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.

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.

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.

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.

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.

Influence of a tumor necrosis factor gene polymorphism in Japanese patients with multiple system atrophy.

We studied promoter region polymorphisms in the tumor necrosis factor (TNF), interleukin (IL)-6, IL-10, and transforming growth factor (TGF)-beta1 genes in Japanese patients with multiple system atrophy (MSA) (n=122) and normal controls (n=277). The frequency of the TNF-1031C, a high producer allele of TNF, was increased significantly in MSA patients compared with controls (chi2=12.36, P=0.0021, Pc=0.0084). In contrast, there was no difference in the genotype or allele frequency in the other cytokine gene polymorphisms. We also failed to detect any difference in the disease onset between each genotype of the polymorphisms examined. Our findings suggest that TNF might have a toxic effect in MSA.

Production of NGF, BDNF and GDNF in mouse astrocyte cultures is strongly enhanced by a cerebral vasodilator, ifenprodil.

Ifenprodil, a non-competitive NMDA-receptor antagonist, has been shown to exhibit marked cytoprotective activities in animal models for focal ischemia and Parkinson's disease. To test the hypothesis that the cytoprotective effect is due to the release of neurotrophic factors (NTFs), we examined the effects of ifenprodil on the NTF contents in mouse astrocyte cultures. The results revealed that ifenprodil strongly enhanced the production of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in these cultures. The ifenprodil-induced NGF secretion was found to be partially mediated by the activation of protein kinase C (PKC) and p42/p44 mitogen-activated protein (MAP) kinase cascade pathways. These findings suggest that the cytoprotective effects of ifenprodil are probably attributed to enhanced secretion of these NTFs from astrocytes.

The effect of tau genotype on clinical features in FTDP-17.

The clinical phenotype of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) varies. This variability is seen not only between kindreds with different mutations but also in families sharing the same mutation. Inheritance of tau haplotype (H1) and genotype (H1/H1) has been established as a risk factor for some neurodegenerative disorders with parkinsonism. We assessed the effect of tau polymorphism on the clinical features of FTDP-17 in 61 cases from 30 separately ascertained families with four different tau mutations, including P301L, +16, N279K, and P301S. There were no significant differences of age at symptomatic onset and disease duration between H1/H1 and H1/H2 genotypes. The comparison between tau genotype and type of initial clinical sign showed an association between the H1/H1 genotype and parkinsonian phenotype and between the H1/H2 genotype and frontotemporal dementia phenotype (OR=11.7; 95% confidence interval, 1.4-98.7; P=0.008). Our results suggest that tau genotype does not influence the disease course. However, it may predispose to a specific clinical sign in the early stage of FTDP-17.

Dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway.

1. This study was undertaken to elucidate dopaminergic mechanisms underlying bladder hyperactivity in a rat model of Parkinson's disease (PD) induced by a unilateral 6-OHDA injection into the substantia nigra pars compacta. 2. In 6-OHDA-lesioned rats, voided volume per micturition (0.41+/-0.04 ml, mean+/-s.e.m.) measured during 24 h in a metabolic cage was significantly smaller than in sham-operated rats (0.67+/-0.07 ml). 3. Cystrometrograms (CMG) in conscious animals revealed significantly smaller bladder capacity (BC) (0.46+/-0.03 ml) in 6-OHDA-lesioned rats than in sham rats (0.72+/-0.06 ml). 4. SKF38393 (D1/D5 receptor agonist, i.v.) significantly increased BC in 6-OHDA rats without apparent effects in sham rats. SKF38393 applied intracerebroventricularly (i.c.v.) under urethane anesthesia also increased BC in 6-OHDA-lesioned rats and by a smaller increment in sham rats. 5. In contrast, quinpirole (D2/D3/D4 receptor agonist, i.v.) significantly reduced BC in sham and 6-OHDA-lesioned rats. Intrathecal injection of quinpirole similarly reduced BC in sham and 6-OHDA-lesioned rats. 6. PD128907 (D(3)-receptor agonist) did not have significant effects on BC in 6-OHDA-lesioned rats. 7. These results indicate that a rat model of PD exhibited bladder hyperactivity as observed in patients with PD, and that stimulation of D1/D5 dopamine receptors at a supraspinal site can suppress bladder hyperactivity in PD, whereas stimulation of D2/D4, but not D3, dopamine receptors had the opposite effect to reduce bladder capacity. Thus, D1/D5 dopamine receptor agonists might be effective in treating neurogenic bladder hyperactivity in PD.

