Impaired transmethylation potential in Parkinson's disease patients treated with l-Dopa

Hyperhomocysteinaemia was reported in patients with Parkinson's disease (PD) treated with l-Dopa. The increase in plasma concentration of this sulfur compound arises from the massive methylation of the drug operated by the enzyme catechol-O-methyltransferase (COMT), which acts as a powerful sink of methyl groups. The contemporary occurrence of C677T polymorphism in homozygosity, leading to a temperature-labile variant of the MTHFR enzyme, induces an even more marked increase in tHcy. Here we show that l-Dopa administration in hyperhomocysteinemic PD patients is able to lower intracellular concentration of S-Adenosylmethionine (AdoMet) in erythrocytes (RBC), while the occurrence of hyperhomocysteinaemia causes a significant increase in S-Adenosylhomocysteine (AdoHcy) level. In patients with PD treated with l-Dopa and hyperhomocysteinemic, the remarkable decrease in AdoMet and the concurrent increase in AdoHcy concentration both contribute to significantly lower the transmethylation potential ([AdoMet]/[AdoHcy]), a useful index of the effectiveness of methyl group transfer by methyltransferases. This decrease could indeed contribute to partly attenuate, through a self-limiting kinetic mechanism, the tendency of developing drug resistance, partly mediated in these patients by COMT upregulation. Our results also support the conclusion that COMT inhibitors (entacapone or tolcapone), when administered in PD patients treated with l-Dopa, may potentiate the endogenous AdoHcy-dependent COMT inhibition mechanism already operative in a variable fashion.     

Systemic administration of catalpol prevents d-galactose induced mitochondrial dysfunction in mice

The aim of this work was to evaluate the mechanisms involved in the effects of catalpol on mitochondrial function through the measurements of nitric oxide synthase (NOS) activity, reactive oxygen species (ROS) production, respiratory complex activities and mitochondrial membrane potential (MMP) in the brain cortex and hippocampus mitochondria of senescent mice induced by d-galactose. Except control group, mice were subcutaneously injected with d-galactose (150 mg/kg body weight) for 6 weeks. Meanwhile, drug group mice were treated with catalpol (2.5, 5, 10 mg/kg body weight) and piracetam (300 mg/kg body weight) for the last 2 weeks. The results indicated that respiratory complex activities decreased while NOS activities increased in d-galactose treated mice brain. The production of ROS increased remarkably and MMP collapsed in the brain of senescent mice induced by d-galactose. Administration of catalpol for 2 weeks significantly decreased ROS production and NOS activities, in accordance with its increase on complex activities and MMP level. Our results suggest that in vivo effects of catalpol on mitochondrial function can occur through different mechanisms, involving inhibiting NOS activity and ROS production, increasing respiratory complex activities and MMP level.     

Site-specific action of l-3,4-dihydroxyphenylalanine in the striatum but not globus pallidus and substantia nigra pars reticulata evokes dyskinetic movements in chronic l-3,4-dihydroxyphenylalanine-treated 6-hydroxydopamine-lesioned rats

Dyskinesia eventually develops in the majority of Parkinson's disease patients treated with l-3,4-dihydroxyphenylalanine (l-DOPA). We have investigated the effect of an acute and local administration of l-DOPA, GABA and glutamate to provoke dyskinetic movements in three basal ganglia structures (striatum, globus pallidus (GP) and substantia nigra pars reticulata (SNr)) of chronically l-DOPA-treated, unilaterally 6-hydroxydopamine-lesioned rats. We demonstrated that l-DOPA administration into the lesioned striatum using the technique of reverse in vivo microdialysis was an effective trigger to switch on dyskinesia. Notably, local l-DOPA perfusion at the same concentration in the ipsilateral GP and SNr did not provoke significant dyskinetic behaviour. Neither GABA nor glutamate triggered dyskinetic movements in the striatum, GP or SNr. We postulate a site-specific action of l-DOPA for the evocation of already established dyskinesia since l-DOPA in the striatum but not in the GP or SNr switched on dyskinetic behaviour.     

