Nigrostriatal Cell Loss Research Articles

El aumento de la mieloperoxidasa sérica se correlaciona con datos clínicos de la enfermedad de Parkinson

Objectives. Myeloperoxidase (MPO) has been implicated in Parkinson´s disease (PD). The objective was to look at the relationship of MPO concentration in serum and cerebrospinal fluid (CSF) with clinical variables of PD. Methods. In this prospective, observational, and cross-sectional study, MPO concentration in serum and the CSF was analyzed in 36 patients with idiopathic PD and 30 controls, who were enrolled from 2012 to 2017. In the group of patients, correlation of MPO content with demographic, clinical and tomographic variables was examined. The extent and degree of nigrostriatal dopaminergic cell loss was evaluated by using SPECT and 123I-Ioflupane, radioligand that has binding affinity for dopamine-transporter (DAT). Results. Serum MPO concentration, not CSF MPO content, was significantly higher in the patients (p<.0001). Significant correlation values were found between serum MPO concentration and rating scales of motor severity (Hoehn-Yahr, MDS-UPDRS part-III), and percentage reduction of DAT binding on basal ganglia (p<.0001). Patients with moderate-advanced disease (Hoehn-Yahr stage 3) showed significantly higher serum MPO content relative to patients with early disease (Hoehn-Yahr stages 1-2, p<.0001). DAT binding was reduced on all striatal regions, and signal reduction was higher in the putamen relative to the caudate nucleus (p<.0001). Percentage reduction of DAT binding on the striatum and putamen significantly correlated with rating scales of motor severity. Conclusions. Myeloperoxidase content in serum is increased in PD patients and correlates with motor severity degree and loss of dopamine-transporter binding on basal ganglia. The results allow proposing that the measurement of MPO level in serum could be useful for PD diagnosis, and that the inhibition of serum MPO would be a promising therapeutic tool. The study also confirms that the putamen shows higher reduction of DAT binding than the caudate nucleus, and degree of nigrostriatal dopaminergic cell loss is well quantified with rating scales of motor severity.

Hyposmia as a marker of (non-)motor disease severity in Parkinson\u2019s disease

The aim of this study was to evaluate the relationship of hyposmia in Parkinson’s disease (PD) with other motor and non-motor symptoms and with the degree of nigrostriatal dopaminergic cell loss. A total of 295 patients with a diagnosis of PD were included. Olfactory function was measured using the University of Pennsylvania Smell Identification Test (UPSIT). Motor symptoms were rated using the Unified Parkinson’s Disease Rating Scale motor subscale (UPDRS III). To evaluate other non-motor symptoms, we used the Mini-Mental State Examination (MMSE) as a measure of global cognitive function and validated questionnaires to assess sleep disturbances, psychiatric symptoms, and autonomic dysfunction. A linear regression model was used to calculate correlation coefficients between UPSIT score and motor and non-motor variables [for psychiatric symptoms a Poisson regression was performed]. In a subgroup of patients (n = 155) with a dopamine transporter (DaT) SPECT scan, a similar statistical analysis was performed, now including striatal DaT binding. In the regression models with correction for age, sex, disease duration, and multiple testing, all motor and non-motor symptoms were associated with UPSIT scores. In the subgroup of patients with a DaT-SPECT scan, there was a strong association between olfactory test scores and DaT binding in both putamen and caudate nucleus. Hyposmia in PD is associated with various motor and non-motor symptoms, like cognition, depression, anxiety, autonomic dysfunction and sleep disturbances, and with the degree of nigrostriatal dopaminergic cell loss. This finding adds further confirmation that hyposmia holds significant promise as a marker of disease progression.

Derivation of Leptomeninges Explant Cultures from Postmortem Human Brain Donors.