Frequency of anti-AChR epsilon subunit-specific antibodies in MG.

A definite diagnosis of myasthenia gravis (MG) relies heavily on acetylcholine receptor (AChR) antibody testing. The relatively high number of antibody-negative patients therefore, causes frequent uncertainty in confirming the diagnosis. We evaluated the sensitivity and specificity of a new, commercially available AChR antibody test that uses an approximately equal mixture of AChR from TE671-epsilon (adult type) and TE671-gamma (fetal type) cells. This assay was used to re-examine 365 seronegative MG sera in which AChR antibody had not been detected by the standard assay that uses fetal type AChR. The new assay detected anti-AChR antibodies in 17 (15.5%) of 110 patients with ocular type and in 33 (12.9%) of 255 patients with generalized type MG. Anti-AChR epsilon subunit-specific antibodies were present in 13.7% of the patients in whom no AChR antibody had been detected by the standard assay, showing an increase from 79 to 82% in overall diagnostic sensitivity.

Increase of antioxidative potential by tert-butylhydroquinone protects against cell death associated with 6-hydroxydopamine-induced oxidative stress in neuroblastoma SH-SY5Y cells.

Recent findings suggest that oxidative stress caused by dopamine could be closely involved in the pathogenesis of Parkinson's disease (PD). tert-Butylhydroquinone (tBHQ) is known as a strong inducer of phase II detoxification enzymes which have antioxidative functions. In this study, we investigated the neuroprotective effect of tBHQ against 6-hydroxydopamine (6-OHDA)-induced cell death using human neuroblastoma SH-SY5Y cells. The pretreatment of SH-SY5Y cells with tBHQ significantly reduced 6-OHDA-induced generation of reactive oxygen species (ROS), the phosphorylation of c-Jun N-terminal kinase (JNK), and subsequent cell death. We also observed that tBHQ increased the intracellular glutathione levels and induced the expression of NAD(P)H:quinone oxidoreductase (NQO1) mRNA. In addition, tBHQ dose-dependently activated the antioxidant responsive element (ARE), which plays a key role in the transcriptional activation of phase II detoxification enzymes including NQO1. These results indicate that an increase of intracellular antioxidative potential in SH-SY5Y cells by tBHQ treatment protects cells from 6-OHDA-induced oxidative stress.

The novel catecholaminergic and serotoninergic activity enhancer R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane up-regulates neurotrophic factor synthesis in mouse astrocytes.

We investigated the effects of the novel catecholaminergic and serotoninergic activity enhancer R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane ((-)-BPAP) on the synthesis and secretion of neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF), in cultured mouse astrocytes. The protein and mRNA levels of the neurotrophic factors were measured using the enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction methods, respectively. The amounts of NGF, BDNF, and GDNF secreted from astrocytes into the culture medium increased by up to 120, two, and seven times higher than those of the control, respectively, by treatment with 0.35 mM (-)-BPAP for 24 h. The increases in NGF and GDNF induced by the treatment with (-)-BPAP was inhibited by concomitant treatment with actinomycin D for transcriptional blockade. Furthermore, the treatment with (-)-BPAP for 6 h increased the mRNA expression of NGF, BDNF, and GDNF. These results suggest that (-)-BPAP up-regulated neurotrophic factor synthesis in cultured astrocytes.

Effects of dopamine agonists bromocriptine, pergolide, cabergoline, and SKF-38393 on GDNF, NGF, and BDNF synthesis in cultured mouse astrocytes.