Lewy body pathology is associated with mitochondrial DNA damage in Parkinson's disease

Mitochondrial dysfunction has been strongly implicated in the pathogenesis of Parkinson's disease (PD) and Alzheimer's disease (AD), but its relation to protein aggregation is unclear. PD is characterized by synuclein aggregation (i.e., Lewy body [LB] formation). In AD, the abnormal accumulation of tau protein forms neurofibrillary tangles. In this study, we laser-dissected LB-positive and -negative neurons from the substantia nigra of postmortem PD brains, and tau-positive and -negative hippocampal neurons from AD brains. We quantified mitochondrial DNA deletions in relation to the cellular phenotype and in comparison with age-matched controls. Deletion levels were highest in LB-positive neurons of PD brains (40.5 ± 16.8%), followed by LB-negative neurons of PD cases (31.8 ± 14.4%) and control subjects (25.6 ± 17.5%; analysis of variance p < 0.005). In hippocampal neurons, deletion levels were 25%–30%, independent of disease status and neurofibrillary tangles. The presented findings imply increased mitochondrial DNA damage in LB-positive midbrain neurons, but do not support a direct causative link of respiratory chain dysfunction and protein aggregation.     

Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease

Molecular hydrogen serves as an antioxidant that reduces hydroxyl radicals, but not the other reactive oxygen and nitrogen species. In the past year, molecular hydrogen has been reported to prevent or ameliorate eight diseases in rodents and one in human associated with oxidative stress. In Parkinson's disease, mitochondrial dysfunction and the associated oxidative stress are major causes of dopaminergic cell loss in the substantia nigra. We examined effects of ∼50%-saturated molecular hydrogen in drinking water before or after the stereotactic surgery on 6-hydroxydopamine-induced nigrostrital degeneration in a rat model of Parkinson's disease. Methamphetamine-induced behavioral analysis showed that molecular hydrogen prevented both the development and progression of the nigrostrital degeneration. Tyrosine hydroxylase staining of the substantia nigra and striatum also demonstrated that pre- and post-treatment with hydrogen prevented the dopaminergic cell loss. Our studies suggest that hydrogen water is likely able to retard the development and progression of Parkinson's disease.     

Ashwagandha leaf extract: A potential agent in treating oxidative damage and physiological abnormalities seen in a mouse model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder that leads to impairment of balance and coordination. Therapy for the disease is still under investigation. Withania somnifera (A-Extract), a herbal medicine, has been known for a spectrum of health-promoting effects including activation of immune, muscle and neuronal systems. Therefore effect of A-Extract in the mouse model of PD was examined. The midbrain and corpus striatum of PD mouse showed increased levels of superoxide dismutase, catalase and malondialdehyde; and reduced levels of glutathione and glutathione peroxidase compared to the control. Treatment with A-Extract 100 mg/kg for 7 days significantly improved all these enzyme levels compared to A-Extract untreated PD mouse brain. In the PD mouse grooming, stride length, movement, rearing were found to be decreased compared to the control. In addition, narrow beam walk and foot slippery errors were increased. Treatment with A-Extract improved all these physiological abnormalities. These data suggests that A-Extract is a potential drug in treating oxidative damage and physiological abnormalities seen in the PD mouse, if documented also in patients with PD.     

Pomegranate juice exacerbates oxidative stress and nigrostriatal degeneration in Parkinson's disease

Numerous factors contribute to the death of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD). Compelling evidence implicates mitochondrial deficiency, oxidative stress, and inflammation as important pathogenic factors in PD. Chronic exposure of rats to rotenone causes a PD-like syndrome, in part by causing oxidative damage and inflammation in substantia nigra. Pomegranate juice (PJ) has the greatest composite antioxidant potency index among beverages, and it has been demonstrated to have protective effects in a transgenic model of Alzheimer's disease. The present study was designed to examine the potential neuroprotective effects of PJ in the rotenone model of PD. Oral administration of PJ did not mitigate or prevent experimental PD but instead increased nigrostriatal terminal depletion, DA neuron loss, the inflammatory response, and caspase activation, thereby heightening neurodegeneration. The mechanisms underlying this effect are uncertain, but the finding that PJ per se enhanced nitrotyrosine, inducible nitric oxide synthase, and activated caspase-3 expression in nigral DA neurons is consistent with its potential pro-oxidant activity.     

Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson's disease

This study aims to elucidate the processes underlying neuroprotection of kaempferol in models of rotenone-induced acute toxicity. We demonstrate that kaempferol, but not quercetin, myricetin or resveratrol, protects SH-SY5Y cells and primary neurons from rotenone toxicity, as a reduction of caspases cleavage and apoptotic nuclei are observed. Reactive oxygen species (ROS) levels and mitochondrial carbonyls decrease significantly. Mitochondrial network, transmembrane potential and oxygen consumption are also deeply preserved. We demonstrate that the main event responsible for the kaempferol-mediated antiapoptotic and antioxidant effects is the enhancement of mitochondrial turnover by autophagy. Indeed, fluorescence and electron microscopy analyses show an increase of the mitochondrial fission rate and mitochondria-containing autophagosomes. Moreover, the autophagosome-bound microtubule-associated protein light chain-3 (LC3-II) increases during kaempferol treatment and chemical/genetic inhibitors of autophagy abolish kaempferol protective effects. Autophagy affords protection also toward other mitochondrial toxins (1-methyl-4-phenyilpiridinium, paraquat) used to reproduce the typical features of Parkinson's disease (PD), but is inefficient against apoptotic stimuli not directly affecting mitochondria (H₂O₂, 6-hydroxydopamine, staurosporine). Striatal glutamatergic response of rat brain slices is also preserved by kaempferol, suggesting a more general protection of kaempferol in Parkinson's disease. Overall, the data provide further evidence for kaempferol to be identified as an autophagic enhancer with potential therapeutic capacity.     

Disruption of neuronal-glial-vascular units in the hippocampus of ovariectomized mice injected with d-galactose

Neuronal-glial-vascular units now have been regarded as the basic functional elements of the CNS; however, their pathophysiological changes in the neurodegenerative condition are poorly defined. Herein we addressed these issues in the hippocampus of an Alzheimer's disease mouse model which was established by ovariectomy and then followed with 8 weeks of d-galactose injection. Immunolocalization of glial fibrillary acidic protein showed that reactive astrogliosis destroyed astrocytic domain organization in the hippocampus of model mice. Electron microscopy further demonstrated microarchitectural damage of neuronal-glial units and gliovascular units in the CA1 stratum radiatum of model group. Moreover, model mice had decreased expressions of glutamate transporter 1, glutamate/aspartate transporter, glutamine synthetase and connexin 43, but an increased expression of water channel protein aquaporin-4 in the hippocampus as revealed by immunohistochemistry and immunoblotting analysis. These results highlight that disruptions in structural integrity of the neuronal-glial-vascular units and associated functions including glutamate clearance, water transport and astrocyte syncytium contribute to the neurodegeneration induced by long-term ovarian hormone deprivation and systemic d-galactose exposure.     

Cyclooxygenase-2 is involved in oxidative damage and alpha-synuclein accumulation in dopaminergic cells

Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the formation of prostaglandins from arachidonic acid. The inducible isoform COX-2 is upregulated in the dopaminergic neurons of the substantia nigra of postmortem Parkinson's disease (PD) patients and in neurotoxin-induced Parkinsonism models. COX-2 has attracted significant attention as an important source of oxidative stress in dopaminergic neurons due to its potential to oxidize catechols including dopamine. However, the role of COX-2 in the pathogenesis of PD has not been fully evaluated. Here, we show that COX-2 induces dopamine oxidation, as evidenced by the findings that COX-2 can facilitate dopamine oxidation in a cell-free system and in COX-2-overexpressing SH-SY5Y cells, and that this can be completely abolished by the selective COX-2 inhibitor meloxicam. Increased COX-2 expression causes oxidative protein modification and α-synuclein accumulation in dopaminergic cells. These data suggest that an abnormal increase in COX-2 expression causes dopamine oxidation and contributes to the preferential vulnerability of dopaminergic cells as in PD.     

Alterations in extracellular tryptophan and dopamine concentrations in rat striatum following peripheral administration of d- and l-tryptophan: An in vivo microdialysis study

Incorporation profiles of d-Trp and l-Trp into the striatum following intraperitoneal (i.p.) administration of d-Trp or l-Trp in male Sprague-Dawley rats (100 mg/kg) were investigated by using a brain microdialysis technique. Alterations in the extracellular dopamine (DA) concentration in the rat striatum were also examined. Incorporation profiles of d-Trp and l-Trp were almost identical; however, transient DA release was only observed 0–30 min following d-Trp administration. Pretreatment with 3-methylpyrazole-5-carboxylic acid, an inhibitor of d-amino acid oxidase (DAAO), significantly suppressed the DA release induced by d-Trp. These findings suggest that d-Trp-induced DA release may be mediated by certain d-Trp metabolites produced by DAAO.     

