Nucleolin in Neurons of the Human Substantia Nigra

Using immunocytochemistry and confocal laser microscopy, the distribution of nucleolin (protein C23) in neurons of the human substantia nigra was investigated. Fragments of the human midbrain (n = 8) with the verified lack of neurodegeneration were used in the study. The material was fixed in zinc ethanol formaldehyde, a special fixative that provides high preservation of antigenic determinants. New morphological data on the distribution of nucleolin in neurons of the human substantia nigra were obtained. Nucleolin was found in the nucleolus and nucleoplasm of dopaminergic neurons but not in the cytoplasm or cell surface. In the nucleolus and nucleoplasm, protein C23 is distributed irregularly in the form of some accumulations (clumps) with fuzzy borders. Moreover, nucleolin distribution varied in structurally similar neurons containing cytoplasmic neuromelanin. The Marinesco bodies typically not exhibiting nucleolin expression were identified in the nucleus, in addition to nucleoli, by confocal laser microscopy with simultaneous use of transmitted light detector. The findings can contribute to elucidation of the role of nucleolin in the specific functions of normal dopaminergic neurons in the human substantia nigra and assessment of probable involvement of C23 in the development of nucleolar stress and neurodegeneration.     

Functional Upregulation of Ca2+ -Activated K+ Channels in the Development of Substantia Nigra Dopamine Neurons

Many connections in the basal ganglia are made around birth when animals are exposed to a host of new affective, cognitive, and sensori-motor stimuli. It is thought that dopamine modulates cortico-striatal synapses that result in the strengthening of those connections that lead to desired outcomes. We propose that there must be a time before which stimuli cannot be processed into functional connections, otherwise it would imply an effective link between stimulus, response, and reward in uterus. Consistent with these ideas, we present evidence that early in development dopamine neurons are electrically immature and do not produce high-frequency firing in response to salient stimuli. We ask first, what makes dopamine neurons immature? and second, what are the implications of this immaturity for the basal ganglia? As an answer to the first question, we find that at birth the outward current is small (3nS-V), insensitive to , TEA, BK, and SK blockers. Rapidly after birth, the outward current increases to 15nS-V and becomes sensitive to , TEA, BK, and SK blockers. We make a detailed analysis of the kinetics of the components of the outward currents and produce a model for BK and SK channels that we use to reproduce the outward current, and to infer the geometrical arrangement of BK and channels in clusters. In the first cluster, T-type and BK channels are coupled within distances of 20 nm (200 Å). The second cluster consists of L-type and BK channels that are spread over distances of at least 60 nm. As for the second question, we propose that early in development, the mechanism of action selection is in a “locked-in” state that would prevent dopamine neurons from reinforcing cortico-striatal synapses that do not have a functional experiential-based value.     

Glial Cell Line-Derived Neurotrophic Growth Factor Inhibits Apoptotic Death of Postnatal Substantia Nigra Dopamine Neurons in Primary Culture

Abstract: Glial cell line-derived neurotrophic factor (GDNF) was identified on the basis of its ability to enhance the development of embryonic mesencephalic dopamine neurons. It remains unknown whether GDNF is a physiologically relevant trophic factor for these neurons. We have shown that natural cell death among dopamine neurons of the substantia nigra occurs largely postnatally. To investigate whether GDNF may have the ability to support these neurons during their period of natural cell death, we have used a postnatal primary culture model. We find that GDNF is able to support the viability of postnatal nigral dopamine neurons by inhibiting apoptotic death. This ability of GDNF shows both regional specificity for the nigra and cellular specificity for the dopamine phenotype. Among eight other neurotrophic factors previously reported to support embryonic dopamine neurons, GDNF was unique in this ability. Thus, GDNF meets this criterion for a physiologically relevant trophic factor for dopamine neurons of the substantia nigra.     