We examined the stimulatory effects of the dopamine agonists bromocriptine, pergolide, cabergoline, and SKF-38393 on the synthesis and secretion of neurotrophic factors (nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF; and glial cell line-derived neurotrophic factor, GDNF) in cultured mouse astrocytes, and clarified the role of dopamine D1 and D2 receptors in these effects. Bromocriptine, a D2 agonist, elevated NGF levels in the culture medium 6.8-fold vs. control, and significantly decreased GDNF and BDNF levels, at 24 h. Both pergolide, a D1/D2 agonist, and cabergoline, a D2/weak D1 agonist, rapidly elevated NGF and GDNF levels at 4-6 h, respectively to 21- and 1.5-fold, respectively, and 84- and 9-fold, respectively, of control levels at 24 h. SKF-38393, a D1 agonist, elevated NGF and GDNF levels to 20- and 2.8-fold of controls, respectively, at 24 h. Relative levels of NGF and GDNF mRNA detected by Northern blot analysis or semiquantitative reverse transcriptase-polymerase chain reaction confirmed that increases in levels of the 2 proteins in culture medium were due to overexpression as opposed to leakage from cells. Cabergoline rapidly increased GDNF mRNA expression at 4 h, producing a potent and long-lasting increase in GDNF levels. Bromocriptine significantly suppressed GDNF synthesis. These findings suggest that stimulation of dopamine D1 receptors may be required for GDNF synthesis and secretion, and that concurrent stimulation of dopamine D1 and D2 receptors may augment synthesis and secretion of NGF and GDNF. These dopamine agonists may play a role in neuronal survival by stimulating NGF and GDNF synthesis in the brain, and as drugs are good candidates as NGF and GDNF inducers.

Apomorphine attenuates 6-hydroxydopamine-induced apoptotic cell death in SH-SY5Y cells.

Enhanced oxidative stress is implicated in the pathogenesis of Parkinson's disease. The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) induces the production of reactive oxygen species (ROS), leading to neuronal cell death. On the other hand, apomorphine, a dopamine D1/D2 receptor agonist and known as a potent antioxidant, has been reported to have a neuroprotective effect. In the present study, we investigated the effect of apomorphine on 6-OHDA-induced apoptotic cell death using the human dopaminergic neuroblastoma cell line, SH-SY5Y. The co-treatment of cells with apomorphine significantly attenuated 6-OHDA-induced ROS generation, the phosphorylation of c-Jun N-terminal kinase (JNK), DNA fragmentation and subsequent apoptotic cell death. In addition, pretreatment with apomorphine for 24 h and the following concomitant treatment enhanced the protective effects against 6-OHDA-induced toxicity except for the attenuation of JNK phosphorylation. We also demonstrated that pretreatment alone with apomorphine for 24 h prior to the exposure confers resistance against 6-OHDA-induced cell toxicity. These findings suggested that apomorphine acts principally as a radical scavenger to suppress the level of ROS and ROS-stimulated apoptotic signaling pathway, whereas the other mechanisms might be involved in the protective effects.

Effects of pergolide on nocturia in Parkinson's disease: three female cases selected from over 400 patients.

We started the subject screening from over 400 patients with Parkinson's disease using strict selection criteria to identify the patients with nocturia who would allow accurate and efficient evaluation of the pergolide effects. The subjects were confined to female patients to exclude patients with potential prostate hypertrophy. The patients treated with bromocriptine at 7.5-15 mg/day adjunctive to l-dopa were selected to replace bromocriptine with pergolide of the equivalent dosage approved in Japan. The nocturia was defined as having more than two episodes of urination during sleep per night on average. The subjects received the urinary sediment test before and during the study for screening urinary tract infection and the study was discontinued when urinary tract infection was found. As a result, we identified total 11 patients with nocturia and three of those completed the 12-week study of switching dopamine agonist from bromocriptine to pergolide. We observed a decrease in nocturia frequency in all three patients, a decrease in irritative urinary symptoms in two and an improvement of sleep QOL in two. The effect of pergolide on nocturia was independent of improvement of parkinsonian symptoms, suggesting a distinct mechanism from that of anti-parkinsonian effects. Our study also suggests that switching from bromocriptine to pergolide improves nocturia, thereby improving sleep status of patients with Parkinson's disease.

Malignant syndrome in Parkinson's disease: concept and review of the literature.

We reviewed literature on malignant syndrome occurring in patients with Parkinson's disease (PD) during the course of drug therapy. Clinical features were high fever, marked rigidity, consciousness disturbance, autonomic dysfunction, and elevation of serum creatine kinase. The clinical features were essentially similar to those of neuroleptic malignant syndrome. The immediate triggering event was, most often, discontinuation or reduction of anti-parkinsonian drugs, particularly of levodopa. But no anti-parkinsonian drug was the exception to the induction of malignant syndrome. Serious complications were severe pneumonia, disseminated intravascular coagulation, and acute renal failure. Early treatment with intravenous fluid infusion and external body cooling are essential for good recovery. Bromocriptine and dantrolene sodium were used frequently. It has been claimed that they are effective; however, randomized controlled studies are needed to explicitly prove the efficacy of these drugs in malignant syndrome associated with PD.