Nitric oxide synthase inhibition attenuates l-DOPA-induced dyskinesias in a rodent model of Parkinson's disease

Chronic l-DOPA pharmacotherapy in Parkinson's disease is often accompanied by the development of abnormal and excessive movements known as l-DOPA-induced dyskinesia. Rats with 6-hydroxydopamine lesion of dopaminergic neurons chronically treated with l-DOPA develop a rodent analog of this dyskinesia characterized by severe axial, limb, locomotor and orofacial abnormal involuntary movements. While the mechanisms by which these effects occur are not clear, they may involve the nitric oxide system. In the present study we investigate if nitric oxide synthase inhibitors can prevent dyskinesias induced by repeated administration of l-DOPA in rats with unilateral 6-hydroxydopamine lesion. Chronic l-DOPA (high fixed dose, 100 mg/kg; low escalating dose, 10–30 mg/kg) treatment induced progressive dyskinesia changes. Two nitric oxide synthase inhibitors, 7-nitroindazole (1–30 mg/kg) and NG-nitro-l-arginine (50 mg/kg), given 30 min before l-DOPA, attenuate dyskinesia. 7-Nitroindazolee also improved motor performance of these animals in the rota-rod test. These results suggest the possibility that nitric oxide synthase inhibitors may be useful to treat l-DOPA-induced dyskinesia.     

Transduced PEP-1-PON1 proteins regulate microglial activation and dopaminergic neuronal death in a Parkinson's disease model

Parkinson's disease (PD) is an oxidative stress-mediated neurodegenerative disorder caused by selective dopaminergic neuronal death in the midbrain substantia nigra. Paraoxonase 1 (PON1) is a potent inhibitor of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) against oxidation by destroying biologically active phospholipids with potential protective effects against oxidative stress-induced inflammatory disorders. In a previous study, we constructed protein transduction domain (PTD) fusion PEP-1-PON1 protein to transduce PON1 into cells and tissue. In this study, we examined the role of transduced PEP-1-PON1 protein in repressing oxidative stress-mediated inflammatory response in microglial BV2 cells after exposure to lipopolysaccharide (LPS). Moreover, we identified the functions of transduced PEP-1-PON1 proteins which include, mitigating mitochondrial damage, decreasing reactive oxidative species (ROS) production, matrix metalloproteinase-9 (MMP-9) expression and protecting against 1-methyl-4-phenylpyridinium (MPP⁺)-induced neurotoxicity in SH-SY5Y cells. Furthermore, transduced PEP-1-PON1 protein reduced MMP-9 expression and protected against dopaminergic neuronal cell death in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. Taken together, these results suggest a promising therapeutic application of PEP-1-PON1 proteins against PD and other inflammation and oxidative stress-related neuronal diseases.     

Comparison of intrastriatal administration of noradrenaline and l-DOPA on dyskinetic movements: A bilateral reverse in vivo microdialysis study in 6-hydroxydopamine-lesioned rats

l-DOPA-induced dyskinesia is known as involuntary debilitating movement, which limits quality of life in patients suffering from Parkinson's disease. The present study focuses on the role of the neurotransmitter noradrenaline (NA) on dyskinetic movements in comparison to the effect of l-DOPA.     

