Changes in the Serum Urate Level Can Predict the Development of Parkinsonism in the 6-Hydroxydopamine Animal Model.

Epidemiological studies indicate that a higher plasma level of uric acid (UA) associates with the reduced risk of Parkinson's disease (PD). To confirm the role of UA as a biomarker for PD, we evaluated changes in the serum UA level in the 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonism in rat. For this purpose, 6-OHDA was administered in the medial forebrain bundle by stereotaxic surgery. According to the apomorphine-induced rotational test, the increased intensity of behavioral symptoms as a function of time was associated with the further reduction of UA level. On the other hand, the level of UA increased in the midbrain of the injured hemisphere. The level of reduction in the serum UA level of rats with severe and moderate symptoms was significantly higher than that of rats with mild symptoms. The immunohistofluorescence and biochemical analyses showed that the serum UA level was also correlated with the death of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), reduced level of striatal dopamine, and severity of oxidative stress in the midbrain. The rats with mild symptoms also showed a significant decrease in TH-positive neurons and striatal dopamine level. These findings suggest a positive correlation between the level of reduction in the serum urate level and severity of 6-OHDA-induced Parkinsonism. In addition, our findings indicated that UA had no marked neuroprotective effects, at least at concentrations obtained in this study. On the other hand, UA was introduced as a biomarker for PD, as a significant decline was observed in the serum UA level of rats with mild behavioral symptoms but with significant dopaminergic cell death in the SNc.

[Effect of afobazole and levodopa on the activity of proline-specific proteinases and adenosine deaminase in blood serum and brain structures of rats with experimental Parkinson's syndrome induced by systemic administration of rotenone]. / Vliianie afobazola i levodopy na aktivnost' prolinspetsificheskikh proteinaz i adenozindezaminazy v syvorotke krovi i strukturakh golovnogo mozga krys s éksperimental'nym parkinsonicheskim sindromom, vyzvannym sistemnym vvedeniem rotenona.

Rats with experimental Parkinson's syndrome induced by seven-day intraperitoneal administration of rotenone at a dose of 2.75 mg/kg have an increased activity of prolylendopeptidase (EC 3.4.21.26, PREP) in blood serum and a decreased activity of adenosine deaminase (EC 3.5.4.4, ADA) in serum and in the prefrontal cortex. PREP and ADA activity in other brain structures (in the striatum, hypothalamus and hippocampus) did not change; dipeptidyl peptidase IV activity (EC 3.4.14.5, DPP-4, CD26) also remained constant in serum and in all the brain structures investigated. Afobazole and levodopa, which exhibit antiparkinsonian activity in this model of Parkinson's syndrome, decrease elevated PREP activity in serum and increase reduced ADA activity in the prefrontal cortex of rats with the experimental pathology. Meanwhile, treatment with the study drugs was associated with a decrease of ADA activity in the other brain structures.

Blockade of fast A-type and TEA-sensitive potassium channels provide an antiparkinsonian effect in a 6-OHDA animal model.

OBJECTIVE: To evaluate the effect of K+ channels inhibitors in treatment of parkinson`s disease (PD). METHODS: This prospective comparative study was conducted in the Qazvin University of Medical Sciences, Iran, from April 2015 to January 2016. Male rats (n=37) received intraperitoneal doses of TEA (2 and 5 mg/kg) or 4-AP (0.5 and 1 mg/kg) twice-daily, before a stereotactic injection of 6-hydroxydopamine (6-OHDA) for the following 7 days. The 6-OHDA was injected into right medial forebrain bundle (MFB) of the rat brains. Development and severity of PD were assessed using the apomorphine-induced rotational test, the elevated body swing test and rotarod tests. Concentration of malondialdehyde (MDA), a marker of oxidative stress, was measured in rat sera. RESULTS: Tetraethylammonium and 4-AP significantly reduced the number of apomorphine-induced rotations and improved motor learning in the rotarod test at both doses. Administration of 4-AP and TEA together was more effective than single administration of either agent. Malondialdehyde measurement showed that pretreatment with TEA could not prevent 6-OHDA-induced oxidative stress. CONCLUSION: Our results showed that pretreatment with TEA and 4-AP has a neuroprotective effect against 6-OHDA in dopaminergic neurons in the substantia nigra.

Gene-gene and gene-environment interaction on the risk of Parkinson's disease.

