to identify the changes in patient-selected goals of Parkinson's disease (PD) patients undergoing bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and examine the relationship among patient-selected goal achievement, standard DBS outcome measures, and overall patient satisfaction. Seventy-five patients undergoing bilateral STN-DBS listed three patient-selected goals before surgery. After six months, patients were asked to restate the three goals and to rate the degree of goal achievement and the overall satisfaction of surgery. The three most frequently selected goals were "dyskinesia", "gait disorder", and "medication off duration". After six months, 80.0% of patients could not accurately recall their pre-DBS goals. "Dyskinesia" was the most consistently selected goal, more patients selected "tremor" and "less medication" at post-DBS compared to pre-DBS, and less patients selected "gait disorder" at post-DBS compared to pre-DBS. 74.7% of patients reported overall satisfaction by stating they were "very much" or "much better after surgery". Patient satisfaction significantly correlated with goal achievement (r = 0.640; p < 0.001). Interestingly, change in UPDRS motor scores did not correlate with patient satisfaction (r = 0.100; p = 0.395). Although recalled goals do not accurately represent the pre-surgical goals, the achievement score for recalled goals significantly correlated with patient satisfaction. Patient goals change due to many reasons. Therefore, follow-up patient counseling to discuss goals and outcomes is important in improving patient satisfaction after STN-DBS.

Targeted upregulation of uncoupling protein 2 within the basal ganglia output structure ameliorates dyskinesia after severe liver failure.

Impaired motor function, due to the dysfunction of the basal ganglia, is the most common syndrome of hepatic encephalopathy (HE), and its etiology remains poorly understood. Neural oxidative stress is shown to be the major cellular defects contributing to HE pathogenesis. Mitochondrial uncoupling protein 2 (UCP2) has been implicated in neuroprotection in several neurological disorders. We explored the neuroprotective role of UCP2 within the substantia nigra pars reticulate (SNr), the output structure of the basal ganglia, in HE. The toxin thioacetamide (TAA) induced HE mice showed hypolocomotion, which was associated with decreased ATP levels and loss of antioxidant substances SOD and GSH within the SNr. Stable overexpression of UCP2 via AAV-UCP2 under the control of the UCP2 promoter in bilateral SNr preserved local ATP level, increased antioxidant substances, and ameliorated locomotion defects after severe liver failure. Contrary to UCP2 overexpression, targeted knockdown of UCP2 within bilateral SNr via AAV-UCP2 shRNA exacerbated the impaired mitochondrial dysfunction and hypokinesia in HE mice. The modulatory effects of UCP2 was due to mediation of K+-Cl- cotransporter-2 (KCC2) expression on GABAergic neurons of SNr. Taken together, our results demonstrate that UCP2 exerts a neural protective role at the subcortical level by increasing the resistance of neurons to oxidative stress, which may offer a novel therapeutic target for the treatment of motor dysfunction diseases.

Resveratrol Protects Against Vacuous Chewing Movements Induced by Chronic Treatment with Fluphenazine.

Typical antipsychotics, which are commonly used to treat schizophrenia, cause motor disorders such as tardive dyskinesia (TD) in humans and orofacial dyskinesia (OD) in rodents. The disease mechanisms as well as treatment effectiveness are still unknown. In this study, we investigated the effect of resveratrol, a polyphenol with neuroprotective properties, on behavioral changes induced by chronic treatment with fluphenazine in rats and the possible relationship between monoamine oxidase (MAO) activity and vacuous chewing movements (VCMs). Rats were treated for 18 weeks with fluphenazine enantate [25 mg/kg, intramuscularly (i.m.), every 21 days] and/or resveratrol (20 mg/kg, offered daily in drinking water). Next, body weight gain, behavioral parameters (VCMs and open field tests-locomotor and rearing activity), and MAO activity were evaluated. Fluphenazine treatment reduced body weight gain, number of crossings and rearings, and the co-treatment with resveratrol did not affect these alterations. Fluphenazine increased the prevalence and intensity of VCMs and the co-treatment with resveratrol reduced the VCMs. Furthermore, a negative correlation was found between the number of VCMs and MAO-B activity in the striatum of rats. Our data suggest that resveratrol could be promissory to decrease OD. Moreover, MAO-B activity in the striatum seems to be related to VCMs intensity.