The h-Current in the Substantia Nigra pars Compacta Neurons: A Re-examination

The properties of the hyperpolarization-activated cation current (I_h) were investigated in rat substantia nigra - pars compacta (SNc) principal neurons using patch-clamp recordings in thin slices. A reliable identification of single dopaminergic neurons was made possible by the use of a transgenic line of mice expressing eGFP under the tyrosine hydroxylase promoter. The effects of temperature and different protocols on the I_h kinetics showed that, at 37°C and minimizing the disturbance of the intracellular milieu with perforated patch, this current actually activates at potentials more positive than what is generally indicated, with a half-activation potential of −77.05 mV and with a significant level of opening already at rest, thereby substantially contributing to the control of membrane potential, and ultimately playing a relevant function in the regulation of the cell excitability. The implications of the known influence of intracellular cAMP levels on I_h amplitude and kinetics were examined. The direct application of neurotransmitters (DA, 5-HT and noradrenaline) physiologically released onto SNc neurons and known to act on metabotropic receptors coupled to the cAMP pathway modify the I_h amplitude. Here, we show that direct activation of dopaminergic and of 5-HT receptors results in I_h inhibition of SNc DA cells, whereas noradrenaline has the opposite effect. Together, these data suggest that the modulation of I_h by endogenously released neurotransmitters acting on metabotropic receptors –mainly but not exclusively linked to the cAMP pathway- could contribute significantly to the control of SNc neuron excitability.     

Comprehensive Profiling of Dopamine Regulation in Substantia Nigra and Ventral Tegmental Area

Dopamine is a vigorously studied neurotransmitter in the CNS. Indeed, its involvement in locomotor activity and reward-related behaviour has fostered five decades of inquiry into the molecular deficiencies associated with dopamine regulation. The majority of these inquiries of dopamine regulation in the brain focus upon the molecular basis for its regulation in the terminal field regions of the nigrostriatal and mesoaccumbens pathways; striatum and nucleus accumbens. Furthermore, such studies have concentrated on analysis of dopamine tissue content with normalization to only wet tissue weight. Investigation of the proteins that regulate dopamine, such as tyrosine hydroxylase (TH) protein, TH phosphorylation, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) protein often do not include analysis of dopamine tissue content in the same sample. The ability to analyze both dopamine tissue content and its regulating proteins (including post-translational modifications) not only gives inherent power to interpreting the relationship of dopamine with the protein level and function of TH, DAT, or VMAT2, but also extends sample economy. This translates into less cost, and yet produces insights into the molecular regulation of dopamine in virtually any paradigm of the investigators'' choice.We focus the analyses in the midbrain. Although the SN and VTA are typically neglected in most studies of dopamine regulation, these nuclei are easily dissected with practice. A comprehensive readout of dopamine tissue content and TH, DAT, or VMAT2 can be conducted. There is burgeoning literature on the impact of dopamine function in the SN and VTA on behavior, and the impingements of exogenous substances or disease processes therein ^1-5. Furthermore, compounds such as growth factors have a profound effect on dopamine and dopamine-regulating proteins, to a comparatively greater extent in the SN or VTA ^6-8. Therefore, this methodology is presented for reference to laboratories that want to extend their inquiries on how specific treatments modulate behaviour and dopamine regulation. Here, a multi-step method is presented for the analyses of dopamine tissue content, the protein levels of TH, DAT, or VMAT2, and TH phosphorylation from the substantia nigra and VTA from rodent midbrain. The analysis of TH phosphorylation can yield significant insights into not only how TH activity is regulated, but also the signaling cascades affected in the somatodendritic nuclei in a given paradigm.We will illustrate the dissection technique to segregate these two nuclei and the sample processing of dissected tissue that produces a profile revealing molecular mechanisms of dopamine regulation in vivo, specific for each nuclei (Figure 1).     

Turnover of Dopamine and Dopamine Metabolites in Rat Brain: Comparison Between Striatum and Substantia Nigra

Measurements of the turnover of dopamine (DA) and DA metabolites have been performed in the striatum and substantia nigra (SN) of the rat. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid have been assessed from the disappearance rates after blocking their formation by inhibition of monoamine oxidase by pargyline and of catechol-O-methyltransferase by tropolone. DA turnover has been measured as 3-methoxytyramine (3-MT) plus DA accumulation rate after MAO inhibition by pargyline and as accumulation rate of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of aromatic amino acid decarboxylase by NSD 1015 or NSD 1034. These measures of DA turnover have been compared with alpha-methyl-p-tyrosine (alpha-MT)-induced DA disappearance rate. In SN all the different measures of DA turnover are in the same range (55-62 nmol/g protein/h) whereas in striatum DOPA accumulation rate after NSD 1015 and alpha-MT-induced DA disappearance rate (16-23 nmol/g/h) are much lower than DOPAC disappearance rate after pargyline, 3-MT plus DA accumulation rate after pargyline, and DOPA accumulation rate after NSD 1034 (39-46 nmol/g/h). The data confirm our previous findings indicating that the fractional turnover rate of DA is more rapid in SN than in striatum and that O-methylation of DA is relatively more important in SN. In striatum at least two pools of DA with different turnover rates appear to exist, whereas in SN, DA behaves as if located in a single compartment.     

