臺灣博碩士論文加值系統

帕金森氏症(Parkinson’s disease, PD)為中樞神經退化性疾病，其成因為長年累積的神經細胞內壓力或者受到環境毒素所影響而導致腦內黑質區(substantia nigra, SN)內的多巴胺(dopamine, DA)神經凋亡，造成黑質區沒有辦法正常分泌多巴胺至紋狀體(striatum)，使得運動中樞傳直紋狀體的細微動作調控訊號沒有辦法被正常調控，從而導致帕金森氏症病患產生動作失調的病徵。目前有效治療帕金森氏症的方法是藉由注射多巴胺的前驅物，左旋多巴胺(L-DOPA)來補足病患在患病時無法正常分泌的多巴胺。但是，長期服用左旋多巴胺的病人多半都會產生異動症的副作用。由於黑質區-紋狀體之間的神經迴路過於複雜，所以目前確切造成異動症的原因尚未明瞭。目前，有研究顯示前腦的血清素(serotonin)神經可能在異動症的產生上扮演著重要的角色，起因於血清素神經可以將左旋多巴吸收並代替以凋亡的多巴胺神經製造出多巴胺釋放到神經突觸之中，但其缺乏多巴胺神經特有的將突觸中過多的多巴胺回收機制，所以造成突觸間多巴胺過多，使得突觸後神經元上的多巴胺受器(dopamine receptor)接收過強訊號而導致左旋多巴胺誘導的異動症(L-DOPA induced dyskinesia, LID)產生。另一方面，有研究指出，tryptophan的代謝在PD中也扮演著重要的角色，tryptophan在腦中的代謝除了往serotonin代謝外，也會經由indol-amine-2, 3-dioxygenase (IDO) 蛋白代謝往kynurenine (KYN) 路徑走，而KYN 路徑上的kynurenine acid (KA) 與 quinolinic acid (QA) 分別與紋狀體腦區在PD狀態下的神經發炎的減緩跟加劇有關。所以在我們的實驗中，會分別去探討在PD或LID狀態下的6-OHDA 單側meduium forebrain bundle (MFB) 損傷凋亡老鼠中，血清素細胞會不會因為細胞在LID時，參與DA生合成的同時，tryotophan 的代謝比重會不會改變。除了上述突觸前神經細胞上的分析，我們也有針對突觸後神經元上的DA受體做分析。我們發現在多巴胺亞型受器第三型(dopamine D3 receptor, D3R)缺乏的老鼠對於異動症的表現有下降的趨勢。為了上述的分析，我們會將老鼠分為四個組別：控制組、控制組施打L-DOPA、PD組及LID組別。在我們的實驗中，我們發現了PD與LID組別中代謝體的改變且不論是在D3R 缺陷或者利用D3R 抑制劑的狀態下，都會使得LID的嚴重程度降低。

Parkinson’s disease (PD), a well-known neurodegenerative disease, characterized by the loss of dopaminergic neurons in the substantia nigra (SN). SN dopamine can either mediate or modulate the motor signals from motor cortex, which explains why PD patients exhibit symptoms of movement disorder. Though akathisia could be improved initially by L-DOPA treatment, most patients develop dyskinesia after prolong medication. Until now, the underlying mechanism of L-DOPA-induced dyskinesia (LID) remained unclear, but numerous reports indicated forebrain serotonin neuron may involve in the development of LID since L-DOPA could be up-taken into serotonin terminals, transforms to dopamine and release into synapse. Consequently, enhanced synaptic dopamine would act on its receptor(s) (i.e. D1, D2 and D3 subtypes) that might be responsible for the LID. On the other hand, activated microglia could also account as one of pathogenesis of LID, of which induces the expression of indol-amine-2, 3-dioxygenase (IDO) that oxidizes L-tryptophan to kynurenine and metabolites, quinolinic acids (QUIN) and kynurenine acids (KYNA). Based on these evidence, in this study, we intend to adopt targeted and global Metabolomic analyses to explore, in particular, if there is alteration in tryptophan metabolism in the striatum after L-DOPA treatment using unilateral 6-OHDA-lesioned hemi-Parkinsonism mice as animal model. If in addition, we also analyzed if expression of post-synaptic dopamine or glutamate receptors would be changed after animals develop LID. Especially, we found symptoms of LID display a different severity in D3 receptor knockout mice. To these purposes, 4 groups of mice were prepared, i.e. sham control, PD control, sham+L-DOPA and PD+L-DOPA mice. We found several metabolites altered in the striatum of LID mice and loss of dopamine D3 receptor or D3 antagonist could alleviate the LID symptoms.

