Protective effect of alpha-synuclein knockdown on methamphetamine-induced neurotoxicity in dopaminergic neurons

The over-expression of α-synuclein is a major factor in the death of dopaminergic neurons in a methamphetamine-induced model of Parkinson's disease. In the present study, α-synuclein knockdown rats were created by injecting α-synuclein-shRNA lentivirus stereotaxically into the right striatum of experimental rats. At 2 weeks post-injection, the rats were injected intraper-itoneally with methamphetamine to establish the model of Parkinson's disease. Expression of α-synuclein mRNA and protein in the right striatum of the injected rats was significantly down-regulated. Food intake and body weight were greater in α-synuclein knockdown rats, and water intake and stereotyped behavior score were lower than in model rats. Striatal dopamine and tyrosine hydroxylase levels were significantly elevated in α-synuclein knockdown rats. Moreover, superoxide dismutase activity was greater in α-synuclein knockdown rat striatum, but the levels of reactive oxygen species, malondialdehyde, nitric oxide synthase and nitrogen monoxide were lower compared with model rats. We also found that α-synuclein knockdown inhibited metham-phetamine-induced neuronal apoptosis. These results suggest that α-synuclein has the capacity to reverse methamphetamine-induced apoptosis of dopaminergic neurons in the rat striatum by inhibiting oxidative stress and improving dopaminergic system function.     

Effect of moxibustion on mTOR-mediated autophagy in rotenone-induced Parkinson's disease model rats

Defects in autophagy-mediated clearance of α-synuclein may be one of the key factors leading to progressive loss of dopaminergic neurons in the substantia nigra. Moxibustion therapy for Parkinson's disease has been shown to have a positive effect, but the underlying mechanism remains unknown. Based on this, we explored whether moxibustion could protect dopaminergic neurons by promoting autophagy mediated by mammalian target of rapamycin(m TOR), with subsequent elimination of α-syn. A Parkinson's disease model was induced in rats by subcutaneous injection of rotenone at the back of their necks, and they received moxibustion at Zusanli(ST36), Guanyuan(CV4) and Fengfu(GV16), for 10 minutes at every point, once per day, for 14 consecutive days. Model rats without any treatment were used as a sham control. Compared with the Parkinson's disease group, the moxibustion group showed significantly greater tyrosine hydroxylase immunoreactivity and expression of light chain 3-Ⅱ protein in the substantia nigra, and their behavioral score, α-synuclein immunoreactivity, the expression of phosphorylated m TOR and phosphorylated ribosomal protein S6 kinase(p-p70S6K) in the substantia nigra were significantly lower. These results suggest that moxibustion can promote the autophagic clearance of α-syn and improve behavioral performance in Parkinson's disease model rats. The protective mechanism may be associated with suppression of the m TOR/p70S6K pathway.     

Differences in brain pathological changes between rotenone and 6-hydroxydopamine Parkinson's disease models

Rotenone and 6-hydroxydopamine are two drugs commonly used to generate Parkinson's disease animal models.They not only achieve degenerative changes of dopaminergic neurons in the substantia nigra,but also satisfy the requirements for iron deposition.However,few studies have compared the characteristics of these two models by magnetic resonance imaging.In this study,rat models of Parkinson's disease were generated by injection of 3 μg rotenone or 10 μg 6-hydroxydopamine into the right substantia nigra.At 1,2,4,and 6 weeks after injection,coronal whole-brain T2-weighted imaging,transverse whole-brain T2-weighted imaging,and coronal diffusion tensor weighted imaging were conducted to measure fractional anisotropy and T2* values at the injury site.The fractional anisotropy value on the right side of the substantia nigra was remarkably lower at 6 weeks than at other time points in the rotenone group.In the 6-hydroxydopamine group,the fractional anisotropy value was decreased,but T2* values were increased on the right side of the substantia nigra at 1 week.Our findings confirm that the 6-hydroxydopamine-induced model is suitable for studying dopaminergic neurons over short periods,while the rotenone-induced model may be appropriate for studying the pathological and physiological processes of Parkinson's disease over long periods.     

