Review: Lower urinary tract dysfunction in animal models of Parkinson's disease (PD): Translational aspects for the treatment of PD patients with overactive bladder.

Although the loss of dopaminergic neurons in the substantia nigra and consequent motor symptoms are the hallmarks of Parkinson's disease (PD), several non-motor symptoms may appear prior to these typical motor symptoms. While a variety of non-motor symptoms have emerged as the primary predictor of PD patients' quality of life, even though motor symptoms are undoubtedly distressing. According to a study, the prevalence of lower urinary tract symptoms (LUTS) varies between 27% and 64%, suggesting that PD-related lower urinary tract dysfunction may be affected by the disease stage, the presence of concomitant conditions affecting the lower urinary tract, and other autonomic dysfunctions. Animal models can serve as a platform for research into the causes of PD-related dysfunction and the evaluation of cutting-edge therapeutic approaches although the majority of animal research have been directed toward motor symptoms of PD. At present, the cause of lower urinary tract dysfunction in PD has not been fully clarified although the increasing evidence showing the multiple mechanisms underlying PD-related LUTS has emerged. In this chapter we summarize the findings of basic research in the studies of the lower urinary tract dysfunction using with different animal PD models and we try to shed light on the translational aspects for the development of future treatment modalities in PD patients with LUTS.

Prevalence and treatment of LUTS in patients with Parkinson disease or multiple system atrophy.

The lower urinary tract is controlled by complex neural mechanisms not only in the periphery, but also in the central nervous systems (CNS). Thus, patients with a wide variety of neurological diseases often also have lower urinary tract symptoms (LUTS), including those with Parkinson disease (PD) or multiple system atrophy (MSA). LUTS are common comorbidities associated with both of these neurodegenerative diseases and are likely to impair patients' quality of life. The motor symptoms of PD and MSA often seem similar; however, the pathophysiology, and thus the treatment of LUTS differs considerably. Antimuscarinics are the first-line treatment of storage LUTS in patients with PD or MSA; however, care should be taken in the management of these patients, especially in those with MSA owing to the high risk of inefficient voiding, and thus an increased post-void residual volume. Other treatments of PD-related LUTS include α-adrenoceptor antagonists, which improve voiding dysfunction, transurethral resection of the prostate for bladder outlet obstruction owing to prostate enlargement, and neuromodulation and intradetrusor botulinum toxin injections for storage LUTS. However, more conservative treatments, including intermittent catheterization, are required for LUTS in patients with MSA, owing to the high incidence of impaired detrusor contractility and detrusor-sphincter dyssynergia.

Official Japanese Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale: validation against the original English version.

BACKGROUND: The Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease (PD) Rating Scale (UPDRS) (MDS-UPDRS) has been developed and is now available in English. Part of the overall program includes the establishment of official non-English translations of the MDS-UPDRS. We present the process for completing the official Japanese translation of the MDS-UPDRS with clinimetric testing results. METHODS: In this trial, the MDS-UPDRS was translated into Japanese, underwent cognitive pre-testing, and the translation was modified after taking the results into account. The final translation was approved as Official Working Draft of the MDS-UPDRS Japanese version and tested in 365 native-Japanese-speaking patients with PD. Confirmatory analyses were used to determine whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Official Working Draft of the Japanese translation. As a secondary analysis, we used exploratory factor analyses to examine the underlying factor structure without the constraint of a pre-specified factor organization. RESULTS: Confirmatory factor analysis revealed that Comparative Fit Index for all Parts of the MDS-UPDRS exceeded the minimal standard of 0.90 relative to the English version and therefore Japanese translation met the pre-specified criterion to be designated called an OFFICIAL MDS TRANSLATION. Secondary analyses revealed some differences between the English-language MDS-UPDRS and the Japanese translation, however, these differences were considered to be within an acceptable range. CONCLUSIONS: The Japanese version of the MDS-UPDRS met the criterion as an Official MDS Translation and is now available for use (www.movementdisorders.org).

Roles of adenosine A1 and A2A receptors in the control of micturition in rats.