Modulation of Dendritic Release of Dopamine by N-Methyl-D-Aspartate Receptors in Rat Substantia Nigra

A superfusion system was used to study the effects of excitatory amino acids (EAA) on release of [3H]dopamine ([3H]DA) previously taken up by rat substantia nigra (SN) slices. The EAA tested (20-250 microM), with the exception of quisqualate and kainate, markedly evoked [3H]DA release from nigral slices when Mg2+ ions were omitted from the superfusion medium. The EAA receptor agonists exhibited the following relative potency in stimulating [3H]DA release: L-glutamate (L-Glu) greater than N-methyl-D-aspartate (NMDA) greater than NM(D,L)A greater than D-Glu much greater than quisqualate = kainate. D-2-Amino-5-phosphonovalerate (100-200 microM), an antagonist for NMDA receptors, substantially reduced [3H]DA release evoked by L-Glu or NMDA. In contrast, L-Glu diethyl ester (100-200 microM) produced a lesser blocking effect on [3H]DA release evoked by the EAA. Further experiments showed that the NMDA-mediated release of [3H]DA was totally suppressed by the omission of Ca2+ or by the addition of tetrodotoxin (0.1 microM) to the superfusion medium. In addition, strychnine, an antagonist for glycine (Gly) receptors, significantly decreased NMDA (100 microM)-evoked as well as glycine (100 microM)-evoked release of [3H]DA from nigral slices. The results shown support the idea that activation of NMDA subtype receptors in SN may trigger a Ca2+-dependent release of DA from dendrites of nigro-striatal DA-containing neurons. Furthermore, a transsynaptic mechanism that may partially involve Gly-containing interneurons is proposed to account for some of the events mediating NMDA receptor activation and DA release in SN.     

Biochemistry of Somatodendritic Dopamine Release in Substantia Nigra: An In Vivo Comparison with Striatal Dopamine Release

Abstract: The somatodendritic release of dopamine in substantia nigra previously has been suggested to be nonvesicular in nature and thus to differ from the classical, exocytotic release of dopamine described for the dopaminergic nerve terminal in striatum. We have compared the effects of reserpine, a compound that disrupts vesicular sequestration of monoamines, on the storage and release of dopamine in substantia nigra and striatum of rats. Reserpine administration (5 mg/kg, i.p.) significantly decreased the tissue level of dopamine in substantia nigra pars reticulata, substantia nigra pars compacta, and striatum. In these brain areas, reserpine-induced reductions in tissue dopamine level occurred within 2 h and persisted at 24 h postdrug. In vivo measurements using microdialysis revealed that reserpine administration rapidly decreased the extracellular dopamine concentration to nondetectable levels in substantia nigra as well as in striatum. In both structures, it was observed that reserpine treatment significantly attenuated the release of dopamine evoked by a high dose of amphetamine (10 mg/kg, i.p.) given 2 h later. In contrast, dopamine efflux in response to a low dose of amphetamine (2 mg/kg, i.p.) was not altered by reserpine pretreatment either in substantia nigra or in striatum. The present data suggest the existence, both at the somatodendritic and at the nerve terminal level, of a vesicular pool of dopamine that is the primary site of transmitter storage and that can be displaced by high but not low doses of amphetamine. The physiological release of dopamine in substantia nigra and in striatum is dependent on the integrity of this vesicular store.     

Postnatal Development of Neurons,Interneurons and Glial Cells in the Substantia Nigra of Mice

We investigated postnatal alterations of neurons, interneurons and glial cells in the mouse substantia nigra using immunohistochemistry. Tyrosine hydroxylase (TH), neuronal nuclei (NeuN), parvalbumin (PV), neuronal nitric oxide synthase (nNOS), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba 1), CNPase (2′,3′-cyclic nucleotide 3′-phosphodiesterase), brain-derived neurotrophic factor (BDNF) and glial cell-line-derived neurotrophic factor (GDNF) immunoreactivity were measured in 1-, 2-, 4- and 8-week-old mice. In the present study, the maturation of NeuN-immunopositive neurons preceded the production of TH in the substantia nigra during postnatal development in mice. Furthermore, the maturation of nNOS-immunopositive interneurons preceded the maturation of PV-immunopositive interneurons in the substantia nigra during postnatal development. Among astrocytes, microglia and oligodendrocytes, in contrast, the development process of oligodendrocytes is delayed in the substantia nigra. Our double-labeled immunohistochemical study suggests that the neurotrophic factors such as BDNF and GDNF secreted by GFAP-positive astrocytes may play some role in maturation of neurons, interneurons and glial cells of the substantia nigra during postnatal development in mice. Thus, our findings provide valuable information on the development processes of the substantia nigra.     