The mechanism behind activation of the Nod-like receptor family protein 3 inflammasome in Parkinson's disease

Previous studies have shown that the ATP-P2 X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein 3(NLRP3)inflammasome.The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy.As inflammation also plays an important role in the pathogenesis of Parkinson's disease,we hypothesized that the ATP-P2 X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson's disease.A male rat model of Parkinson's disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra.The P2 X4 receptor and the NLRP3 inflammasome(interleukin-1βand interleukin-18)were activated.Intracerebroventricular injection of the selective P2 X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2 H-benzofuro[3,2-e]-1,4-diazepin-2-one(5-BDBD)or knockdown of P2 X4 receptor expression by si RNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation.Our results suggest that the ATP-P2 X4 receptor signaling pathway mediates NLRP3 inflammasome activation,dopaminergic neurodegeneration,and dopamine levels.These findings reveal a novel role of the ATP-P2 X4 axis in the molecular mechanisms underlying Parkinson's disease,thus providing a new target for treatment.This study was approved by the Animal Ethics Committee of Qingdao University,China,on March 5,2015(approval No.QYFYWZLL 26119).     

Baicalin and deferoxamine alleviate iron accumulation in different brain regions of Parkinson’s disease rats

Previous studies found that iron accumulates in the substantia nigra of Parkinson’s disease patients. However, it is still unclear whether other brain regions have iron accumulation as well. In this experiment, rats with rotenone-induced Parkinson’s disease were treated by gastric perfusion of baicalin or intraperitoneal injection of deferoxamine. Immunohistochemical staining demonstrated that iron accumulated not only in the substantia nigra pars compacta, but also significantly in the striatum globus pallidus, the dentate gyrus granular layer of the hippocampus, the dentate-interpositus and the facial nucleus of the cerebellum. Both baicalin and deferoxamine, which are iron chelating agents, significantly inhibited iron deposition in these brain areas, and substantially reduced the loss of tyrosine hydroxylase-positive cells. These chelators also reduced iron content in the substantia nigra. In addition to the substantia nigra, iron deposition was observed in other brain regions as well. Both baicalin and deferoxamine significantly inhibited iron accumulation in different brain regions, and had a protective effect on dopaminergic neurons.     

Growth differentiation factor 5:a neurotrophic factor with neuroprotective potential in Parkinson’s disease

Parkinson’s disease is the most common movement disorder worldwide,affecting over 6 million people.It is an age-related disease,occurring in 1%of people over the age of 60,and 3%of the population over 80 years.The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra,and their axons,which innervate the striatum,resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease.This is paralleled by the intracellular accumulation ofα-synuclein in several regions of the nervous system.Current therapies are solely symptomatic and do not stop or slow disease progression.One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum,to protect the remaining dopaminergic neurons of the nigrostriatal pathway.However,clinical trials of two well-established neurotrophic factors,glial cell line-derived neurotrophic factor and neurturin,have failed to meet their primary end-points.This failure is thought to be at least partly due to the downregulation byα-synuclein of Ret,the common co-receptor of glial cell line-derived neurorophic factor and neurturin.Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors,that signals through the Ret-independent canonical Smad signaling pathway.Here,we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease.We discuss new work on growth/differentiation factor 5’s mechanisms of action,as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in theα-synuclein rat model of Parkinson’s disease.These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.     

Degree of dopaminergic degeneration measured by ~(99m)Tc-TRODAT-1 SPECT/CT imaging

To prevent and treat Parkinson's disease in its early stages,it is essential to be able to detect the degree of early dopaminergic neuron degeneration.Dopamine transporters(DAT) in the striatum regulate synaptic dopamine levels,and striatal ~(99m)Tc-TRODAT-1 single-photon emission computed tomography(-SPECT) imaging is a marker for presynaptic neuronal degeneration.However,the association between the degree of dopaminergic degeneration and in vivo ~(99m)Tc-TRODAT-1 SPECT imaging is unknown.Therefore,this study investigated the association between the degree of 6-hydroxydopamine(6-OHDA)-induced dopaminergic degeneration and DAT imaging using ~(99m)Tc-TRODAT-1 SPECT in rats.Different degrees of nigrostriatal dopamine depletion were generated by injecting different doses of 6-OHDA(2,4,and 8 μg) into the right medial forebrain bundle.The degree of nigrostriatal dopaminergic neuron degeneration was assessed by rotational behavior and immunohistochemical staining.The results showed that striatal ~(99m)Tc-TRODAT-1 binding was significantly diminished both in the ipsilateral and the contralateral sides in the 4 and 8 μg 6-OHDA groups,and that DAT ~(99m)Tc-TRODAT-1 binding in the ipsilateral striatum showed a high correlation to apomorphine-induced rotations at 8 weeks post-lesion(r = –0.887,P 0.01).There were significant correlations between DAT ~(99m)Tc-TRODAT-1 binding in the ipsilateral striatum and the amount of tyrosine hydroxylase immunoreactive neurons in the ipsilateral substantia nigra in the 2,4,and 8 μg 6-OHDA groups at 8 weeks post-lesion(r = 0.899,P 0.01).These findings indicate that striatal DAT imaging using ~(99m)Tc-TRODAT-1 is a useful technique for evaluating the severity of dopaminergic degeneration.     