AIMS: Adenosine is a neurotransmitter that exerts numerous physiological effects in many organs. However, few studies have focused on the role of adenosine receptors in the control of micturition. Therefore, we examined the role of adenosine A1 and A2A receptors in the control of bladder activity in rats with normal or acetic acid (AA) irritated bladders. METHODS: Cystometrograms during saline or 0.2% AA infusion were recorded under urethane anesthesia in female Sprague-Dawley rats. After a stabilization period, CCPA (A1 receptor agonist) and/or ZM24138 (A2A receptor antagonist) were administered intravenously (i.v.), intrathecally (i.t.), intracerebroventricularly (i.c.v.), or intravesically. Micturition parameters were recorded and compared before and after drug administration. RESULTS: I.v., i.t., or i.c.v. administration of CCPA or ZM24138 significantly increased intercontraction intervals (ICIs) in both saline and AA infusion groups. During AA infusion, the inhibitory effects induced by i.c.v. CCPA or i.t. ZM24138 were significantly greater than those by i.t. or i.c.v. administration, respectively. Intravesical administration of CCPA, but not ZM24138, significantly increased ICI. CONCLUSIONS: These results indicated that: (1) when nociceptive signals from the bladder increase, adenosine A1 receptor-mediated inhibition of micturition is enhanced in the brain, compared to the normal condition, (2) A1 receptor activation also exerts a peripheral inhibitory effect on micturition, and (3) adenosine A2A receptor-mediated excitatory mechanisms are enhanced in the spinal cord following C-fiber bladder afferent stimulation. Thus adenosine A1 receptor agonists and A2A receptor antagonists might be effective for the treatment of overactive bladder and/or bladder hypersensitive disorders, in which C-fiber afferent function is enhanced.

Blood pressure fluctuation and hypertension in patients with Parkinson's disease.

OBJECTIVES: Blood pressure (BP) abnormalities have been known in Parkinson's disease (PD) patients. The present study aimed at determining how the BPs of PD patients fluctuate in a day. METHODS: A total of 37 PD patients and 44 OD (other disease) patients, all of who were inpatients, were monitored every 30 min by 24-h ambulatory blood pressure monitoring (ABPM). RESULTS: The average systolic BP and the number of patients who showed postprandial hypotension were not different between the two groups. However, occurrence of nocturnal hypertension, BP fluctuation of over 100 mmHg in a day and BP of over 200 mmHg were significantly more frequently observed in the PD patients than in the OD patients. In the PD patients, these parameters were not different between those who were suffering from the disease for less than 10 years and those with the disease for 10 years or longer, as well as between those who had a Hoehn-Yahr staging scale of 2-3 and those with a scale of 4-5. CONCLUSION: Twenty-four-hour ABPM, not BP measurement once a day, enables us to determine the actual BP in PD patients. Although hypotension is a severe risk factor for falling and syncope, we emphasize the importance of monitoring rather hypertension and fluctuating BP in PD patients that may lead to a variety of other undesirable conditions. Management of hypotension, hypertension, and BP fluctuation is an important issue in the future.

Efficacy and safety of extended- versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial.

OBJECTIVES: To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). METHODS: After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. RESULTS: Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. CONCLUSIONS: In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Suppression of bladder overactivity by adenosine A2A receptor antagonist in a rat model of Parkinson disease.

PURPOSE: Overactive bladder is highly prevalent among patients with Parkinson disease. Adenosine is an important neurotransmitter in the central nervous system but it is not fully clarified how adenosine receptors regulate the micturition reflex. Thus, we examined the effect of an adenosine A2A receptor antagonist on the micturition reflex in a rat model of Parkinson disease. MATERIALS AND METHODS: In a rat model of Parkinson disease induced by 6-hydroxydopamine (Tocris Bioscience, Ellisville, Missouri) injection we examined the effects of the adenosine A2A receptor antagonist ZM241385, the dopamine D1 receptor agonist SKF38393 and the dopamine D2 receptor agonist quinpirole on bladder activity. RESULTS: Intravenous administration of ZM241385 increased the intercontraction interval in a dose dependent manner in rats with Parkinson disease and sham operated rats but the inhibitory effect was greater in the Parkinson disease group. Intrathecal and intracerebroventricular administration of ZM241385 increased the intercontraction interval in each group. However, in rats with Parkinson disease the inhibitory effects induced by intracerebroventricular administration of ZM241385 were greater than in sham operated rats. Intravenous administration of SKF38393 increased the intercontraction interval in rats with Parkinson disease and subsequent administration of ZM further increased the intercontraction interval. However, SKF38393 did not increase the intercontraction interval after ZM241385 application. Also, ZM241385 increased the intercontraction interval without being affected by pre-administration or post-administration of quinpirole, which decreased the intercontraction interval. CONCLUSIONS: Results indicate that the adenosine A2A receptor mediated excitatory mechanism is enhanced at a supraspinal site to induce bladder overactivity and A2A receptor inhibition effectively suppresses bladder overactivity in rats with Parkinson disease. Thus, adenosine A2A receptor antagonists could be useful for bladder dysfunction in Parkinson disease cases.