BACKGROUND: Even with numerous studies the cause of Parkinson's disease (PD) remains elusive. It has been hypothesized that interactions between genetic and environmental factors may play an important role in the pathogenesis of PD. OBJECTIVES: To examine the gene-gene and gene-environment interaction on PD risk with respect to gene polymorphism of cytochrome P450 2D6 (CYP2D6) and glutathione S-transferases pi 1 (GSTP1), organochlorine pesticides (OCPs) and metals. METHODS: This study included 70 patients of PD and 100 age-matched controls. The restriction fragment length polymorphism was used for analysis of genetic polymorphism. OCPs and serum metal levels were estimated by using gas chromatography and an autoanalyser respectively. RESULTS: The CYP2D6*4 mt and GSTP1 *B allelic variants were significantly associated with increase in PD risk. We found a statistically significant difference in ß -hexachlorocyclohexane (ß-HCH), dieldrin, 1,1-dichloro-2,2-bis(pchlorophenyl) ethylene (pp'-DDE) and copper levels between the patients and controls. We found significantly high levels of ß-HCH, dieldrin and pp'-DDE in the CYP2D6*4 mt allelic variants, ß-HCH and pp'-DDE in the GSTP1*B allelic variants and dieldrin in the GSTP1*C allelic variants when comparing CYP2D6*4 non-mt, GSTP1 non-*B and GSTP1 non-*C allelic variants in patients of PD respectively. CONCLUSION: This study demonstrates that the CYP2D6*4 and GSTP1 genes may be considered as candidate genes for PD and they may also interact with ß- HCH, dieldrin and pp'-DDE to influence the risk for PD.

Preventive effect of rikkunshito on gastric motor function inhibited by L-dopa in rats.

We previously reported that ghrelin prevented l-dopa (LD)-induced inhibition of gastric emptying (GE) of a non-nutrient solution in rats. Parkinson's disease treatment involves the combined administration of l-dopa with the enzyme l-amino acid decarboxylase inhibitor, carbidopa (CD) to reduce peripheral formation of dopamine. We investigated the effect LD/CD given orogastrically (og) on GE of a non-nutrient or nutrient meal and whether og pretreatment with rikkunshito, a kampo medicine clinically used to treat gastroparesis, influenced LD/CD effect on GE and postprandial antral and duodenal motility in conscious rats. LD/CD (20/2 mgkg(-1)) decreased significantly GE to 26.3 ± 6.0% compared to 61.2 ± 3.2% in og vehicle monitored 20-min after a non-nutrient meal and to 41.9 ± 5.8% compared to 72.9 ± 5.2% in og vehicle monitored 60 min after a nutrient meal. Rikkunshito (0.5 or 1.0 g kg(-1)) reduced the LD/CD (20/2 mg kg(-1)) inhibition of GE of non-nutrient meal (36.9 ± 7.4% and 46.6 ± 4.8% respectively vs. 12.1 ± 7.4% in og vehicle plus LD/CD) while having no effect alone (56.6 ± 8.5%). The ghrelin antagonist, [d-Lys(3)]-GHRP-6 (1 mg kg(-1)) injected intraperitoneally partially reversed rikkunshito preventive effect on LD/CD-inhibited GE. Rikkunshito (1.0 g kg(-1)) blocked LD/CD (20/2 mg kg(-1))-induced delayed GE of a nutrient meal and the reduction of postprandial antral motility. In 6-hydroxydopamine-induced Parkinson's disease rat model, rikkunshito (1.0 g kg(-1), og) also prevented LD/CD-inhibited gastric emptying of a nutrient meal and enhanced fasting plasma levels of acylated ghrelin. These data indicate that oral rikkunshito alleviates the delayed GE induced by LD/CD in naïve and PD rat model in part through ghrelin-related mechanisms.

Manganese-induced parkinsonism in methcathinone abusers: bio-markers of exposure and follow-up.