帕金森病黑质多巴胺神经元易损伤性的内在因素

帕金森病（Parkinson’s disease,PD）主要症状是由中脑黑质致密部（substantia nigra compact,SNc）的多巴胺（dopamine,DA）神经元死亡引起。帕金森病发病过程中,路易小体病理（Lewy pathology,LP）和线粒体功能障碍最为突出,但SNc 多巴胺神经元为什么特别易遭受这两种病理损害尚不清楚。研究表明,与脑内其他神经元相比,SNc 多巴胺神经元具有特殊的解剖形态、生理和生化表型。SNc 多巴胺神经元具有高分支无髓鞘轴突和众多的突触终端,突触末梢物质和能量代谢的高要求需要大量的线粒体,巨大突触终端增加了突触蛋白质的表达、转运和降解的负担。SNc 多巴胺神经元具有独特的自主起搏电活动和缓慢钙振荡特性,Cav1-3钙通道活动及后续的级联反应增加了SNc 多巴胺神经元线粒体负担,增加了基础氧化应激、线粒体损伤和自噬,降低了处理错误折叠蛋白质的能力。SNc 多巴胺神经元特有的神经递质——多巴胺易被氧化成为反应性醌,具有潜在毒性,可破坏葡糖脑苷脂酶导致其活性降低,引起线粒体氧化应激和溶酶体功能障碍。总之,SNc 多巴胺神经元具有的这些内在因素综合起来,可能导致了其对线粒体功能障碍和路易小体病理损伤的易感性,并且SNc 多巴胺神经元所处的神经网络障碍也促使了帕金森病的进展。认识到这些特征会对研究帕金森病相关病理学机制和阻止疾病进展创造新的机会。     

Identification of Intact Neurotensin in the Substantia Nigra After Its Retrograde Axonal Transport in Dopaminergic Neurons

Two hours after the injection of (3-[125I]iodotyrosyl3) neurotensin into the striatum, a labeling was observed in the ipsilateral substantia nigra. In the present study, we demonstrated by HPLC that this radioactivity corresponded to intact neurotensin and to degradation products of this peptide. This finding provides the first clearcut evidence that a neuropeptide can be internalized and retrogradely transported in brain neurons. Therefore, the fact that intact neurotensin can be seen to exist over a long period of time in the cell body suggests that the retrograde transport process could perhaps be involved in the long-term effects of neuropeptides.     

Connections Between NO Synthase-Containing Neurons of the Pedunculopontine Tegmental Nucleus and the Substantia Nigra in Rats

Experiments on rats with detection of the NADP-d-activity in neurons of the pedunculopontine tegmental nucleus (PPTg) and their processes demonstrated that between the substantia nigra (SN) and PPTg there are connections established by the neurons containing nitric oxide synthase (NOS). Two types of connections were observed. Axon-like collaterals of the neuronal pathways sent by PPTg neurons toward the forelimb penetrate the SN from its dorsal side. In addition, dendrites of the NOS-containing neurons localized within the rostral PPTg part penetrate the caudoventral region of the reticular SN (SNr). It is supposed that NO produced by these processes within the SN can exert modulating influences on synaptic transmission in this structure; when produced in excessive amounts under some pathological conditions, NO can be a factor evoking neurodegeneration in the midbrain.     