Postmenopausal effects of intrastriatal estrogen on catalepsy and pallidal electroencephalogram in an animal model of Parkinson's disease

The main objective was to test the preventive and treatment effects of central injection of estrogen (ES) on muscular rigidity and pallidal EEG in menopausal rats' model of Parkinson's disease (PD). We hypothesized that intrastriatal pretreatment and post-lesion treatment by estrogen improve the pallidal local EEG and muscular stiffness in animal model of menopause with PD. Forty-eight female Wistar rats (300-350 g) were ovariectomized (OVX) and divided into two main groups: Non-pretreated subgroups; sham (S), lesioned (L), post-lesion treated (LT) and pretreated subgroups; pretreated (Pt), pretreated and then lesioned (PtL), pretreated and post-lesion treated (PtLT). Pallidal local EEG was recorded by a bipolar recording electrode and muscle stiffness was scored by Dekundy's test in freely moving rats. Muscle stiffness and pallidal local EEG were indicated as main outcome measures. In pretreated group the local pallidal EEG was decreased in sham-operated rats compared with non-pretreated group (P<0.01), and SNc lesioning decreased EEG in the non-pretreated (P<0.01), while it increased the EEG in the pretreated group (P<0.01). In both groups administration of ES restore the EEG to the respective sham-operated group (P<0.01). Regarding muscle stiffness, it increased after SNc lesioning in both pretreated and non-pretreated groups and ES administration decreased the rigidity significantly (P<0.05, P<0.001 respectively). However, the lesion-induced rigidity in pretreated groups was significantly less than non-pretreated groups (P<0.05). Because of its modulatory effect estrogen may protect dopaminergic neurons from injury and may interfere with the uptake of 6-hydroxydopamine (6-OHDA) into the nigral dopaminergic neurons or alter dopamine release and uptake in remaining neurons.     

Levels of reduced and oxidized coenzymeQ-10 and 8-hydroxy-2′-deoxyguanosine in the cerebrospinal fluid of patients with living Parkinson's disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process

The aim of this study was to investigate the possibility that mitochondrial oxidative damage, oxidative DNA damage or both contribute to the neurodegenerative process of Parkinson's disease (PD). We employed high-performance liquid chromatography (HPLC) using an electrochemical detector to measure concentrations of the reduced and oxidized forms of coenzymeQ-10 (CoQ-10) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the cerebrospinal fluid (CSF) of 20 patients with PD and 20 age-matched controls with no neurological disease. The percentage of oxidized to total CoQ-10 (%CoQ-10) in the CSF of the PD group (80.3 ± 17.9%) was significantly higher than in the control group (68.2 ± 20.4%, P < 0.05). In addition, the concentration of 8-OHdG in the CSF of PD patients was greater than in the CSF of controls (P < 0.0001) and was positively correlated with the duration of illness (r_s = 0.87, P < 0.001). Finally, the %CoQ-10 was correlated with concentrations of 8-OHdG in the CSF of PD patients (r_s = 0.56, P < 0.01). The present study suggests that both mitochondrial oxidative damage and oxidative DNA damage play important roles in the pathogenesis of early PD development.     

Investigation of tyrosine hydroxylase and BDNF in a low-dose rotenone model of Parkinson's disease

Tyrosine hydroxylase (TH, the rate limiting-enzyme in catecholamine synthesis) is regulated acutely via phosphorylation of 3 serine residues—Ser19, 31 and 40, and chronically via changes in TH protein levels. In this study, we aimed to investigate how TH is regulated in the brain, gut and adrenal gland as well as changes in mature brain-derived neurotrophic factor (mBDNF) and proBDNF levels in a low-dose (2 mg/kg, 5 days/week for 4 weeks) rotenone model of Parkinson's disease (PD). Rearing behaviour decreased by week 3 in the rotenone group (p < 0.01), with further decreases in rearing by week 4 (p < 0.001); however, TH remained unchanged in the substantia nigra (SN) and striatum; TH levels were also unaltered in other catecholaminergic cell groups of the brainstem such as A1C1 neurons or locus coeruleus. In the olfactory bulb, TH protein decreased (2.5-fold, p < 0.01) while Ser31 phosphorylation increased (1.4-fold, p < 0.05) in the rotenone group. In contrast, TH protein was increased in the adrenal gland (2-fold, p < 0.05) and colon (5-fold, p < 0.05) of rotenone rats. mBDNF levels were not changed in the SN but were significantly reduced in plasma and significantly increased in the colon (2-fold, p < 0.01) of rotenone-treated rats. This is the first study to assess TH and BDNF in the brain and periphery in the rotenone model before SN/striatum degeneration is evident. Together these results suggest that low-dose rotenone may have some potential to model the early stages of PD.     