BACKGROUND AND PURPOSE: Methcathinone abuse is a new cause of manganism. The psychostimulant is prepared from pseudoephedrine using potassium permanganate as an oxidant. We describe the clinical, biological, neuroimaging characteristics and follow-up results in a large Estonian cohort of intravenous methcathinone users. METHODS: During 2006-2012 we studied 38 methcathinone abusers with a mean age of 33 years. Subjects were rated by the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (HY), and Schwab and England (SE) rating scales. Twenty-four cases were reassessed 9-70 (20 ±â€…15) months after the initial evaluation. Manganese (Mn) in plasma and hair was analysed by inductively coupled plasma-atom emission spectrometry. Magnetic resonance imaging (MRI) was performed in 11, and single-photon emission computed tomography (SPECT) with iodobenzamide (IBZM) in eight subjects. RESULTS: The average total UPDRS score was 43 ±â€…21. The most severely affected domains in UPDRS Part III were speech and postural stability, the least affected domain was resting tremor. At follow-up there was worsening of HY and SE rating scales. Subjects had a higher mean level of Mn in hair (2.9 ±â€…3.8 ppm) than controls (0.82 ±â€…1.02 ppm), P = 0.02. Plasma Mn concentrations were higher (11.5 ±â€…6.2 ppb) in active than in former users (5.6 ±â€…1.8 ppb), P = 0.006. Active methcathinone users had increased MRI T1-signal intensity in the globus pallidus, substantia nigra and periaquaductal gray matter. IBZM-SPECT showed normal symmetric tracer uptake in striatum. CONCLUSION: Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible.

How does an occupational neurologist assess welders and steelworkers for a manganese-induced movement disorder? An international team's experiences in Guanxi, China Part II.

The Occupational Medicine Forum is prepared by the ACOEM Occupational and Environmental Medical Practice Committee and does not necessarily represent an official ACOEM position. The Forum is intended for health professionals and is not intended to provide medical or legal advice, including illness prevention, diagnosis or treatment, or regulatory compliance. Such advice should be obtained directly from a physician and/or attorney.

ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese.

INTRODUCTION: A higher prevalence of individuals affected by Parkinsonism was found in Valcamonica, Italy. This may be related to ferro-alloy smelters in the area, releasing manganese (Mn) in the air, soil and water for about a century. There exists individual susceptibility for Mn neurotoxicity. AIM: To analyse how polymorphism in genes regulating Mn metabolism and toxicity can modify neurophysiological effects of Mn exposure. MATERIALS AND METHODS: Elderly (N=255) and adolescents (N=311) from Northern Italy were examined for neuromotor and olfactory functions. Exposure to Mn was assessed in blood and urine by atomic absorption spectroscopy and in soil by a portable instrument based on X-Ray fluorescence technology. Polymorphisms in the Parkinson-related gene ATPase type 13A2 (ATP13A2, also called PARK9: rs3738815, rs2076602, rs4920608, rs2871776 and rs2076600), and in the secretory pathway Ca(2+)/Mn(2+) ATPase isoform 1 gene (SPCA1: rs218498, rs3773814 and rs2669858) were analysed by TaqMan probes. RESULTS: For both adolescents and elderly, negative correlations between Mn in soil and motor coordination (R(s)=-0.20, p<0.001; R(s)=-0.13, p=0.05, respectively) were demonstrated. Also among adolescents, negative correlations were seen between Mn in soil with odor identification (R(s)=-0.17, p<0.01). No associations were seen for Mn in blood or urine. ATP13A2 polymorphisms rs4920608 and rs2871776 significantly modified the effects of Mn exposure on impaired motor coordination in elderly (p for interaction=0.029, p=0.041, respectively), also after adjustments for age and gender. The rs2871776 altered a binding site for transcription factor insulinoma-associated 1. CONCLUSIONS: ATP13A2 variation may be a risk marker for neurotoxic effects of Mn in humans.

[Vascular or "lower body Parkinsonism": rise and fall of a diagnosis]. / Vascularis vagy "lower body Parkinsonizmus". Egy diagnózis tündöklése és Bukása.