Even though great progress has been made in the clinical characterization of Parkinson's disease, several studies report that the diagnosis of Parkinson's disease is not pathologically confirmed in up to 25% of clinically diagnosed Parkinson's disease. Therefore, tissue collected from clinically diagnosed patients with idiopathic Parkinson's disease can have a high rate of misdiagnosis; hence in vitro studies from such tissues to study Parkinson's disease as a preclinical model can become futile. By collecting postmortem human leptomeninges with a confirmed neuropathological diagnosis of Parkinson's disease and characterized by nigrostriatal cell loss and intracellular protein inclusions called Lewy bodies, one can be certain that clinically observed parkinsonism is not caused by another underlying disease process (e.g. tumor, arteriosclerosis). This protocol presents the dissection and preparation of postmortem human leptomeninges for derivation of a meningeal fibroblast culture. This procedure is robust and has a high success rate. The challenge of the culture is sterility as the brain procurement is generally not performed under sterile conditions. Therefore, it is important to supplement the culture media with a cocktail of penicillin, streptomycin, and amphotericin B. The derivation of meningeal fibroblasts from autopsy-confirmed cases with Parkinson's disease provides the foundation for in vitro modeling of Parkinson's disease. Meningeal fibroblasts appear 3-9 days after sample preparation and about 20-30 million cells can be cryopreserved in 6-8 weeks. The meningeal fibroblast culture is homogenous and the cells express fibronectin, a commonly used marker to identify meninges.

Implementation of the European multicentre database of healthy controls for [123I]FP-CIT SPECT increases diagnostic accuracy in patients with clinically uncertain parkinsonian syndromes

Even though [(123)I]FP-CIT SPECT provides high accuracy in detecting nigrostriatal cell loss in neurodegenerative parkinsonian syndromes (PS), some patients with an inconclusive diagnosis remain. We investigated whether the diagnostic accuracy in patients with clinically uncertain PS with previously inconclusive findings can be improved by the use of iterative reconstruction algorithms and an improved semiquantitative evaluation which additionally implemented a correction algorithm for patient age and gamma camera dependency (EARL-BRASS; Hermes Medical Solutions, Sweden). We identified 101 patients with inconclusive findings who underwent an [(123)I]FP-CIT SPECT between 2003 and 2010 as part of the diagnostic process of suspected PS at the University of Munich, and re-evaluated these scans using iterative reconstruction algorithms and the new corrected EARL-BRASS. Clinical follow-up was obtained in 62 out of the 101 patients and constituted the gold standard for the re-evaluation to assess the possible improvement in diagnostic accuracy. Clinical follow-up confirmed the diagnosis of PS in 11 of the 62 patients. In patients in whom both visual and semiquantitative analysis showed concordant findings (48 patients), a high negative predictive value (93%), positive predictive value (100%) and accuracy (94%) were found, and thus a correct diagnosis was obtained in 45 of the 48 patients. Among the 14 patients with discordant findings, the additional semiquantitative analysis correctly identified all five of nine patients patients without PS by nonpathological semiquantitative findings in visually pathological or inconclusive scans. In contrast, four of the remaining five patients with decreased semiquantitative values but visually normal scans did not show a PS during follow-up. The age-corrected and camera-corrected mode of evaluation using EARL-BRASS provided a notable improvement in the diagnostic accuracy of [(123)I]FP-CIT SPECT in PS patients with previously inconclusive findings. The gain in accuracy might be achieved by better discrimination between physiological low striatal [(123)I]FP-CIT binding due to age-related loss of the dopamine transporter or pathological loss of binding.