BALB/c-Fcgr2bPdcd1 mouse expressing anti-urothelial antibody is a novel model of autoimmune cystitis.

We report the impact of anti-urothelial autoantibody (AUAb) on urinary bladder phenotype in BALB/c mice deficient of the FcγRIIb and PD-1. AUAb was present in serum samples from approximately half of the double-knockout (DKO) mice, as detected by immunofluorescence and immunoblots for urothelial proteins including uroplakin IIIa. The AUAb-positive DKO mice showed degeneration of urothelial plaque and umbrella cells, along with infiltration of inflammatory cells in the suburothelial layer. TNFα and IL-1ß were upregulated in the bladder and the urine of AUAb-positive DKO mice. Voiding behavior of mice was analyzed by the Voided Stain on Paper method. 10-week-old and older AUAb-positive DKO mice voided significantly less urine per void than did wild type (WT) mice. Furthermore, administration of the AUAb-containing serum to WT mice significantly reduced their urine volume per void. In summary, this report presents a novel comprehensive mouse model of autoimmune cystitis.

Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study.

The objectives of this study were to evaluate the efficacy of istradefylline at an oral dose of 20 mg or 40 mg once daily for 12 weeks in Parkinson's disease (PD) patients with motor complications on levodopa therapy based on the change in the daily OFF time compared with placebo and to assess the safety at these doses. A total of 363 subjects were randomly assigned to receive 20 mg/day istradefylline (n = 119), 40 mg/day istradefylline (n = 125), or placebo (n = 119). The primary outcome variable was the change from baseline at endpoint in daily OFF time based on patients' ON/OFF diaries. At endpoint, the daily OFF time reduced from baseline by 1.31 hours for 20 mg/day istradefylline (P = 0.013 as compared to the placebo), 1.58 hours for 40 mg/day istradefylline (P < 0.001), and 0.66 hours for placebo; istradefylline significantly reduced the daily OFF time compared with placebo. The UPDRS Part III subscale score (ON state) reduced by 5.7 at endpoint in both istradefylline groups and 3.7 in the placebo group (P = 0.006 for 20 mg/day and P = 0.006 for 40 mg/day group as compared with placebo). The most commonly reported drug-related treatment emergent adverse event (TEAE) was dyskinesia, which occurred in 2.5% (3/119) of subjects receiving placebo, 8.5% (10/118) receiving 20 mg/day istradefylline, and 6.4% (8/125) receiving 40 mg/day istradefylline. We conclude that istradefylline at 20 mg and 40 mg once daily is effective in relieving wearing-off fluctuations of PD patients. In addition, istradefylline was well tolerated at both doses.

The effect of dopamine agonists: the expression of GDNF, NGF, and BDNF in cultured mouse astrocytes.

In Parkinson's disease, cell death is selectively induced in mesencephalic nigral dopaminergic neurons. At present, no disease modifying therapy or radical treatment has been found for this disease. Some dopamine agonists may have a neuroprotective action in cultured cells and animal models. In the present study, we examined stimulating effects of a non-ergoline D(2) dopamine agonist, ropinirole, on synthesis/secretion of neurotrophic factors, including NGF, BDNF, and GDNF, in cultured mouse astrocytes. These effects were compared with those of ergoline dopamine agonists, SKF-38393, a D(1) agonist, bromocriptine, D(2) agonist, and apomorphine, D(1)/D(2) agonist. Ropinirole elevated GDNF levels to 4-fold, and NGF levels to 6.3-fold, compared with the control group. Of the dopamine agonists examined, ropinirole produced and secreted more GDNF than a 1.8-fold greater amount of apomorphine, a lesser amount of bromocriptine, or a 2.8-fold greater amount of SKF-38393, which served as the control group.

Amantadine for dyskinesias in Parkinson's disease: a randomized controlled trial.

BACKGROUND: Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias. METHODS: In this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson's disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg/day) or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS) during each treatment period. The secondary outcome measures were changes in the Unified Parkinson's Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias), part IVb (motor fluctuations), and part III (motor function). RESULTS: RDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5). UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD) of 1.83 (1.56)] compared with placebo-treated patients [0.03 (1.51)]. However, there were no significant effects on UPDRS-IVb or III scores. CONCLUSIONS: Results from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60-70% of patients. TRIAL REGISTRATION: UMIN Clinical Trial Registry UMIN000000780.