Panax notoginseng saponins influence on transplantation of neural stem cell-derived dopaminergic neurons in a rat model of Parkinson’s disease

BACKGROUND:Dopaminergic neurons differentiated from neural stem cells have been successfully used in the treatment of rat models of Parkinson's disease;however,the survival rate of transplanted cells has been low.Most cells die by apoptosis as a result of overloaded intracellular calcium and the formation of oxygen free radicals.OBJECTIVE:To observe whether survival of transplanted cells,transplantation efficacy.and dopaminergic differentiation from neural stem cells is altered by Panax notoginseng saponins(PNS) in a rat model of Parkinson's disease.DESIGN,TIME AND SETTING:Cellular and molecular biology experiments with randomized group design.The experiment was performed at the Animal Experimental Center,First Hospital of Sun Yat-sen University from April to October 2007.MATERIALS:Thirty-two adult,healthy,male Sprague Dawley rats,and four healthy Sprague Dawley rat embryos at gestational days 14-15 were selected.The right ventral mesenceDhalon was injected with 6-hydroxydopamine to establish a model of Parkinson's disease.6-hydroxydopamine and apomorphine were purchased from Sigma.USA.METHODS:Neural stem cells derived from the mesencephalon of embryonic rats were cultivated and passaged in serum-free culture medium.Lesioned animals were randomly divided into four groups(n=8):dopaminergic neuron,dopaminergic neuron PNS,PNS,and control.The dopaminergic neuron group was iniected with 3 μ L cell suspension containing dopaminergic neurons difierentiated from neural stem cells.The dopaminergic neurons PNS group received 3 μ L dopaminergic cell suspension combined with PNS (250 mg/L).The PNS group received 3 μL PNS(250 mg/L),and the control group received 3 μL DMEM/F12 culture medium.MAIN OUTCOME MEASURES:The rats were transcardially perfused with 4% paraformaldehyde at 60 days post-grafting for immunohistochemistry.The rats were intraperitoneally injected with apomorphine (0.5 mg/kg)to induce rotational behavior.RESULTS:Cell counts of tyrosine hydroxylase-positive neurons in the dopaminergic neuron PNS group were(732±82.6)cells/400-fold field.This was significantly greater than the dopaminergic neuron group [(326±34.8)cells/400-fold field,P<0.01].Compared to the control group,the rotational asymmetry of rats that received dopaminergic neuron transplants was significantly decreased,beginning at 20 days after operation(P<0.0 1).Rotational asymmetry was fugher reduced between 10～60 days post-surgery in the dopaminergic neuron PNS group,compared to the dopaminergic neuron group(P<0.01).CONCLUSION:Panax notoginseng saponins can increase survival and effectiveness of dopaminergic neurons differentiated from neural stem cells for transplantation in a rat model of Parkinson's disease.     

Cortical regulation of striatal projection neurons and interneurons in a Parkinson's disease rat model

Striatal neurons can be either projection neurons or interneurons, with each type exhibiting distinct susceptibility to various types of brain damage. In this study, 6-hydroxydopamine was injected into the right medial forebrain bundle to induce dopamine depletion, and/or ibotenic acid was injected into the M1 cortex to induce motor cortex lesions. Immunohistochemistry and western blot assay showed that dopaminergic depletion results in significant loss of striatal projection neurons marked by dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein, molecular weight 32 k Da, calbindin, and μ-opioid receptor, while cortical lesions reversed these pathological changes. After dopaminergic deletion, the number of neuropeptide Y-positive striatal interneurons markedly increased, which was also inhibited by cortical lesioning. No noticeable change in the number of parvalbumin-positive interneurons was found in 6-hydroxydopamine-treated rats. Striatal projection neurons and interneurons show different susceptibility to dopaminergic depletion. Further, cortical lesions inhibit striatal dysfunction and damage induced by 6-hydroxydopamine, which provides a new possibility for clinical treatment of Parkinson's disease.     