UNLABELLED: The "arteriosclerotic parkinsonism", which is called vascular parkinsonism (VP), was first described by Critchley'. The broad based slow gait, reduced stride lenght, start hesitation, freezing and paratonia was mentioned as "lower body parkinsonism" (LBP) which can be associated by slow speech, dysexecutive syndrome, and hand tremor of predominantly postural character. In VP the DAT-scan proved normal dopamine content of the striatum in contrast with Parkinson's disease (PD). Additionally, Lewy bodies of brainstem type were not found in VR Probability of VP increases if central type pathologic gait is prominent; the hands are slightly involved, the MRI indicates transparent periventricular white substance and/or brain atrophy. In some cases differentiation of gait apraxia and parkinsonism could be challenging. There is no rigor of the lower limbs at rest in neither of them, the disturbance of movement is evoked by the gait itself. Three subtypes of "gait ignition failure" has been recently described: (1) ignition apraxia, (2) equilibrium apraxia and (3) mixed gait apraxia. The primary progressive freesing gait was considered as a Parkinson-plus syndrome. Freesing occurs more frequently in diseases with pakinsonism than in PD. The grade of ventricle dilatation and the frontal leukoaraiosis was similar in LBP and gait apraxia. In cases of normal pressure hydrocephalus the impaired gait may mimic PD. Pathologic gait in VP can be explained by the lesions of the senso-motor association pathways in dorsal paramedian white substance within the vulnerable borderzone region. These may be colocalized with the representation of the lower extremities in the posterior third of the supplementer motor area. Rektor2 proposed to change the name of LBP to "cerebrovascular gait disorder". Notwithstandig central type gait disorder develops also in many degenerative diseases other than cerebro-vascular origin. The neuronal net controling the regulation of movement is widespread, therefore several cortical and subcortical lesions could elicit large variations of pathologic gait, ie.: ataxia, apraxia, ignition failure, akinesis etc. IN CONCLUSION: most of the central gait disorders regarding the pathology and their appearance can not be called "parkinsonism"; these are much closer related to the localization of lesions rather than to the diagnostic categories.

MPTP administration increases plasma levels of acute phase proteins in non-human primates (Macaca fascicularis).

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Parkinsonian patients and animal models of PD show inflammatory phenomena such as microglial activation and cytokine production that could modulate the progression of the disease, since they play a crucial role in the degenerative process. Since acute phase proteins (APPs) are involved in a number of homeostatic alterations and inflammatory processes, we analyzed the levels of APPs in primates before and after treatment with MPTP. A significant increase in C-reactive protein (CRP), serum amyloid A (SAA) and haptoglobin (HP) levels after MPTP treatment. These results demonstrate that MPTP induces a systemic generalized inflammatory reaction after specific dopaminergic neurotoxicity insult, suggesting that the inflammatory process in Parkinsonism may affect other immune-inflammatory responses outside the brain.

Serum concentrations of haloperidol pyridinium metabolites and the relationship with tardive dyskinesia and parkinsonism: a cross-section study in psychiatric patients.

INTRODUCTION: The objective of this study was to provide more clinical data of the potential neurotoxic metabolite haloperidol pyridinium (HP+) in psychiatric patients during long-term treatment with haloperidol and to investigate a possible relationship with extrapyramidal adverse effects. METHODS: Serum concentrations of HP+, reduced haloperidol pyridinium (RHP+), haloperidol (H), and reduced haloperidol (RH) were measured for 41 psychiatric patients of a nursing residence (27 females, 14 males, 34-79 years of age). Severity of tardive dyskinesia (TD) and parkinsonism were rated with the Tardive Dyskinesia Rating Scale (TDRS) and Extrapyramidal Symptom Rating Scale (EPS), respectively. In addition, several patient- and treatment-related variables were investigated, for example cumulative dose (Dcum) of haloperidol. RESULTS: Serum concentration were 0.69 microg/L (0-1.53) for HP+ and 0.41 microg/L (0-1.50) for RHP+ with ratios HP+/H of 0.072 (0.017-0.18) and RHP+/RH of 0.094 (0-0.36) at doses of 10.6 mg/day (3.6-30) [mean (range) in each case]. Multiple regression revealed decreased clearance of HP+ with age. One third of patients with more severe TD (TDRS > or = 10, n = 14) had an increased relative body burden of HP+ and H, as calculated by HP+/H * Dcum of haloperidol than patients with less severe or no TD (TDRS < 10, n = 27), i. e. 5.8 g (2.0-11.9) and 3.3 g (0-9.5), respectively [mean (range), p = 0.005, U test]. Patients with mild to severe parkinsonism (EPS > 0.3, n = 16) had a significantly higher aromatization ratio HP+/H than patients with no or minimal parkinsonism (EPS < or = 0.3, n = 25), i. e. 0.14 (0.04-0.36) and 0.06 (0-0.16), respectively [mean (range), p = 0.003, U test]. CONCLUSION: In psychiatric patients treated with haloperidol for the long-term, the severity of TD and parkinsonism is associated with an increased ratio HP+/H. This is explained by the neurotoxicity of HP+ according to the pyridinium hypothesis.