Early addition of selegiline to L-Dopa treatment is beneficial for patients with Parkinson disease.

OBJECTIVES: To evaluate the clinical outcome of Parkinson disease (PD) patients treated with selegiline (with L-Dopa/decarboxylase inhibitor) in the early stage of the disease in comparison with that of late-stage use of selegiline. METHODS: The study and the reference groups were extracted from a large database of the registry of all selegiline users (4692) between year 1998 and 2003 according to the defined criteria. The study group consisted of 106 PD patients who received selegiline within 5 years from the onset of the disease and were followed up for 7 years in average. The reference group consisted of 585 PD patients with comparable disease duration who received selegiline for 16 weeks from 9 to 11 years (mean [SD], 9.9 [0.7]) after the onset of the disease, and the evaluation was made before and after the treatment with selegiline. RESULTS: The sum of the Unified Parkinson's Disease Rating Scale (UPDRS) scores of 6 major motor symptoms of the study group was significantly lower than that of the reference group (mean [SD], 7.78 [4.30] vs 11.41 [3.88]; P < 0.0001) when compared at a point with the same disease duration (9.8 [1.7] vs 9.9 [0.7] years). The mean UPDRS score of the reference group after 4 months' treatment with selegiline did not reach that of the study group (mean [SD], 9.40 [3.76] vs 7.78 [4.30]; P = 0.0002). CONCLUSIONS: The clinical outcome as evaluated by the selected UPDRS motor scores was better for L-Dopa-treated patients who received selegiline within 5 years from the onset compared with those who received selegiline approximately 10 years from the onset.

Nationwide survey of acute juvenile female non-herpetic encephalitis in Japan: relationship to anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: To study the incidence and clinical features of acute juvenile female non-herpetic encephalitis (AJFNHE) in Japan. METHODS: A nationwide questionnaire on patients with severe non-herpetic encephalitis of unknown etiology with a prolonged clinical course or death was sent to the departments of Internal Medicine, Neurology, Pediatrics, and Emergency and Critical Care at all hospitals with 200 beds or more in Japan. RESULTS: The recovery rate was 25% (1,279 out of 5,030 departments) and 90 patients were enrolled in this study. The annual incidence was 0.33/10(6) population. 85% of patients were female. The means and standard deviations of age at onset and hospital stay were 26+/-10 years and 180+/-228 days. As first symptoms, fever and psychosis were presented in 90%. Among the neurological symptoms, disturbance of consciousness was presented in 92%, convulsions in 65%, and involuntary movements in 55%. Respiratory failure during hospitalization was observed in 71% and required care with mechanical ventilation. The detection rate of anti-GluR epsilon2 and/or delta1 antibodies was 67% of patients. Anti-N-methyl-D-aspartate receptor NR1/NR2 antibody was detected in all four examined patients with anti-GluR epsilon2 antibody, and also detected in both of the two examined patients without anti-GluR epsilon2 antibody. As for outcome, 46% returned to work and 37% returned home, but 7% died. Associated tumors were demonstrated in 39%. All reported patients had ovarian tumors, among which teratoma was the most frequent. CONCLUSION: A nationwide survey provided data for the annual incidence and clinical features of AJFNHE in Japan.

High risk factors for valvular heart disease from dopamine agonists in patients with Parkinson's disease.

An association between ergot-derived dopamine agonists and asymptomatic valvular heart disease in Parkinson's disease has been established. For safe use of these agonists, it is important to specify those at high risk for valvular heart disease among patients with Parkinson's disease. We performed a nested case-control study of 223 patients with Parkinson's disease. In results of multivariable logistic analyses, use of pergolide, use of cabergoline, age, male sex, and hypertension were independent significant risk factors for left-sided valvular regurgitation. In patients receiving cabergoline or pergolide, elderly (>or=70 years) hypertensive patients had a markedly high risk for valvular regurgitation (odds ratio 94.5) as compared to non-elderly (<70 years) patients without hypertension. The risk of valvular regurgitation caused by pergolide or cabergoline was found to be highly enhanced by comorbid hypertension or aging, suggesting that special attention should be paid when prescribing cabergoline or pergolide for those patients.

Degeneration of dementia with Lewy bodies measured by diffusion tensor imaging.