NGF—Tf偶联物对PD模型中黑质神经元的保护作用

中华眼镜蛇毒纯化的神经生长因子（ＮＧＦ）与的转铁蛋白（Ｔｆ）通过生物素－亲和素偶联,观察其对于１－甲基－４－苯基－１,２,３,６－四氢吡啶（ＭＰＴＰ）引发的小鼠帕金森病（ＰＤ）模型中黑质神经元的保护作用。电镜下对小鼠脑组织切片的观察表明：ＭＰＴＰ组元的髓鞘脱落,并出现大量空泡和线粒体峭变形;光镜下对ＨＥ染色的切片则观察到ＭＰＴＰ组神经元中再现空泡,Ｎｉｓｓｌ体溶解,胞核固缩,并有Ｌｅｗｙ小体形成,     

Activation of Caspase-3 in Developmental Models of Programmed Cell Death in Neurons of the Substantia Nigra

Programmed cell death has been proposed to play a role in the death of neurons in acute and chronic degenerative neurologic disease. There is now evidence that the caspases, a family of cysteine proteases, mediate programmed cell death in various cells. In neurons, caspase-3 (CPP32/Yama/apopain), in particular, has been proposed to play a role. We examined the expression of caspase-3 in three models of programmed cell death affecting neurons of the substantia nigra in the rat: natural developmental neuron death and induced developmental death following either striatal target injury with quinolinic acid or dopamine terminal lesion with intrastriatal injection of 6-hydroxydopamine. Using an antibody to the large (p17) subunit of activated caspase-3, we have found that activated enzyme is expressed in apoptotic profiles in all models. Increased p17 immunostaining correlated with increased enzyme activity. The subcellular distribution of activated caspase-3 differed among the models: In natural cell death and the target injury model, it was strictly nuclear, whereas in the toxin model, it was also cytoplasmic. We conclude that p17 immunostaining is a useful marker for programmed cell death in neurons of the substantia nigra.     

Biotransformation of l-DOPA to Dopamine in the Substantia Nigra of Freely Moving Rats: Effect of Dopamine Receptor Agonists and Antagonists

Abstract: We investigated the effects of continuous intranigral perfusion of dopamine D1 and D2 receptor agonists and antagonists on the biotransformation of locally applied l -DOPA to dopamine in the substantia nigra of freely moving rats by means of in vivo microdialysis. The "dual-probe" mode was used to monitor simultaneously changes in extracellular dopamine levels in the substantia nigra and the ipsilateral striatum. Intranigral perfusion of 10 µ M l -DOPA for 20 min induced a significant 180-fold increase in extracellular nigral dopamine level. No effect of the intranigral l -DOPA administration was observed on dopamine levels in the ipsilateral striatum, suggesting a tight control of extracellular dopamine in the striatum after enhanced nigral dopamine levels. Continuous nigral infusion with the D1 receptor agonist CY 208243 (10 µ M ) and with the D2 receptor agonist quinpirole at 10 µ M (a nonselective concentration) attenuated the l -DOPA-induced increase in dopamine in the substantia nigra by 85 and 75%, respectively. However, perfusion of the substantia nigra with a lower concentration of quinpirole (1 µ M ) and the D1 antagonist SCH 23390 (10 µ M ) did not affect the nigral l -DOPA biotransformation. The D2 antagonist (−)-sulpiride (10 µ M ) also attenuated the l -DOPA-induced dopamine release in the substantia nigra to ∼10% of that of the control experiments. We confirm that there is an important biotransformation of l -DOPA to dopamine in the substantia nigra. The high concentrations of dopamine formed after l -DOPA administration may be the cause of dyskinesias or further oxidative stress in Parkinson's disease. Simultaneous administration of D1 receptor agonists with l -DOPA attenuates the biotransformation of l -DOPA to dopamine in the substantia nigra. The observed effects could occur via changes in nigral GABA release that in turn influence the firing rate of the nigral dopaminergic neurons.     

Characterization and Pharmacological Responsiveness of Dopamine Release Recorded by Microdialysis in the Substantia Nigra of Conscious Rats