The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations

Background

Parkinson''s disease is a genetically complex disease with mixed mode of inheritance. Recently, a haplotype across the sepiapterin reductase (SPR) gene, which is located in the PARK3 linkage region, was shown to modulate age of onset of Parkinson''s disease in sibships from North America.

Objective

To make a thorough assessment of the SPR gene region in sporadic Parkinson''s disease.

Methods

A linkage study in 122 European sibship families with five microsatellite and 17 single nucleotide polymorphism (SNP) markers in and around the SPR gene region, and an association analysis in 340 sporadic cases of Parkinson''s disease and 680 control subjects from Germany with 40 SNPs. Linkage was evaluated by non‐parametric linkage scores and genotypic or haplotype association was tested by regression analysis, assuming different risk effect models.

Results

Significant LOD scores between 2 and 3 were obtained at the two SPR‐flanking markers D2S2110 and D2S1394 and seven SNP markers around the SPR gene. We found the previously reported promoter SNP rs1876487 also significantly associated with age of onset in our sib pair families (p‐value 0.02). One strong linkage disequilibrium (LD) block of 45 kb including the entire SPR gene was observed. Within this LD block all 14 inter‐correlated SNPs were significantly associated with Parkinson''s disease affection status (p‐value 0.004).

Conclusions

DNA polymorphisms in a highly intercorrelated LD block, which includes the SPR gene, appear to be associated with both sporadic and familial Parkinson''s disease. This confirms a previous study showing that SPR potentially modulates the onset of or risk for Parkinson''s disease.     

Supplementation with l-glutathione improves oxidative status and reduces protein nitration in myenteric neurons in the jejunum in diabetic Rattus norvegicus

Diabetes mellitus is a syndrome with multiple etiologies, characterized by chronic hyperglycemia that increases the production of reactive oxygen species and decreases antioxidant defenses. The present study evaluated oxidative stress parameters and protein nitration in myenteric neurons in the jejunum in diabetic rats supplemented with l-glutathione. Rats (90?days of age) were distributed into four groups (n?=?6/group): normoglycemic (N), normoglycemic supplemented with l-glutathione (NGT), diabetic (D), and diabetic supplemented with l-glutathione (DGT). At 210?days of age, the animals were sacrificed, and the jejunum was collected, washed, and subjected to various procedures: tert-butyl hydroperoxide chemiluminescence (CL), determination of total antioxidant capacity (TAC), determination of catalase activity, quantification of nitric oxide (NO), and double-labeling of HuC/D-immunoreactive myenteric neurons and nitrotyrosine (3-NT). Diabetes increased oxidative stress in the jejunum in the D group, reflected by increases in lipid peroxidation, TAC, catalase activity, and NO. The D group exhibited an increase in the percentage of myenteric neurons that were double-labeled with 3-NT. Supplementation with l-glutathione did not cause differences in the average CL curves between the D and DGT groups, but reductions of TAC and catalase activity were observed. Supplementation with l-glutathione promoted a reduction of neurons that contained 3-NT in the DGT group. Diabetes mellitus promoted oxidative stress in the jejunum, and supplementation with l-glutathione improved oxidative status by preventing protein nitration in myenteric neurons in diabetic animals that received supplementation.     

Neuroprotective effect of silymarin in 6-hydroxydopamine hemi-parkinsonian rat: Involvement of estrogen receptors and oxidative stress

This study examined neuroprotective effect of silymarin (SM) in a model of Parkinson's disease (PD). Unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated i.p. with SM (100 and 200 mg/kg) 1 h before neurotoxin injection. Fulvestrant was used to evaluate the involvement of estrogen receptors. Net apomorphine-induced rotations and number of Nissl-stained neurons of substantia nigra pars compacta (SNC) were counted in addition to measurement of oxidative stress markers. SM administration only at a dose of 200 mg/kg attenuated the rotational behavior in 6-OHDA-lesioned rats and protected the neurons of SNC against its toxicity and fulvestrant partially attenuated this beneficial effect of SM. In addition, pretreatment with SM at a dose of 200 mg/kg significantly decreased the 6-OHDA-induced thiobarbituric acid reactive substances (TBARS) formation. SM exhibits a dose-dependent neuroprotective effect against 6-OHDA toxicity, partly through attenuating oxidative stress and via an estrogenic pathway.