Advances in biomaterials for preventing tissue adhesion.

Adhesion is one of the most common postsurgical complications, occurring simultaneously as the damaged tissue heals. Accompanied by symptoms such as inflammation, pain and even dyskinesia in particular circumstances, tissue adhesion has substantially compromised the quality of life of patients. Instead of passive treatment, which involves high cost and prolonged hospital stay, active intervention to prevent the adhesion from happening has been accepted as the optimized strategy against this complication. Herein, this paper will cover not only the mechanism of adhesion forming, but also the biomaterials and medicines used in its prevention. Apart from acting as a direct barrier, biomaterials also show promising anti-adhesive bioactivity though their intrinsic physical and chemical are still not completely unveiled. Considering the diversity of human tissue organization, it is imperative that various biomaterials in combination with specific medicine could be tuned to fit the microenvironment of targeted tissues. With the illustration of different adhesion mechanism and solutions, we hope this review can become a beacon and further inspires the development of anti-adhesion biomedicines.

Report: Protective effects of rice bran oil in haloperidol-induced tardive dyskinesia and serotonergic responses in rats.

Effect of administration of Rice bran oil (RBO) was evaluated on haloperidol elicited tardive dyskinesia in rats. Albino Wistar rats treated with haloperidol in drinking water at a dose of 0.2mg/kg/day and RBO by oral tubes at a dose of 0.4 mL/day for 5 weeks. Motor coordination, VCMs and 8-hydroxy-2-(di-n-propylamino) tetraline)[8-OH-DPAT] _syndrome were monitored. Striatal serotonin (5-hydroxytryptamine; 5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels were determined by high performance liquid chromatography (HPLC-EC). Rats treated with haloperidol orally at a dose of for a period of 5 weeks developed VCMs, which increased progressively as the treatment continued for 5 weeks. Motor coordination impairment started after the 1st week and was maximally impaired after 3 weeks and gradually returned to the 1st week value. Co-administration of RBO prevented haloperidol_induced VCMs as well impairment of motor coordination. The intensity of 8-OH-DPAT_induced syndrome and decreased 5-HT metabolism were greater in water + haloperidol treated animals than RBO + haloperidol treated animals. The present study suggested that involvement of free radical in the development of TD and point to RBO as a possible therapeutic option to treat this hyperkinetic motor disorder.

Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors.

Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice.

Levodopa/benserazide microsphere (LBM) prevents L-dopa induced dyskinesia by inactivation of the DR1/PKA/P-tau pathway in 6-OHDA-lesioned Parkinson's rats.

L-3, 4-dihydroxyphenylalanine (L-dopa) is the gold standard for symptomatic treatment of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). In the present study, L-dopa and benserazide were loaded by poly (lactic-co-glycolic acid) microspheres (LBM), which can release levodopa and benserazide in a sustained manner in order to continuous stimulate dopaminergic receptors. We investigated the role of striatal DR1/PKA/P-tau signal transduction in the molecular event underlying LID in the 6-OHDA-lesioned rat model of PD. We found that animals rendered dyskinetic by L-dopa treatment, administration of LBM prevented the severity of AIM score, as well as improvement in motor function. Moreover, we also showed L-dopa elicits profound alterations in the activity of three LID molecular markers, namely DR1/PKA/P-tau (ser396). These modifications are totally prevented by LBM treatment, a similar way to achieve continuous dopaminergic delivery (CDD). In conclusion, our experiments provided evidence that intermittent administration of L-dopa, but not continuous delivery, and DR1/PKA/p-tau (ser396) activation played a critical role in the molecular and behavioural induction of LID in 6-OHDA-lesioned rats. In addition, LBM treatment prevented the development of LID by inhibiting the expression of DR1/PKA/p-tau, as well as PPEB mRNA in dyskintic rats.

Resveratrol prevents akinesia and restores neuronal tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta of diabetic rats.