Biopterin metabolism in patients with malignant syndrome.

We examined the autopsied brains of two parkinsonian patients who had malignant syndrome (MS). Neopterin and biopterin contents, and GTP cyclohydrolase I activity were measured in various region of the brain. We found relatively higher GTP cyclohydrolase I activities in the hypothalamus compared with other regions of the brain from patients with MS. This finding suggested a possible involvement of biopterin metabolism in pathophysiology of MS. This is the first report on biopterin metabolism in the brains of patients with MS.

A collaborative study on the malignant syndrome in Parkinson's disease and related disorders.

We report the results of a collaborative study on malignant syndrome (MS) that developed in patients being treated with levodopa and other anti-parkinsonian drugs. We analyzed clinical features, laboratory findings, precipitating events, and risk factors for poor outcome. The study was conducted in five centers in Japan. Patients who developed MS between January 1991 and December 1997 were included. The enrollment criteria used were the same as those for neuroleptic MS proposed by Levenson et al. (1985).A total of 99 episodes were encountered in 93 patients (72 with Parkinson's disease and 21 with secondary parkinsonism); one patient had four recurrences of MS and three patients had two recurrences. High fever was the most frequent clinical manifestation of MS followed by worsening of parkinsonism, and then altered levels of consciousness. Serum creatine kinase was abnormally elevated in all the patients studied. Life-threatening complications were rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. The most frequent precipitating event was discontinuation or dose reduction of anti-parkinsonian drugs, particularly levodopa. No drug was the exception in the precipitation of MS. Intercurrent infection was the next most common precipitating event. MS developed without drug withdrawal or infection in some patients. In five patients, severe "wearing off" phenomenon was the only event preceding the onset of MS. Hot weather and dehydration appeared to be the cause in three patients. Among the total of 99 episodes, patients recovered to the pre-MS state following 68 episodes (68.7%); in the remaining 31.3%, patients failed to recover to their previous state. Older age, higher Hoehn and Yahr stage during the symptomatic phase of MS, higher akinesia score, and the absence of wearing off phenomenon prior to developing MS were associated with poor outcome. The most frequently used treatments of MS were intravenous fluid, levodopa, dantrolene sodium, and intragastric bromocriptine. Early introduction of treatment is important. Any elevation of body temperature during the course of anti-parkinsonian drug treatment should be considered as MS until proved otherwise.

Prevention and treatment of malignant syndrome in Parkinson's disease: a consensus statement of the malignant syndrome research group.

We report a consensus statement of the collaborative research group on the prevention and treatment of malignant syndrome (MS) in Parkinson's disease. The syndrome is quite similar to neuroleptic MS. Although sudden withdrawal of levodopa was the most frequent cause, many other precipitating events were found such as intercurrent infections, dehydration, hot weather, discontinuation of other anti-parkinsonian drugs, and "wearing off" phenomenon. Awareness of this syndrome is most important for its early detection and the prompt commencement of treatment. MS should be suspected whenever the body temperature rises above 38 degrees C without an apparent cause. Treatment consists of ample intravenous fluid, cooling the body, anti-parkinsonian drugs (particularly levodopa and bromocriptine), dantrolene sodium, and antibiotics if infection is present. Rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure constitute serious complications.

[Parkinson's disease: the disease concept, etiology and diagnostic bases].

Parkinson's disease (PD) is caused by degeneration of nigral dopaminergic neurons. This results in dysfunction of the basal ganglia, thereby exhibiting movement disorders. The four cardinal signs of PD include bradykinesia, rigidity, resting tremor and postural instability. In the majority of patients with PD, the four cardinal signs are ameliorated by levodopa. In addition to anti-parkinson medication, surgery of the basal ganglia for PD has been applied. Local electrical stimulation of particular nuclei of the basal ganglia (deep brain stimulation) for PD has also proved to give satisfactory outcome. Both genetic and environment factors are considered to contribute to the initiation of PD. Some mutations of particular genes (e.g., alpha-synuclein) are found to link to parkinsonian families.