High serum homocysteine levels in young male schizophrenic and schizoaffective patients with tardive parkinsonism and/or tardive dyskinesia.

BACKGROUND: The pathogenesis of neuroleptic-induced tardive movement disorders (TMD), including tardive parkinsonism and tardive dyskinesia (TD), has not yet been established. An elevated serum level of total homocysteine has been implicated as a risk factor for various neuropathologic states and some movement disorders. The aim of our study was to determine whether there is an association between serum total homocysteine level and the presence of TMD among schizophrenic and schizoaffective patients. METHOD: This study was conducted in Be'er Sheva Mental Health Center from August 2002 to May 2004. Fifty-eight patients with schizophrenia or schizoaffective disorder (DSM-IV) and TMD for at least 1 year (38 men, 20 women; age range, 28-73 years) were compared to a control group of 188 patients with DSM-IV-diagnosed schizophrenia or schizoaffective disorder without TMD (123 men, 65 women; age range, 19-66 years) regarding serum total homocysteine levels. RESULTS: Men with TMD (demonstrating tardive parkinsonism and/or TD) had significantly higher mean serum total homocysteine levels compared to sex- and age group-matched controls. The difference between groups was almost entirely attributable to the homocysteine levels of young male patients (age group, 19-40 years old) with TMD. CONCLUSION: High serum total homocysteine level may constitute a risk factor for certain variants of TMD, especially in young schizophrenic or schizo-affective male patients. Further prospective studies are needed to clarify these findings.

Antiparkinsonian actions of CP-101,606, an antagonist of NR2B subunit-containing N-methyl-d-aspartate receptors.

In the setting of nigrostriatal dopamine depletion, glutamatergic pathways to the striatum and basal ganglia output nuclei become overactive. Systemically administered glutamate receptor antagonists may have direct antiparkinsonian actions in rodents, but there is little evidence for this in primates. Glutamate antagonists may also potentiate conventional dopaminergic therapies; however, there is concern that broad spectrum, nonselective antagonists may have unwanted side-effects. Because subunit-selective antagonists may avoid these liabilities, we have examined the antiparkinsonian effects of a selective antagonist of the NR2B subunit of the NMDA receptor. In rats, CP-101,606 decreased haloperidol-induced catalepsy with an ED(50) of about 0.5 mg/kg. In MPTP-treated monkeys, CP-101,606 (1 mg/kg) reduced parkinsonian motor symptoms by 20%. At a dose of 0.05 mg/kg, CP-101,606 markedly potentiated the effect of a submaximal dose of levodopa, reducing motor symptoms by about 50% compared to vehicle and by about 30% compared to levodopa alone. No side-effects were apparent at any dose of CP-101,606. We conclude that CP-101,606 has direct antiparkinsonian actions in both rodents and monkeys and it synergistically potentiates levodopa in MPTP-treated monkeys. Clinical evaluation of selective NR2B antagonists may be warranted in Parkinson's disease.

Relationship between negative symptoms in chronic schizophrenia and neuroleptic dose, plasma levels and side effects.

The negative symptoms of schizophrenia are often difficult to distinguish from the side effects of antipsychotic medication. In this study, we tried to clarify this issue by studying a group of patients in a clinic setting where a wide range of antipsychotic doses were being prescribed. Thirty-one patients meeting DSM-III-R criteria for schizophrenia or schizoaffective disorder were studied. Clinical ratings were carried out to assess the positive and negative symptoms of schizophrenia, parkinsonism, akathisia and tardive dyskinesia. Plasma levels were also measured for the majority of patients. Antipsychotic plasma levels were found to be highly correlated with dose. Antipsychotic dose and plasma levels were not correlated with the severity of negative symptoms, akathisia or parkinsonism. However, the severity of positive symptoms and tardive dyskinesia were positively correlated with both dose and plasma level. These findings do not support the hypothesis that higher doses of antipsychotic medication are associated with more severe negative symptoms.

Monoamine oxidase molecular activity in platelets of parkinsonian and demented patients.