Chemical Exchange Saturation Transfer MR Imaging is Superior to Diffusion-Tensor Imaging in the Diagnosis and Severity Evaluation of Parkinson's Disease: A Study on Substantia Nigra and Striatum.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by nigrostriatal cell loss. To date, the diagnosis of PD is still based primarily on the clinical manifestations, which may be typical and obvious only in advanced-stage PD. Thus, it is crucial to find a reliable marker for the diagnosis of PD. We conducted this study to assess the diagnostic efficiency of chemical exchange saturation transfer (CEST) imaging and diffusion-tensor imaging (DTI) in PD at 3 T by evaluating changes on substantia nigra and striatum. Twenty-three PD patients and twenty-three age-matched normal controls were recruited. All patients and controls were imaged on a 3-T MR system, using an eight-channel head coil. CEST imaging was acquired in two transverse slices of the head, including substantia nigra and striatum. The magnetization transfer ratio asymmetry at 3.5 ppm, MTRasym(3.5 ppm), and the total CEST signal intensity between 0 and 4 ppm were calculated. Multi-slice DTI was acquired for all the patients and normal controls. Quantitative analysis was performed on the substantia nigra, globus pallidus, putamen, and caudate. The MTRasym(3.5 ppm) value, the total CEST signal intensity, and fractional anisotropy value of the substantia nigra were all significantly lower in PD patients than in normal controls (P = 0.003, P = 0.004, and P < 0.001, respectively). The MTRasym(3.5 ppm) values of the putamen and the caudate were significantly higher in PD patients than in normal controls (P = 0.010 and P = 0.009, respectively). There were no significant differences for the mean diffusivity in these four regions between PD patients and normal controls. In conclusion, CEST MR imaging provided multiple CEST image contrasts in the substantia nigra and the striatum in PD and may be superior to DTI in the diagnosis of PD.

The diagnostic accuracy of dopamine transporter SPECT imaging to detect nigrostriatal cell loss in patients with Parkinson's disease or clinically uncertain parkinsonism: a systematic review.

In specialized movement disorder centers, Parkinson’s disease (PD) is wrongly diagnosed in 6 to 25% of cases. To improve the accuracy of the clinical diagnosis, it is necessary to have a reliable and practical reference standard. Dopamine transporter single-photon emission computed tomography (DAT SPECT) imaging might have the potential (high diagnostic accuracy and practical to use) to act as reference standard in detecting nigrostriatal cell loss in patients with (early stage) parkinsonism. We performed a systematic review to evaluate if DAT SPECT imaging can be used as such. Relevant studies were searched in the MEDLINE and EMBASE databases. Studies were selected when they met the following criteria: (1) all patients were adults with a clinical diagnosis of PD or clinically uncertain parkinsonism and (2) the study reported original data. In addition, studies needed to fulfill one of the two following criteria: (1) patients underwent at least one DAT SPECT and had a neuropathological confirmed diagnosis and (2) patients underwent at least two DAT SPECT scans, performed at least 2 years apart. The search identified 1,649 articles. Eight studies fulfilled our selection criteria and were included in this review. There was only one study including patients with diagnostic uncertainty. Sensitivity and specificity of DAT SPECT imaging to detect nigrostriatal cell loss were 98%. The other studies included patients with a diagnosis of PD in whom there was no uncertainty. In these studies, sensitivity was 100%. Our systematic review indicates that DAT SPECT imaging seems to be accurate to detect nigrostriatal cell loss in patients with parkinsonism.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0087-1) contains supplementary material, which is available to authorized users.

Early-onset cortico-cortical synchronization in the hemiparkinsonian rat model.

Changes in synchronized neuronal oscillatory activity are reported in both cortex and basal ganglia of Parkinson's disease patients. The origin of these changes, in particular their relationship with the progressive nigrostriatal dopaminergic denervation, is unknown. Therefore, in the present study we studied interregional neuronal synchronization in motor cortex and basal ganglia during the development of dopaminergic degeneration induced by a unilateral infusion of 6-hydroxydopamine (6-OHDA) into the rat medial forebrain bundle. We performed serial local field potential recordings bilaterally in the motor cortex and the subthalamic nucleus of the lesioned hemisphere prior to, during, and after development of the nigrostriatal dopaminergic cell loss. We obtained signal from freely moving rats in both resting and walking conditions, and we computed local spectral power, interregional synchronization (using phase lag index), and directionality (using Granger causality). After neurotoxin injection the first change in phase lag index was an increment in cortico-cortical synchronization. We observed increased bidirectional Granger causality in the beta frequency band between cortex and subthalamic nucleus within the lesioned hemisphere. In the walking condition, the 6-OHDA lesion-induced changes in synchronization resembled that of the resting state, whereas the changes in Granger causality were less pronounced after the lesion. Considering the relatively preserved connectivity pattern of the cortex contralateral to the lesioned side and the early emergence of increased cortico-cortical synchronization during development of the 6-OHDA lesion, we suggest a putative compensatory role of cortico-cortical coupling.