Dementia with Lewy bodies (DLB) is the second most common form of dementia. It is thought to involve impairment of the visual association area. In this study, we applied diffusion tensor imaging (DTI) to examine the microstructural interruption of visual association areas in patients with DLB. The DTI metrics of three visual association fibres - the inferior longitudinal fasciculus (ILF), visual pathway, and splenial fibres - were compared between 14 patients with DLB and 13 healthy subjects. The fractional anisotropy value of the ILF was significantly lower in patients with DLB than in healthy subjects. The difference in the mean diffusivity value of ILF was at trend level. The lambda(2),(3) of ILF were significantly lower in patients with DLB; however, there was no difference in lambda(1). DTI metrics of the visual pathway and splenial fibres showed no differences between the groups. Our results showed degeneration of the ILF, which is responsible for visuospatial cognition. ILF dysfunction may influence the clinical features in DLB.

Ropinirole is effective on motor function when used as an adjunct to levodopa in Parkinson's disease: STRONG study.

We report the results of a randomized, double-blind, placebo-controlled, 16-week study to evaluate the efficacy and safety of ropinirole, 0.75 to 15.0 mg/day, as an adjunct to levodopa. A total of 243 patients were randomly assigned into placebo or ropinirole groups. The mean (standard deviation) dose of ropinirole at endpoint was 7.12 (2.88) mg/day. The primary endpoint-the mean reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) total motor score-was significantly greater for the ropinirole group than the placebo group (-9.5 vs. -4.5, P = 0.00001). The mean reduction in the UPDRS total activities of daily living (ADL) score was also significantly greater for ropinirole than for placebo (-2.7 vs. -1.0, P = 0.0002). The percentage of patients showing at least a 20% reduction in the percentage of time spent "off" was significantly greater for the ropinirole group than for the placebo group (58.7% vs. 38.6%, P = 0.030). A total of 84.3 and 65.6% of the patients experienced adverse events while receiving ropinirole or placebo, respectively. The results showed that ropinirole was more effective than placebo in improving motor function and ADL when used as an adjunct to levodopa in patients with advanced Parkinson's disease.

Placebo-controlled, double-blind dose-finding study of entacapone in fluctuating parkinsonian patients.

We conducted a multicenter randomized, placebo-controlled double-blind parallel-group study in Japanese Parkinson's disease (PD) patients with wearing-off motor fluctuations to determine the clinical efficacy and safety of entacapone as an adjunct to concomitant treatment with levodopa and a dopa decarboxylase inhibitor (DCI). We randomized 341 patients to receive entacapone 100 or 200 mg or placebo per dose of levodopa/DCI for 8 weeks. The primary efficacy variable was on time change while awake, determined by patients' diaries. Mean baseline on time in each group was approximately 8 hours. Mean on time change at final assessment was 1.4 hours each for entacapone 100-mg and 200-mg groups and by 0.5 hours for the placebo group (P < 0.05). The two entacapone doses were equally efficacious. Adverse events occurred in 79 patients (69.9%) in placebo, 82 (72.6%) in 100 mg, and 98 (86.0%) in 200 mg. The most common adverse event with entacapone was an increase in dyskinesias. The overall safety profile was satisfactory in both entacapone groups. In conclusion, both entacapone 100 and 200 mg were equally effective in increasing on time of PD patients with wearing-off fluctuations, although the safety and tolerability profile appeared more favorable for the 100-mg dose.

Dopaminergic mechanisms controlling urethral function in rats.

AIMS: To investigate the role of dopamine receptor subtypes in the control of urethral activity. METHODS: Simultaneous recordings of intravesical and urethral perfusion pressure (UPP) were performed in rats under urethane anesthesia. Changes in coordinated activity of the bladder and urethral sphincter were examined following intravenous (i.v.), intrathecal (i.t.), or intracerebroventricular (i.c.v.) administration of dopamine D1- and D2-like receptor agonists (SKF38393 and quinpirole, respectively) and antagonists (SCH23390 and remoxipride, respectively). RESULTS: Quinpirole (0.03, 0.1, and 0.3 mg/kg i.v.) dose-dependently decreased baseline urethral pressure to 45.33 +/- 5.8, 33.7 +/- 3.3 (P < 0.05, n = 6), and 27.7 +/- 3.3 cm H(2)O (P < 0.05, n = 5) from the control value (46.0 +/- 4.0 cm H(2)O), respectively. i.c.v. injection of quinpirole (1 microg) decreased baseline urethral pressure to 33.6 +/- 5.0 cm H(2)O (P < 0.05, n = 4) from the control value (51.4 +/- 4.9 cm H(2)O) in contrast to the insignificant effects of i.t. administration of the drug (3 microg). The decrement of baseline pressure induced by quinpirole (0.1 mg/kg i.v.) was suppressed by alpha-bungarotoxin (BGT), a neuromuscular blocking agent. SCH23390 (1 and 3 mg/kg, i.v.) dose-dependently decreased the frequency of high frequency oscillation (HFO) of the urethral sphincter. SKF38393 or remoxipride did not have significant effects on any parameters of bladder and urethral activity. CONCLUSIONS: These results indicate that activation of D2-like dopamine receptors at a supraspinal site can suppress activity of the striated muscle urethral sphincter. Thus, decreased urethral resistance induced by D2 dopamine receptor activation might aggravate urge incontinence symptoms often seen in patients with Parkinson's disease (PD).