Platelet monoamine oxidase activity levels have been evaluated in several neuropsychiatric disorders, to identify biochemical markers for pathological brain functioning. In the present work, we assayed both total and molecular monoamine oxidase activity in platelets of parkinsonian and demented patients: both showed significantly higher enzyme activity values than healthy controls. Thus, high platelet monoamine oxidase activity levels seem to be related to an increased intrinsic activity of single enzyme molecules. A significant positive correlation was found between platelet monoamine oxidase activity and severity of illness in both disorders: monoamine oxidase activity, therefore, may be considered as a state-dependent marker for neuro-degeneration. Such findings are discussed with reference to central nervous system biochemical abnormalities in parkinsonian and demented subjects; it might be that in both Parkinson's Disease and in dementia of Alzheimer type some central biochemical changes are reflected in certain peripheral tissues (thrombocytes, for instance), or that a systemic derangement accompanies the cerebral involvement.

NGF in experimental models of Parkinson disease.

We have now applied the enzyme immunoassay using anti-NGF monoclonal antibody (MAb) 27/21 and a blocking test validating the specificity of the immunoreactivity for NGF in serum samples to examine NGF levels in normal rat sera, hemiparkinsonian rat sera, normal monkey sera, and MPTP-treated monkey sera. The levels of NGF in treated animals showed reductions when compared with serum from normal animals. The NGF level alterations observed in lesioned animals and in human parkinsonian patients evidence a relationship between this neurotrophic factor and the neurodegenerative changes observed in Parkinson disease (PD).

Effect of plasma levels of large neutral amino acids and degree of parkinsonism on the blood-to-brain transport of levodopa in naive and MPTP parkinsonian monkeys.

We investigated the transport of levodopa from blood to brain in control and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys by using intracerebral microdialysis. The degree of parkinsonism was established by the monkey's clinical score and its postmortem striatal dopamine level. We administered levodopa plus carbidopa either orally or by intravenous injection. We estimated the blood-to-brain transport of levodopa as the ratio of its concentration in the brain's extracellular fluid to that in arterial plasma. This ratio was reduced in the MPTP parkinsonian monkeys, and we found an inverse relationship between the monkeys' ability to transport levodopa from blood to brain and their degree of parkinsonism. The oral administration of a high-protein meal or the intravenous infusion of large neutral amino acids before the administration of the levodopa plus carbidopa reduced the transport of levodopa into the brain, as measured by microdialysate collected from the striatum. We found that in two animals an intraperitoneal injection of the beta-adrenergic agonist isoproterenol increased the blood-to-brain transport of levodopa. Pharmacologic manipulation of the transport of levodopa from blood to brain may offer a new strategy for the treatment of Parkinson's disease.

Levodopa and dopamine agonists in the treatment of Parkinson's disease: advantages and disadvantages.

Recent studies have suggested that free radicals play a key role in the progression of Parkinson's disease (PD). Although levodopa is the most effective therapeutic agent in the treatment of PD and has improved the quality of life and increased life expectancy, its beneficial effects are not permanent. Long-term treatment with levodopa produces a variety of side effects in patients with PD. We have previously reported that levodopa may accelerate the progression of PD in certain patients. To determine whether neuronal damage can be caused by levodopa overdoses, we estimated the effects of levodopa on free radical formation. Electron spin resonance spectrometry showed that levodopa oxidation produced levodopa radicals. Furthermore, chronic administration of levodopa increased thiobarbituric acid-reacting substances (TBARS) in various brain regions of 6-hydroxydopamine (6-OHDA; i.c.v.)-pretreated mice, although levodopa administration in control mice had no effect on TBARS. These results indicate that high dose levodopa accelerates neuronal degeneration in some parkinsonian brains. We then evaluated the protective effects of bromocriptine on striatal dopaminergic neurons, with determination of dopamine (DA) and its metabolites as markers. Pretreatment of bromocriptine completely protected mice against the decreases in striatal DA and its metabolites induced by intracerebroventricular injection of 6-OHDA, while levodopa/carbidopa had no protective effects. Furthermore, in an in vitro system that generated .OH from FeSO4-H2O2, bromocriptine dose-dependently scavenged .OH. These findings clearly indicate that bromocriptine has neuroprotective effects against neurotoxins such as 6-OHDA, probably due in part to its free redical scavenging activity.(ABSTRACT TRUNCATED AT 250 WORDS)