Pharmacological Prolyl Hydroxylase Domain Inhibition as a Therapeutic Target for Parkinson’s Disease

Previously published data from our laboratory demonstrated that pharmacological inhibition of a family of enzymes known as prolyl hydroxylase domain proteins prevents neurotoxicity associated with the acute 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine intoxication model of Parkinson's disease in young animals. In this study, we assessed whether prolyl hydroxylase domain inhibition was neuroprotective in an inducible genetic dopaminergic glutathione depletion model previously characterized by our laboratory that more closely recapitulates the age-related and progressive nature of the human disease. Pharmacological prolyl hydroxylase domain inhibition via 3,4-dihydroxybenzoate was found to significantly attenuate hallmark mitochondrial dysfunction and loss of dopaminergic substantia nigral pars compacta neurons associated with this model. These studies further validate the possibility that prolyl hydroxylase domain inhibition may constitute a viable therapy for Parkinson's disease.

Treadmill exercise alleviates short-term memory impairment in 6-hydroxydopamine-induced Parkinson’s rats

Progressive loss of dopaminergic neurons in substantia nigra is a key pathogenesis of Parkinson’s disease. In the present study, we investigated the effects of treadmill exercise on short-term memory, apoptotic dopaminergic neuronal cell death and fiber loss in the nigrostriatum, and cell proliferation in the hippocampal dentate gyrus of Parkinson’s rats. Parkinson’s rats were made by injection of 6-hydroxydopamine (6-OHDA) into the striatum using stereotaxic instrument. Four weeks after 6-OHDA injection, the rats in the 6-OHDA-injection group exhibited significant rotational asymmetry following apomorphine challenge. The rats in the exercise groups were put on the treadmill to run for 30 min once a day for 14 consecutive days starting 4 weeks after 6-OHDA injection. In the present results, extensive degeneration of the dopaminergic neurons in the substantia nigra with loss of dopaminergic fibers in the striatum were produced in the rats without treadmill running, which resulted in short-term memory impairment. However, the rats performing treadmill running for 2 weeks alleviated nigrostriatal dopaminergic cell loss and alleviated short-term memory impairment with increasing cell proliferation in the hippocampal dentate gyrus of Parkinson’s rats. The present results show that treadmill exercise may provide therapeutic value for the Parkinson’s disease.

Substantia nigra echogenicity is correlated with nigrostriatal impairment in Machado-Joseph disease

BackgroundSeveral studies have demonstrated increased substantia nigra (SN) echogenicity in Parkinson's disease (PD) and Machado-Joseph disease (MJD). Pathological substrate of PD is characterized by dopaminergic nigrostriatal cell loss, also found in MJD. Also, SN hyperechogenicity might be associated with nigrostriatal dysfunction in PD, when comparing dopamine transporter binding with SN echogenicity. The present study aimed to correlate the SN echogenic size and striatal dopamine transporter density in MJD patients. MethodsWe performed TCS in 30 subjects and SPECT with [99mTc]-TRODAT-1 in 18 subjects with MJD. Fifteen healthy subjects matched for age and gender formed a control group. TCS and [99mTc]-TRODAT-1 SPECT findings from both MJD patients and control subjects were compared. ResultsThere were no differences regarding age (p = 0.358) or gender (p = 0.566) between groups (MJD versus control group). Mean DAT binding potentials and SN echogenicity were significantly different between groups. There was a significant negative correlation with regard to the SN echogenic size and the ipsilateral striatal TRODAT-1 uptake: the higher the SN echogenicity, the lower the DAT uptake in the ipsilateral cerebral hemisphere. ConclusionIncrease in SN echogenic size likely correlates with presynaptic dopaminergic nigrostriatal dysfunction in MJD, suggesting a concurrent in vivo pathophysiological mechanism.

Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk.