This study evaluated the effects of resveratrol on locomotor behaviors, neuronal and glial densities, and tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta of rats with streptozotocin-induced diabetes. Animals were divided into four groups: non-diabetic rats treated with saline (SAL), non-diabetic rats treated with resveratrol (RSV), diabetic rats treated with saline (DM) and diabetic rats treated with resveratrol (DM+RSV). The animals received oral gavage with resveratrol (20 mg/kg) for 35 days. The open field test and the bar test were performed to evaluate bradykinesia and akinesia, respectively. The Nissl-stained neuronal and glial densities and the dopaminergic neuronal density were estimated using planar morphometry. Tyrosine hydroxylase immunoreactivity was evaluated using regional and cellular optical densitometry. In relation to the locomotor behaviors, it was observed that the DM group developed akinesia, which was attenuated by resveratrol in the DM+RSV group, while the DM and DM+RSV groups showed bradykinesia. Our main morpho-physiological results demonstrated: a decrease in the cellular tyrosine hydroxylase immunoreactivity in the DM group, which was attenuated by resveratrol in the DM+RSV group; a higher neuronal density in the RSV group, when compared to the DM and DM+RSV groups; an increase in the glial density in the DM group, which was also reversed by resveratrol in the DM+RSV group. Resveratrol treatment prevents akinesia development and restores neuronal tyrosine hydroxylase immunoreactivity and glial density in the substantia nigra pars compacta of diabetic rats, suggesting that this polyphenol could be a potential therapeutic option against diabetes-induced nigrostriatal dysfunctions.

Exendin-4 treatment enhances L-DOPA evoked release of striatal dopamine and decreases dyskinetic movements in the 6-hydoxydopamine lesioned rat.

OBJECTIVES: To determine whether the glucagon-like 1 peptide analogue exendin-4 (EX-4) augments the neurochemical effects of a single L-DOPA treatment and whether EX-4 can decrease L-DOPA induced dyskinesias (LIDS). METHODS: Rats were lesioned with 6-hydroxydopamine (6-OHDA) and 7 days later given EX-4 for 7 days. The following day, rats were given L-DOPA and extracellular dopamine was measured. The animals were then killed to determine tissue dopamine. To study LIDS, EX-4 and/or L-DOPA were co-administered daily, 7 days after 6-OHDA. LIDS were determined on Days 2, 4, 8, 12 and 16 prior to neurochemical assessment. KEY FINDINGS: EX-4 reduced 6-OHDA induced damage. Acute effects of L-DOPA were potentiated by EX-4 in lesioned rats. Treatments with EX-4 caused a progressive reduction in LIDS. CONCLUSIONS: EX-4 treatment potentiates the effects of a single dose of L-DOPA. This augmentation indicates that lower L-DOPA doses might be used to the same effect in patients. The reduction in LIDS suggests that co-treatment with EX-4 could allow the use of L-DOPA with fewer side-effects and possibly therefore allow earlier introduction of L-DOPA in the clinic.

Optimized adeno-associated viral vector-mediated striatal DOPA delivery restores sensorimotor function and prevents dyskinesias in a model of advanced Parkinson's disease.

Viral vector-mediated gene transfer utilizing adeno-associated viral vectors has recently entered clinical testing as a novel tool for delivery of therapeutic agents to the brain. Clinical trials in Parkinson's disease using adeno-associated viral vector-based gene therapy have shown the safety of the approach. Further efforts in this area will show if gene-based approaches can rival the therapeutic efficacy achieved with the best pharmacological therapy or other, already established, surgical interventions. One of the strategies under development for clinical application is continuous 3,4-dihydroxyphenylalanine delivery. This approach has been shown to be efficient in restoring motor function and reducing established dyskinesias in rats with a partial lesion of the nigrostriatal dopamine projection. Here we utilized high purity recombinant adeno-associated viral vectors serotype 5 coding for tyrosine hydroxylase and its co-factor synthesizing enzyme guanosine-5'-triphosphate cyclohydrolase-1, delivered at an optimal ratio of 5 : 1, to show that the enhanced 3,4-dihydroxyphenylalanine production obtained with this optimized delivery system results in robust recovery of function in spontaneous motor tests after complete dopamine denervation. We found that the therapeutic efficacy was substantial and could be maintained for at least 6 months. The tyrosine hydroxylase plus guanosine-5'-triphosphate cyclohydrolase-1 treated animals were resistant to developing dyskinesias upon peripheral l-3,4-dihydroxyphenylalanine drug challenge, which is consistent with the interpretation that continuous dopamine stimulation resulted in a normalization of the post-synaptic response. Interestingly, recovery of forelimb use in the stepping test observed here was maintained even after a second lesion depleting the serotonin input to the forebrain, suggesting that the therapeutic efficacy was not solely dependent on dopamine synthesis and release from striatal serotonergic terminals. Taken together these results show that vector-mediated continuous 3,4-dihydroxyphenylalanine delivery has the potential to provide significant symptomatic relief even in advanced stages of Parkinson's disease.