Resistin concentrations in murine adipose tissue and serum measured by a new enzyme immunoassay.

OBJECTIVE: In an attempt to clarify the conflicting data on resistin mRNA expression and protein analysis by western blotting in adipose tissue and serum, we developed a sensitive enzyme-linked immunosorbent assay (ELISA) for direct measurement of mouse resistin. RESEARCH METHODS AND PROCEDURES: We developed polyclonal antibodies directed to the N (21 to 40) and C (79 to 91) termini of mouse resistin. Then, affinity-purified anti-C-terminal resistin immunoglobin G (IgG) was biotinylated. ELISA was based on the sandwiching of antigen between antibody IgG coated on polystyrene plates and biotinylated antibody IgG. The bound biotinylated antibody was quantified with streptavidin-linked horseradish peroxidase. RESULTS: New ELISA can measure a concentration as low as 0.5 ng/mL of recombinant mouse resistin and is sensitive and specific enough to measure resistin protein in various adipose tissues and in sera. In normal mice, decreases in resistin concentrations in both white adipose tissue and serum were age dependent during 6 to 24 weeks of development. Resistin concentrations were significantly higher in omental adipose tissue in comparison with perirenal and abdominal adipose tissues and were 2- to 5-fold higher in females than males during the growth period. ob/ob mice had significantly lower resistin concentrations than the control mice in both sera and the white adipose tissues, particularly in the omental fat. The treatment by testosterone, but not progesterone or beta-estradiol, in cultured adipocytes reduces resistin protein levels in a dose-dependent manner. DISCUSSION: New sensitive ELISA for mouse resistin clarified that the resistin concentrations in normal mice were markedly elevated in the omental adipose depots as compared with the perirenal and abdominal adipocyte depots and significantly elevated compared with adipose tissues in genetically obese mice.

Neuroprotection and enhanced recovery with edaravone after acute spinal cord injury in rats.

STUDY DESIGN: The effect of edaravone, a novel free radical scavenger, was assessed functionally and histologically using a rat spinal cord contusion model. OBJECTIVE: To investigate the effect of edaravone on neuroprotection after spinal cord injury in rats. SUMMARY OF BACKGROUND DATA: The spinal cord injury results in immediate physical damage (primary injury), followed by a prolonged neural tissue disorder (secondary injury). This secondary injury process has been suggested to be induced by lipid peroxidation. Edaravone has been reported to inhibit lipid peroxidation in cerebral ischemia models. METHODS: Spinal cord injury at the T10 level was induced with a weight drop device (10 g weight, 25 mm height). Edaravone was administered intravenously as a bolus dose of 5 mg/kg at 5 minutes, 24 hours, and 48 hours after injury (edaravone-treated rats). In control rats, nothing was administered. Functional assessment was conducted weekly using the Basso-Beattie-Bresnahan locomotor rating scores. Histologically, a percentage of spared white matter area was calculated. The effects of intravenous administration of edaravone on lipid peroxide formation in rat spinal cord homogenate were examined using the thiobarbituric acid test for malonyldialdehyde production. RESULTS: Six weeks after injury, edaravone-treated rats showed significantly higher motor score and larger spared white matter area than control rats. The administration of edaravone attenuated malonyldialdehyde production in spinal cord homogenate by >45%. CONCLUSION: Edaravone enhanced functional recovery and preserved more spinal cord tissue after spinal cord injury in rats. The attenuation of posttraumatic lipid peroxide formation by edaravone partially contributed to this enhancement.