Different susceptibility to 1-methyl-4-phenylpyridium (MPP+)-induced nigro-striatal dopaminergic cell loss between C57BL/6 and BALB/c mice is not related to the difference of monoamine oxidase-B (MAO-B)

Subcutaneous and intraperitoneal administrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induce selective dopaminergic (DA-ergic) neuronal death in many animal species. After passing through the blood-brain barrier (BBB), MPTP is converted to 1-methy-4-phenylpiridinium (MPP(+)) by astrocytic monoamine oxidase-B (MAO-B). MPP(+) then induces the dopaminergic neuronal death. In mice, marked strain differences in the susceptibility to MPTP-injection have been reported. To clarify which factor(s) cause the strain differences, MPTP or MPP(+) was intracerebroventricularly (icv) injected into adult C57BL/6 (highly susceptible to MPTP) and BALB/c (resistant to MPTP) mice. The brain tissues including the striatum and substantia nigra pars compacta (SNpc) were examined immunohistochemically using an antibody to tyrosine hydrocyrase (TH). MPP(+)-injected C57BL/6 mice showed a significant decrease in TH-immunopositive areas in the striatum at Day 3 post injection (p<0.01), and TH-positive cells in the SNpc at Days 1 and 3 (p<0.01), respectively, compared to saline-injected control mice. In addition, MPP(+)-injected BALB/c mice showed a significant decrease in TH-positive areas in the striatum at Days 1 and 3, and SNpc TH-positive cells in the SNpc at Day 3, respectively (p<0.05). However, the decrease rates in the BALB/c mice were lower than that in C57BL/6 mice. MPTP-injected C57BL/6 mice, however, showed no lesions in the striatum and SNpc at Days 1 and 7 after icv injection. All the present findings indicate that factors other than MAO-B can influence the strain susceptibility between C57BL/6 and BALB/c mice after the conversion from MPTP to MPP(+).

α-Synuclein Transgenic Mice Reveal Compensatory Increases in Parkinson's Disease-Associated Proteins DJ-1 and Parkin and Have Enhanced α-Synuclein and PINK1 Levels After Rotenone Treatment

Parkinson's disease (PD) is a severe neurodegenerative disorder characterised by loss of dopaminergic neurons of the substantia nigra. The pathological hallmarks are cytoplasmic inclusions termed Lewy bodies consisting primarily of aggregated alpha-synuclein (alphaSN). Different lines of transgenic mice have been developed to model PD but have failed to recapitulate the hallmarks of this disease. Since treatment of rodents with the pesticide rotenone can reproduce nigrostriatal cell loss and other features of PD, we aimed to test chronic oral administration of rotenone to transgenic mice over-expressing human alphaSN with the A53T mutation. Initial assessment of this transgenic line for compensatory molecular changes indicated decreased brain beta-synuclein expression and significantly increased levels of the PD-associated oxidative stress response protein, DJ-1, and the E3 ubiquitin ligase enzyme, Parkin. Rotenone treatment of 30 mg/kg for 25 doses over a 35-day period was tolerated in the transgenic mice and resulted in decreased spontaneous locomotor movement and increased cytoplasmic alphaSN expression. The mitochondrial Parkinson's-associated PTEN-induced kinase 1 protein levels were also increased in transgenic mouse brain after rotenone treatment; there was no change in brain dopamine levels or nigrostriatal cell loss. These hA53T alphaSN transgenic mice provide a useful model for presymptomatic Parkinson's features and are valuable for study of associated compensatory changes in early Parkinson's disease stages.

WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease

Parkinson's disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non-selective cannabinoid receptor agonist WIN55,212-2 (WIN) protects mouse nigrostriatal neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP-induced loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta independently of CB1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4-dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP-treated mice. At 3 days post-MPTP, we found significant microglial activation and up-regulation of CB2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP-induced microglial activation, whereas genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP-associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid receptors protects against MPTP-induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.