指導教授推薦書
口試委員審定書
誌謝 iii
中文摘要 iv
Abstract vi
目錄 viii
圖表目錄 x
I. Introduction 1
1. Parkinson’s disease 1
2. Substantia nigra pars compacta (SNpc) and striatum (ST) 1
3. Dopamine receptors 2
4. L-DOPA treatment and L-DOPA induced dyskinesia 3
5. Role of D1 receptor signaling in L-DOPA-induced dyskinesia 5
6. Role of D3R signaling in L-DOPA-induced dyskinesia 6
7. metabolisms in Parkinson’s disease and LID 6
8. Signal transduction changes in striatum of LID 8
9. Metabolisms biomarker between Parkinson’s disease and LID 9
II. Specific Aims 10
III. Materials and Methods 11
A. Animals and Surgical Procedures 11
B. Cylinder Test 11
C. Apomorphine-induced rotation 12
D. Chronic L-DOPA Treatment 12
E. D3 receptor inhibition by FAUC-365 treatment 13
F. Rating the AIM Scores 13
G. Liquid chromatography (LC) coupled to electrospray ionization (ESI) and tandem mass spectrometry (MS/MS) 14
Chemicals and Materials 14
Sample preparation 15
LC- ESI+- MS/MS 15
H. Nuclear Magnetic Resonance (NMR) 16
Sample preparation 16
NMR experimental protocols 16
cpmgpr1d (Bruker pulse sequence name) 16
Data analysis 17
I. Metaboanalyst 3.0 Pathway Analysis 17
J. Real-Time PCR 17
K. Western Blot 18
L. Statistics 19
IV. Results 20
1. Validation of neural damage of nigrostriatal Pathway 20
2. 6-OHDA-lesioned mice exhibited PD symptoms 20
3. Apomorphine-induced rotation in 6-OHDA lesioned PD mice 21
4. 6-OHDA-lesioned mice induced LID after chronic L-DOPA treatment 21
5. Biochemical phenotypes in LID mice 22
6. D3 receptor inhibition reduced the severity of LID 23
7. DA Receptors Plasticity 23
8. Tryptophan Metabolism in the striatum of PD and LID mice 24
9. Global metabolite analyses in the striatum 25
10. Global metabolite analyses in serum of PD and LID patients 26
V. Discussion 27
VI. Figures and Legends 34
VII.References 59

圖表目錄
Table 1. Flow chart of all the experimental groups conducted in this thesis study. 34
Figure 1. Tyrosine hydroxylase (TH) expression in control and 6-OHDA-lesioned striatum.. 35
Figure 2. Cylinder test on MFB 6-OHDA-lesioned mice. 35
Figure 3. Apomorphine-induced rotation test on MFB 6-OHDA-lesioned mice. 36
Figure 4. Horizontal locomotor AIM in LID mice. 37
Figure 5. Axial and limb AIM scores in LID mice.. 38
Figure 6. Total and phospho-ERK1 signals in the striatum of 4 experimental groups. 39
Figure 7. Total and phospho-ERK2 signals in the striatum of 4 experimental groups.. 40
Figure 8. Total and phospho-DARPP-32 signals in the striatum of 4 experimental groups. 41
Figure 9. Total and phospho-mTOR signals in the striatum of 4 experimental groups.. 42
Figure 10. Total and phospho-ERK1 signals in the striatum of 4 experimental groups. 43
Figure 11. Total and phospho-ERK2 signals in the striatum of 4 experimental groups.. 44
Figure 12. Total and phospho-DARPP-32 signals in the striatum of 4 experimental groups.. 45
Figure 13. AIM rating between D3KO, FAUC-365-treated and WT mice.. 46
Figure 14. Horizontal locomotor AIM rating among FAUC-365, D3KO and WT mice. 47
Figure 15. Expression of dopamine D1 and D2 receptors in the striatum of D3KO and WT mice. 48
Figure 16. Metabolic profile of striatal serotonin pathway. 49
Figure 17. Metabolic profile of tryptophan-kynurnine pathway.. 50
Figure 18. KA-QA comparison in the striatum of PD and LID mice.. 51
Figure 19. Global analyses of metabolic profiles in the striatum among 4 experimental groups.. 52
Figure 20. Metabolites that contribute to the difference after global analyses of metabolism in the striatum.. 53
Figure 21. Global analyses of serum metabolites between PD-LID and PD-non-LID patients.. 54
Figure 22. VIP score from global analyses between PD-LID and PD-non-LID patients.. 55
Figure 23. Global analyses of serum metabolites among NC, PD-LID and PD-non-LID patients.. 55
Figure 24. Global analyses of serum metabolites differences in between PD with non-LID or LID.. 56
Figure 25. Global analyses of serum metabolism between NC and non-LID PD patients.. 56
Figure 26. Global analyses of serum metabolism between NC and LID PD patients.. 57
Figure 27. Global analyses of serum metabolism between NC and PD patients. 57
Figure 28. Global analyses of serum metabolism between long and short duration PD patients. 58

Abercrombie ED, Bonatz AE, Zigmond MJ (1990) Effects of L-dopa on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats. Brain research 525:36-44.
Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Movement disorders : official journal of the Movement Disorder Society 16:448-458.
Andersen PH, Gingrich JA, Bates MD, Dearry A, Falardeau P, Senogles SE, Caron MG (1990) Dopamine receptor subtypes: beyond the D1/D2 classification. Trends in pharmacological sciences 11:231-236.
Andersson M, Hilbertson A, Cenci MA (1999) Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson's disease. Neurobiology of disease 6:461-474.
Arai R, Karasawa N, Nagatsu I (1996) Aromatic L-amino acid decarboxylase is present in serotonergic fibers of the striatum of the rat. A double-labeling immunofluorescence study. Brain research 706:177-179.
Aubert I, Guigoni C, Hakansson K, Li Q, Dovero S, Barthe N, Bioulac BH, Gross CE, Fisone G, Bloch B, Bezard E (2005) Increased D1 dopamine receptor signaling in levodopa-induced dyskinesia. Annals of neurology 57:17-26.
Bagga V, Dunnett SB, Fricker RA (2015) The 6-OHDA mouse model of Parkinson's disease - Terminal striatal lesions provide a superior measure of neuronal loss and replacement than median forebrain bundle lesions. Behavioural brain research 288:107-117.
Berthet A, Bezard E (2009) Dopamine receptors and L-dopa-induced dyskinesia. Parkinsonism & related disorders 15 Suppl 4:S8-12.
Bettinetti L, Schlotter K, Hubner H, Gmeiner P (2002a) Interactive SAR studies: Rational discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists. Journal of medicinal chemistry 45:4594-4597.
Bettinetti L, Schlotter K, Hubner H, Gmeiner P (2002b) Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists. Journal of medicinal chemistry 45:4594-4597.
Bezard E, Ferry S, Mach U, Stark H, Leriche L, Boraud T, Gross C, Sokoloff P (2003) Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nature medicine 9:762-767.
Camandola S, Mattson MP (2017) Brain metabolism in health, aging, and neurodegeneration. The EMBO journal.
Carta AR, Tronci E, Pinna A, Morelli M (2005) Different responsiveness of striatonigral and striatopallidal neurons to L-DOPA after a subchronic intermittent L-DOPA treatment. The European journal of neuroscience 21:1196-1204.
Carta M, Bezard E (2011) Contribution of pre-synaptic mechanisms to L-DOPA-induced dyskinesia. Neuroscience 198:245-251.
Cenci MA (2007) Dopamine dysregulation of movement control in L-DOPA-induced dyskinesia. Trends in neurosciences 30:236-243.
Connop BP, Boegman RJ, Jhamandas K, Beninger RJ (1995) Excitotoxic action of NMDA agonists on nigrostriatal dopaminergic neurons: modulation by inhibition of nitric oxide synthesis. Brain research 676:124-132.
Cote SR, Chitravanshi VC, Bleickardt C, Sapru HN, Kuzhikandathil EV (2014) Overexpression of the dopamine D3 receptor in the rat dorsal striatum induces dyskinetic behaviors. Behavioural brain research 263:46-50.
Cragg SJ, Rice ME (2004) DAncing past the DAT at a DA synapse. Trends in neurosciences 27:270-277.
Darmopil S, Martin AB, De Diego IR, Ares S, Moratalla R (2009) Genetic inactivation of dopamine D1 but not D2 receptors inhibits L-DOPA-induced dyskinesia and histone activation. Biological psychiatry 66:603-613.
Duty S (2012) Targeting glutamate receptors to tackle the pathogenesis, clinical symptoms and levodopa-induced dyskinesia associated with Parkinson's disease. CNS drugs 26:1017-1032.