The extracellular concentration of dopamine (DA) and 3,4-dihydroxyphenylacetic acid in the substantia nigra (SN) and striatum was estimated by microdialysis. The dialysate content of DA from the SN was recorded during infusion of a DA uptake blocker (nomifensine; 5 mumol/L) dissolved in the perfusion fluid. Perfusion of tetrodotoxin (1 mumol/L) produced a virtually complete disappearance of nigral and striatal DA release. Dendritic as well as terminal release of DA was inhibited for several hours when the nerve impulse flow in dopaminergic neurons was blocked by systemic administration of gamma-butyrolactone (750 mg/kg, i.p.). The systemic administration (0.3 mg/kg, i.p.) as well as infusion (1 mumol/L) of the D2 agonist (-)-N-0437 [2-(n-propyl-N-2-thienylethylamino)-5-hydroxytetralin] produced a significant decrease in the release of DA in both the striatum and the SN. DA levels were recorded in the striatum both with and without addition of nomifensine to the perfusion fluid. The decrease in the striatum after (-)-N-0437 was suppressed in the presence of nomifensine. Infusion (1 mumol/L) as well as systemic administration (40 mg/kg) of sulpiride caused a similar increase in the release of striatal DA; this increase was, in both experiments, potentiated by nomifensine coinfusion. Sulpiride administration induced a small increase in the release of nigral DA. Infusion of (-)-N-0437 or (-)-sulpiride into the nigra caused a moderate decrease and increase, respectively, of striatal DA level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biphasic and Opposite Effects of Dopamine and Apomorphine on Endogenous GABA Release in the Rat Substantia Nigra

Abstract: A push-pull cannula technique was used to study the in vivo release of endogenous GABA in the rat substantia nigra. Intranigral application of both dopamine (DA) and apomorphine produced biphasic changes in the rate of endogenous GABA release. The presence of 10 μM-DA in the perfusion medium increased GABA release (140%). At 25 μM-DA, both stimulation and inhibition of the nigral GABA release were observed. Higher concentrations of DA produced a decrease of the GABA release (50%). A small amount of apomorphine (10 μM in the perfusion medium) resulted in a decrease in GABA release (75%). Application of 25 μM-apomorphine produces opposite effects, similar to those observed after addition of 25 μM-DA. We observed an enhanced GABA release from the substantia nigra at 100 μM-apomorphine in the perfusion medium (360%). The presence of 5 μM-haloperidol produced a small decrease in the rate of GABA release (80%). Both the inhibitory effect of 25 μM-DA and the excitatory effect of 100 μM-apomorphine could be blocked by haloperidol added to the perfusion medium. Dibutyryl cyclic AMP (1.5 mM) and 2-amino-6, 7-dihydroxyl(1, 2, 3, 4) tetrahydronapthalene (ADTN) (50 μM) added to the perfusion medium produced an inhibition of nigral GABA release (55% and 35% respectively) similar to that observed after addition of 50 μM-DA. The amounts of lysine and ethanolamine (measured with GABA concurrently) released into the perfusion medium did not change in most of the experiments. The changes in the rates of release of these compounds that were observed in some experiments were either in the same or in the opposite direction of the change in GABA release. These results suggest that dopaminergic processes within the substantia nigra affect GABA-ergic neurotransmission and that DA and apomorphine have different effects on GABA release.     

Dopamine Reduction in the Substantia Nigra of Parkinson's Disease Patients Confirmed by In Vivo Magnetic Resonance Spectroscopic Imaging

Objectives

Metabolic changes in the substantia nigra of patients with Parkinson''s disease were previously investigated in different molecular-pathological examinations. The aim of our study was the in vivo measurement of these alterations using three-dimensional magnetic resonance spectroscopic imaging.

Methods

21 patients with Parkinson''s disease and 24 controls were examined using magnetic resonance spectroscopic imaging at 3 Tesla. The spectra of rostral and caudal substantia nigra regions were analyzed using LCModel. For spectral fitting, an adjusted basis data set with pathology-specific metabolites and macromolecules was used to better reproduce the in vivo spectra. To assess differences between both groups more accurately, especially in metabolites at lower concentrations, group-averaged spectra were evaluated in addition to the analysis of individual data.

Results

We found significantly decreased N-acetylaspartate, choline, creatine, myo-inositol, glutathione and dopamine concentrations in patients with Parkinson''s disease compared to controls, whereas glutamine+glutamate, γ-aminobutyric acid, and homovanillic acid were slightly increased. According to anatomical features, clear differences in the biochemical profiles were found between rostral and caudal substantia nigra voxels in both groups.

Conclusions

Reduced N-acetylaspartate and dopamine concentrations result from progressive degeneration of dopamine-producing neurons within the substantia nigra pars compacta. Decreased creatine levels can be interpreted as impaired energy metabolism due to mitochondrial dysfunction. Lower glutathione concentrations might be a cause or consequence of oxidative stress. Furthermore, slightly increased glutamine+glutamate and γ-aminobutyric acid levels are expected based on post mortem data in Parkinson''s disease. To the best of our knowledge, this is the first non-invasive confirmation of these metabolic changes.