Changes on 5-HT 2 receptor mRNAs in striatum and subthalamic nucleus in Parkinson's disease model

Changes on 5-HT 2 receptor mRNAs in striatum and subthalamic nucleus in Parkinson's disease model. PHYSIOL. BEHAV. 00(0), 000-000, 2006. Abnormal interactions between the serotonin and dopamine systems may underlie the high prevalence of non-motor complications in Parkinson's disease (PD). Here, we demonstrate that the genes encoding serotonin 5-HT 2A and 5-HT 2C receptors are differently regulated by dopamine in the 6-hydroxydopamine (6-OHDA) rat model of PD. Nigrostriatal cell loss causes an up-regulation of 5-HT 2AR mRNA, but a down-regulation of 5-HT 2CR mRNA, in striatum. Repeated injections with L-DOPA/benserazide reverse the effect of 6-OHDA lesioning on 5-HT 2AR, but not on 5-HT 2CR, gene expression. Neither 6-OHDA-lesioning nor L-DOPA/benserazide treatment had any effect on 5-HT 2AR mRNA in cortex or on 5-HT 2CR mRNA in nucleus subthalamicus. These data suggest that the regulation of 5-HT 2AR in striatum, in the 6-OHDA rat model of PD, is mainly dependent upon alterations in dopamine levels. 5-HT 2CR, on the other hand, are regulated by nigrostriatal cell loss and by the accompanied reduction of factor(s), other than dopamine, that are normally co-expressed with dopamine. The apparent imbalance between 5-HT 2AR and 5-HT 2CR levels in this PD model indicates a potential role for these receptors in the pathophysiology of neuropsychiatric symptoms, such as depression and L-DOPA-induced hallucinations, which are co-morbid with PD. The fact that 5-HT 2CR are differentially regulated as compared to 5-HT 2AR to alterations in the dopamine tone predicts that pharmacological manipulations at 5-HT 2CR, but not at 5-HT 2AR, will result in similar effects in PD patients whether they are treated or not with dopamine replacement.

Treadmill exercise alleviates apoptotic nigrostriatal dopaminergic neuronal cell death and enhances cell proliferation in 6‐hydroxydopamine‐induced Parkinson’s rats

In Parkinson’s disease, progressive loss of dopaminergic neurons in substantia nigra leads to motor dysfunction and cognitive disturbances. Endogenous 6-hydroxydopamine (6-OHDA) is a neurotoxin which selectively injures catecholaminergic neurons and it causes progressive loss of nigral dopaminergic neurons. In the present study, we investigated the effects of treadmill exercise on short-term memory, on apoptotic dopaminergic neuronal cell death and fiber loss, and on cell proliferation in the hippocampal dentate gyrus following 4 weeks after 6-hydroxydopamine (6-OHDA) injection into the striatum in rats. Four weeks after 6-OHDA injection, the rats in the 6-OHDA-injection-group exhibited significant rotational asymmetry following apomorphine challenge compared with the sham-operated group. The rats in the exercise groups were put on the treadmill to run for 30 minutes once a day for 14 consecutive days starting 4 weeks after 6-OHDA injection. In the 6-OHDA-injection group, treadmill exercise alleviated nigrostriatal dopaminergic cell loss and suppressed caspase-3 expression in the substantia nigra. In addition, treadmill exercise enhanced short-term memory and increased cell proliferation in the hippocampal dentate gyrus in the 6-OHDA-injection rats. As shown in the present study, treadmill exercise may provide therapeutic value for the treatment of Parkinson’s disease patients. This study was supported by the Brain Korea 21 Project in 2006.

Protection against dopaminergic nigrostriatal cell death by excitatory input ablation.

The importance of enhanced glutamatergic neurotransmission in the basal ganglia and related structures has recently been highlighted in the development of Parkinson's disease. The pedunculopontine tegmental nucleus (PPN) is the major origin of excitatory, glutamatergic input to dopaminergic nigrostriatal neurons of which degeneration is well known to cause Parkinson's disease. Based on the concept that an excitatory mechanism mediated by glutamatergic neurotransmission underlies the pathogenesis of neurodegenerative disorders, we made an attempt to test the hypothesis that removal of the glutamatergic input to the nigrostriatal neurons by PPN lesions might prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey. The PPN was lesioned unilaterally with microinjection of kainic acid, and, then, MPTP was administered systemically. In these monkeys, the degree of parkinsonian motor signs was behaviourally evaluated, and the histological changes in the dopaminergic nigrostriatal system were analysed by means of tyrosine hydroxylase immunohistochemistry. The present results revealed that nigrostriatal cell loss and parkinsonian motor deficits were largely attenuated in the MPTP-treated monkey group whose PPN had been lesioned, compared with the control, MPTP-treated monkey group with the PPN intact. This clearly indicates that the onset of MPTP neurotoxicity is suppressed or delayed by experimental ablation of the glutamatergic input to the nigrostriatal neurons. Such a protective action of excitatory input ablation against nigrostriatal cell death defines evidence that nigral excitation driven by the PPN may be implicated in the pathophysiology of Parkinson's disease.