Fahn S (2003) Description of Parkinson's disease as a clinical syndrome. Annals of the New York Academy of Sciences 991:1-14.
Fiorentini C, Busi C, Gorruso E, Gotti C, Spano P, Missale C (2008) Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization. Molecular pharmacology 74:59-69.
Fiorentini C, Savoia P, Bono F, Tallarico P, Missale C (2014) The D3 dopamine receptor: From structural interactions to function. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology.
Fiorentini C, Savoia P, Savoldi D, Barbon A, Missale C (2013) Persistent activation of the D1R/Shp-2/Erk1/2 pathway in l-DOPA-induced dyskinesia in the 6-hydroxy-dopamine rat model of Parkinson's disease. Neurobiology of disease 54:339-348.
Gao HM, Hong JS (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends in immunology 29:357-365.
Gardoni F, Sgobio C, Pendolino V, Calabresi P, Di Luca M, Picconi B (2012) Targeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias. Neurobiology of aging 33:2138-2144.
Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain research Brain research reviews 20:269-287.
Gitler AD, Dhillon P, Shorter J (2017) Neurodegenerative disease: models, mechanisms, and a new hope. Disease models & mechanisms 10:499-502.
Hallett PJ, Standaert DG (2004) Rationale for and use of NMDA receptor antagonists in Parkinson's disease. Pharmacology & therapeutics 102:155-174.
Hartai Z, Klivenyi P, Janaky T, Penke B, Dux L, Vecsei L (2005) Kynurenine metabolism in plasma and in red blood cells in Parkinson's disease. Journal of the neurological sciences 239:31-35.
Hemmings HC, Jr., Greengard P, Tung HY, Cohen P (1984) DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. Nature 310:503-505.
Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y (2003) Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains. Acta neuropathologica 106:518-526.
Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP (2016) Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients 8.
Kang GA, Bronstein JM, Masterman DL, Redelings M, Crum JA, Ritz B (2005) Clinical characteristics in early Parkinson's disease in a central California population-based study. Movement disorders : official journal of the Movement Disorder Society 20:1133-1142.
Kebabian JW, Greengard P (1971) Dopamine-sensitive adenyl cyclase: possible role in synaptic transmission. Science 174:1346-1349.
Kikuchi S, Kim SU (1993) Glutamate neurotoxicity in mesencephalic dopaminergic neurons in culture. Journal of neuroscience research 36:558-569.
Ko WK, Li Q, Bezard E (2014) Effects of L-tryptophan on L-DOPA-induced dyskinesia in the L-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of Parkinson's disease. Neuroscience letters 566:72-76.
Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends in neurosciences 19:312-318.
Kulkarni SK, Ninan I (1996) Current concepts in the molecular diversity and pharmacology of dopamine receptors. Methods and findings in experimental and clinical pharmacology 18:599-613.
Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P (1992) Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. Proceedings of the National Academy of Sciences of the United States of America 89:8155-8159.
Lundblad M, Andersson M, Winkler C, Kirik D, Wierup N, Cenci MA (2002) Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease. The European journal of neuroscience 15:120-132.
Mayeux R (2003) Epidemiology of neurodegeneration. Annual review of neuroscience 26:81-104.
McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38:1285-1291.
Mela F, Millan MJ, Brocco M, Morari M (2010) The selective D(3) receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect L-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats. Neuropharmacology 58:528-536.
Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature reviews Immunology 4:762-774.
Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiological reviews 78:189-225.
Nemeth H, Toldi J, Vecsei L (2006) Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies. Journal of neural transmission Supplementum 285-304.
Niznik HB, Van Tol HH (1992) Dopamine receptor genes: new tools for molecular psychiatry. Journal of psychiatry & neuroscience : JPN 17:158-180.
Paul S, Nairn AC, Wang P, Lombroso PJ (2003) NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling. Nature neuroscience 6:34-42.
Philibin SD, Hernandez A, Self DW, Bibb JA (2011) Striatal signal transduction and drug addiction. Frontiers in neuroanatomy 5:60.
Pioli EY, Meissner W, Sohr R, Gross CE, Bezard E, Bioulac BH (2008) Differential behavioral effects of partial bilateral lesions of ventral tegmental area or substantia nigra pars compacta in rats. Neuroscience 153:1213-1224.