Dopamine in Parkinson’s Disease: Precise Supplementation with Motor Planning

正Parkinson’s disease (PD) is the second most common neurodegenerative disorder which mainly affects the motor system. The pathological characteristics of PD include the loss of dopaminergic neurons in the substantia nigra region and dopamine depletion in the striatum.Dopamine functions as a neurotransmitter that is     

Gastrodin inhibits neuroinflammation in rotenone-induced Parkinson's disease model rats

The present study showed that the latency of rats moving on a vertical grid was significantly prolonged,and the number of rats sliding down from the declined plane was increased remarkably,in rotenone-induced Parkinson’s disease model rats compared with control rats.The moving latency recovered to normal levels,but the number of slides was significantly increased at 28 days after model establishment.The slope test is a meaningful approach to evaluate the symptoms of Parkinson’s disease model rats treated with rotenone.In addition,loss of substantia nigral dopaminergic neurons in model rats was observed at 1 day after the model was established,and continued gradually at 14 and 28 days.The expression of tyrosine hydroxylase-positive cells was significantly increased in gastrodin-treated rats at 14 days.Significant numbers of activated microglia cells were observed in model rats at 14 and 28 days;treatment of rats with Madopar at 28 days suppressed microglial activation.Treatment of rats with gastrodin or Madopar at 28 days significantly reduced interleukin-1β expression.The loss of substantia nigral dopaminergic neurons paralleled the microglial activation in Parkinson’s disease model rats treated with rotenone.The inflammatory factors tumor necrosis factor-α and interleukin-1β are involved in the substantia nigral damage.Gastrodin could protect dopaminergic neurons via inhibition of interleukin-1β expression and neuroinflammation in the substantia nigra.     

Necrostatin-1 protection of dopaminergic neurons

Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson's disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before exposure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death process of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range(5–30 μM) elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Parkinson's disease.     

Angiotensin-(1–7)reducesα-synuclein aggregation by enhancing autophagic activity in Parkinson's disease

Abnormal accumulation ofα-synuclein contributes to the formation of Lewy bodies in the substantia nigra,which is considered the typical pathological hallmark of Parkinson's disease.Recent research indicates that angiotensin-(1-7)plays a crucial role in several neurodegenerative disorders,including Parkinson's disease,but the underlying mechanisms remain elusive.In this study,we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson's disease model.We investigated whether angiotensin-(1-7)is neuroprotective in this model by continuous administration of angiotensin-(1-7)into the right substantia nigra for 4 weeks.We found that angiotensin-(1-7)infusion relieved characteristic parkinsonian behaviors and reducedα-synuclein aggregation in the substantia nigra.Primary dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone,angiotensin-(1-7),and/or the Mas receptor blocker A-779 for 24 hours.After binding to the Mas receptor,angiotensin-(1-7)attenuated apoptosis andα-synuclein aggregation in rotenone-treated cells.Primary dopaminergic neurons were also treated with angiotensin-(1-7)and/or the autophagy inhibitor 3-methyladenine for 24 hours.Angiotensin-(1-7)increasedα-synuclein removal and increased the autophagy of rotenone-treated cells.We conclude that angiotensin-(1-7)reducesα-synuclein aggregation by alleviating autophagy dysfunction in Parkinson's disease.Therefore,the angiotensin-(1-7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson's disease and angiotensin-(1-7)has potential therapeutic value for Parkinson's disease.All experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital(approval No.DWSY-2000932)in January 2020.     

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson’s disease☆

Parkinson＇s disease （PD） is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor （BDNF） mRNA （20%） than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.     

Curcumin protects nigral dopaminergic neurons by iron-chelation in the 6-hydroxydopamine rat model of Parkinson’s disease