Incomplete nigrostriatal dopaminergic cell loss and partial reductions in striatal dopamine produce akinesia, rigidity, tremor and cognitive deficits in middle-aged rats

The present study was conducted to determine if the full array of parkinsonian symptoms could be detected in rats with nigrostriatal cell loss and striatal dopamine depletions similar to levels reported in the clinical setting, and to determine if older rats exhibit more robust parkinsonian deficits than younger rats. Young (2 months old) and middle-aged (12 months old) rats received bilateral striatal infusions of 6-OHDA, over the next 3 months they were assessed with a battery of behavioral tests, and then dopaminergic nigrostriatal cells and striatal dopamine and DOPAC levels were quantified. The results of the present study suggest that: (1) the full array of parkinsonian symptoms (i.e. akinesia, rigidity, tremor and visuospatial cognitive deficits) can be quantified in rats with incomplete nigrostriatal dopaminergic cell loss and partial reductions in striatal dopamine levels (2) parkinsonian symptoms were more evident in middle-aged rats with 6-OHDA infusions, and (3) there was evidence of substantial neuroplasticity in the older rats, but regardless of the age of the animal, endogenous compensatory mechanisms were unable to maintain striatal dopamine levels after rapid, lesion-induced nigrostriatal cell loss. These results suggest that using older rats with nigrostriatal dopaminergic cell loss and reductions in striatal dopamine levels similar to those in the clinical condition, and measuring behavioral deficits analogous to parkinsonian symptoms, might increase the predictive validity of pre-clinical rodent models.

Clinicopathological study of 35 cases of multiple system atrophy.

The clinical and pathological features of 35 cases with multiple system atrophy collected in the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) between 1985 and 1992 have been analysed. The median age of onset was 55 (range 33.3-75.8) years and median survival was 7.3 (range 2.1-11.5) years. Parkinsonism, usually asymmetric, occurred in all, and autonomic failure in all but one case. Cerebellar signs were noted in 34% and pyramidal features in 54% of the cases. Glial cytoplasmic inclusions were found in all cases with adequate fixation. Lewy bodies were detected in three cases. The substantia nigra was (usually severely) depleted of cells in all cases. With two exceptions the putamen was atrophic; the caudate and pallidum were less commonly and less severely affected. Overall nigrostriatal cell loss correlated with severity of disease at the time of death. The latest, but not the best, recorded levodopa response tended to be inversely related to the degree of putaminal degeneration. The olivopontocerebellar system was involved in 88% of the cases, the cerebellar vermis usually being more severely affected than the hemispheres. The presence of associated cerebellar pathology was, however, unrelated to the presence of cerebellar signs in life.

Medical treatment of Parkinson's disease.

Parkinson’s disease (PD) is a progressive neurodegenerative disease. It’s main feature is the nigrostriatal neuronal cell loss resulting in striatal dopamine (DA) deficiency. L-dopa + peripheral amino acid decarboxylase inhibitor (DDI: Sinemet or Madopar) is still the most effective agent for the symptomatic treatment of PD, but the dopa therapy is far from perfect. For advanced cases especially for patients with wearing off of the drug effect, fluctuation of response and “on-off, ” the conventional preparation such as Sinemet or Madopar due to their short T1/2 is no longer suitable for clinical use. Thus controlled release preparation e.g. Sinemet CR or Madopar HBS is preferable.KeywordsStriatal DopamineAdvanced CaseCOMT InhibitorProgressive Neurodegenerative DiseasePsychiatric ComplicationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.