Rabey JM, Hefti F (1990) Neuromelanin synthesis in rat and human substantia nigra. Journal of neural transmission Parkinson's disease and dementia section 2:1-14.
Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE, Abdalla M, Study G (2006) Development of dyskinesias in a 5-year trial of ropinirole and L-dopa. Movement disorders : official journal of the Movement Disorder Society 21:1844-1850.
Santini E, Heiman M, Greengard P, Valjent E, Fisone G (2009) Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA-induced dyskinesia. Science signaling 2:ra36.
Santini E, Valjent E, Usiello A, Carta M, Borgkvist A, Girault JA, Herve D, Greengard P, Fisone G (2007) Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. The Journal of neuroscience : the official journal of the Society for Neuroscience 27:6995-7005.
Schmidt WJ, Kretschmer BD (1997) Behavioural pharmacology of glutamate receptors in the basal ganglia. Neuroscience and biobehavioral reviews 21:381-392.
Sebastianutto I, Maslava N, Hopkins CR, Cenci MA (2016) Validation of an improved scale for rating l-DOPA-induced dyskinesia in the mouse and effects of specific dopamine receptor antagonists. Neurobiology of disease 96:156-170.
Shuen JA, Chen M, Gloss B, Calakos N (2008) Drd1a-tdTomato BAC transgenic mice for simultaneous visualization of medium spiny neurons in the direct and indirect pathways of the basal ganglia. The Journal of neuroscience : the official journal of the Society for Neuroscience 28:2681-2685.
Sibley DR, Monsma FJ, Jr. (1992) Molecular biology of dopamine receptors. Trends in pharmacological sciences 13:61-69.
Solis O, Garcia-Montes JR, Gonzalez-Granillo A, Xu M, Moratalla R (2017) Dopamine D3 Receptor Modulates l-DOPA-Induced Dyskinesia by Targeting D1 Receptor-Mediated Striatal Signaling. Cerebral cortex 27:435-446.
Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nature reviews Drug discovery 1:609-620.
Szabo N, Kincses ZT, Toldi J, Vecsei L (2011) Altered tryptophan metabolism in Parkinson's disease: a possible novel therapeutic approach. Journal of the neurological sciences 310:256-260.
Takeuchi H, Mizuno T, Zhang G, Wang J, Kawanokuchi J, Kuno R, Suzumura A (2005) Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. The Journal of biological chemistry 280:10444-10454.
Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. Acta physiologica Scandinavica Supplementum 367:69-93.
Valjent E, Bertran-Gonzalez J, Herve D, Fisone G, Girault JA (2009) Looking BAC at striatal signaling: cell-specific analysis in new transgenic mice. Trends in neurosciences 32:538-547.
Valjent E, Pascoli V, Svenningsson P, Paul S, Enslen H, Corvol JC, Stipanovich A, Caboche J, Lombroso PJ, Nairn AC, Greengard P, Herve D, Girault JA (2005) Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proceedings of the National Academy of Sciences of the United States of America 102:491-496.
van Kampen JM, Stoessl AJ (2003) Effects of oligonucleotide antisense to dopamine D3 receptor mRNA in a rodent model of behavioural sensitization to levodopa. Neuroscience 116:307-314.
Visanji NP, Fox SH, Johnston T, Reyes G, Millan MJ, Brotchie JM (2009) Dopamine D3 receptor stimulation underlies the development of L-DOPA-induced dyskinesia in animal models of Parkinson's disease. Neurobiology of disease 35:184-192.
Westin JE, Vercammen L, Strome EM, Konradi C, Cenci MA (2007) Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors. Biological psychiatry 62:800-810.
Winkler C, Kirik D, Bjorklund A, Cenci MA (2002) L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of parkinson's disease: relation to motor and cellular parameters of nigrostriatal function. Neurobiology of disease 10:165-186.
Yamada H, Aimi Y, Nagatsu I, Taki K, Kudo M, Arai R (2007) Immunohistochemical detection of L-DOPA-derived dopamine within serotonergic fibers in the striatum and the substantia nigra pars reticulata in Parkinsonian model rats. Neuroscience research 59:1-7.
Zadori D, Klivenyi P, Toldi J, Fulop F, Vecsei L (2012) Kynurenines in Parkinson's disease: therapeutic perspectives. Journal of neural transmission 119:275-283.
Zinger A, Barcia C, Herrero MT, Guillemin GJ (2011) The involvement of neuroinflammation and kynurenine pathway in Parkinson's disease. Parkinson's disease 2011:716859.