Objective Curcumin is a plant polyphenolic compound and a major component of spice turmeric (Curcuma longa). It has been reported to possess free radical-scavenging, iron-chelating, and anti-inflammatory properties in dif- ferent tissues. Our previous study showed that curcumin protects MES23.5 dopaminergic cells from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. The present study aimed to explore this neuroprotective effect in the 6-OHDA-lesioned rat model of Parkinson’s disease in vivo. Methods Rats were given intragastric curcumin for 24 days. 6-OHDA lesioning was conducted on day 4 of curcumin treatment. Dopamine content was assessed by high-performance liquid chromatography with electrochemical detection, tyrosine hydroxylase (TH)-containing neurons by immunohistochemistry, and iron-containing cells by Perls’ iron staining. Results The dopamine content in the striatum and the number of TH-immunoreactive neurons decreased after 6-OHDA treatment. Curcumin pretreatment reversed these changes. Further studies demonstrated that 6-OHDA treatment increased the number of iron-staining cells, which was dramatically decreased by curcumin pretreatment. Conclusion The protective effects of curcumin against 6-OHDA may be attributable to the ironchelating activity of curcumin to suppress the iron-induced degeneration of nigral dopaminergic neurons.     

The role of synphilin-1 in the pathogenesis of Parkinson＇s disease

Parkinson＇s disease （PD） is one of the commonest neurodegenerative disorders characterized by the loss of dopaminergic （DAergic） neurons in the substantia nigra and the appearance of Lewy bodies （LBs）, whose cytoplasmic inclusions are highly enriched with ubiquitin, synphilin- 1, α-synuclein and park：in. Synphilin- 1 is an α-synuclein-binding protein and a major component of LBs, It is widely accepted that synphilin- 1 is involved in the pathogenic process of PD. This review will provide an overall view of the role of synphilin- 1 in the pathogenesis of Parkinson＇ s disease and the latest findings in this field.     

Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration

Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopamine neurotrophic factor(h CDNF)has recently emerged as a strong candidate for Parkinson's disease therapy.This study shows that h CDNF expression in dopamine neurons using the neurotensinpolyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological,biochemical,and behavioral alterations.Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the h CDNF gene,ranging in size from 20 to 150 nm,enabled the expression of a secretable h CDNF in vitro.Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable h CDNF in dopamine neurons,whose levels remained constant throughout the study in the substantia nigra compacta and striatum.Compared with the lesioned group,tyrosine hydroxylase-positive(TH⁺)nigral cell population and TH+fiber density rose in the substantia nigra compacta and striatum after h CDNF transfection.An increase inβIII-tubulin and growth-associated protein 43 phospho-S41(GAP43 p)followed TH⁺cell recovery,as well as dopamine and its catabolite levels.Partial reversal(80%)of drugactivated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved.Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects.These findings support the potential of nanoparticle-mediated h CDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease.The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use(authorization No.162-15)on June 9,2019.     

Detecting dopaminergic neuronal degeneration using diffusion tensor imaging in a rotenone-induced rat model of Parkinson's disease: fractional anisotropy and mean diffusivity values

Dopamine content in the basal ganglia is strongly associated with the degree of dopaminergic neuron loss in the substantia nigra pars com-pacta. Symptoms of Parkinson's disease might not arise until more than 50% of the substantia nigra pars compacta is lost and the dopamine content in the basal ganglia is reduced by more than 80%. Greater diagnostic sensitivity and specificity would allow earlier detection of Parkinson's disease. Diffusion tensor imaging is a recently developed magnetic resonance imaging technique that measures mean diffusiv-ity and fractional anisotropy, and responds to changes in brain microstructure. When the microscopic barrier (including cell membranes, microtubules and other structures that interfere with the free diffusion of water) is destroyed and extracellular fluid volume accumulates, the mean diffusivity value increases; when the integrity of the microstructure (such as myelin) is destroyed, fractional anisotropy value decreases. However, there is no consensus as to whether these changes can reflect the early pathological alterations in Parkinson's disease. Here, we established a rat model of Parkinson's disease by injecting rotenone (or sunflower oil in controls) into the right substantia nigra. Diffusion tensor imaging results revealed that in the stages of disease, at 1, 2, 4, and 6 weeks after rotenone injection, fractional anisotropy value decreased, but mean diffusivity values increased in the right substantia nigra in the experimental group. Fractional anisotropy values were lower at 4 weeks than at 6 weeks in the right substantia nigra of rats from the experimental group. Mean diffusivity values were mark-edly greater at 1 week than at 6 weeks in the right corpus striatum of rats from the experimental group. These findings suggest that mean diffusivity and fractional anisotropy values in the brain of rat models of Parkinson's disease 4 weeks after model establishment can reflect early degeneration of dopaminergic neurons. The change in fractional anisotropy values after destruction of myelin integrity is likely to be of greater early diagnostic significance than the change in mean diffusivity values.