Neuroprotective effect of L-DOPA co-administered with the adenosine A2A receptor agonist CGS 21680 in an animal model of Parkinson's disease.

Adenosine A2A receptors are a new target for drug development in Parkinson's disease. Some experimental and clinical data suggest that A2A receptor antagonists can provide symptomatic improvement by potentiating the effects of L-DOPA as well as a decrease in secondary effects such as L-DOPA-induced dyskinesia. L-DOPA-induced behavioral sensitization in unilateral 6-hydroxydopamine-lesioned rats is frequently used as an experimental model of L-DOPA-induced dyskinesia. In the present work this model was used to evaluate the effect of the A2A receptor agonist CGS 21680 and the A2A receptor antagonist MSX-3 on L-DOPA-induced behavioral sensitization and 6-hydroxydopamine-induced striatal dopamine denervation. L-DOPA-induced behavioral sensitization was determined as an increase in L-DOPA-induced abnormal involuntary movements and enhancement of apomorphine-induced turning behavior. Striatal dopamine innervation was determined by measuring tyrosine-hydroxylase immunoreactivity. Chronic administration of MSX-3 was not found to be effective at counteracting L-DOPA-induced behavioral sensitization. On the other hand, CGS 21680 completely avoided the development of L-DOPA-induced behavioral sensitization. The analysis of the striatal dopamine innervation showed that L-DOPA-CGS 21680 co-treatment conferred neuroprotection to the toxic effects of 6-hydroxydopamine. This neuroprotective effect was dependent on A2A and D2 receptor stimulation, since it was counteracted by MSX-3 and by the D2 receptor antagonist haloperidol. These results open new therapeutic avenues in early events in Parkinson's disease.

Relevance of the MPTP primate model in the study of dyskinesia priming mechanisms.

For nearly 20 years, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model has allowed great strides to be made in our understanding of the maladaptive changes underlying the levodopa-related motor response complications occurring in most parkinsonian patients. Studies indicate that sustained dopamine D2 receptor occupancy can prevent and reverse existing dyskinesias. Recent experiments in levodopa-treated MPTP animals, co-administered either a threshold dose of cabergoline or a glutamate NMDA NR2B-selective antagonist (CI-1041), have afforded protection against dyskinesia, perhaps through presynaptic inhibition of glutamate release and blockade of supersensitive postsynaptic NMDA receptors in the striatum, respectively. Some of the biochemical events that have correlated with dyskinesias, namely upregulated GABA(A) receptors in the internal pallidum, rise in pre-proenkephalin-A gene expression in the striatum, and upregulated striatal glutamate ionotropic receptors and adenosine A(2a) receptors, may be counteracted by these preventive strategies.

Biofeedback rehabilitation for prevention of synkinesis after facial palsy.

OBJECTIVE: We developed a new training method of biofeedback rehabilitation for the prevention of synkinesis after facial palsy and evaluated the efficacy of the training. METHODS: Twenty-seven patients with complete facial palsy were divided randomly into 2 groups. Twelve of the patients were treated with the training method, and the other 15 patients served as controls. Patients were instructed to keep their eyes open symmetrically during mouth movements using a mirror. Thirty minutes of daily training was continued for a period of 10 months. The degree of synkinesis was evaluated by computing the percent asymmetry of eye opening width. RESULTS: The percent asymmetry of eye opening width was significantly greater in the training group than in the control group (P < 0.05). The results indicate that the degree of synkinesis is much less in the training group than in the control group. CONCLUSION: Our new training method is very effective for preventing the development of synkinesis after facial palsy.