Activation of the peroxisome proliferator activated receptor-gamma (PPAR)-γ is proposed as a neuroprotective strategy to treat neurodegenerative disorders. In this study, we examined if LSN862 (LSN), a novel non-thiazoledinedione partial PPAR-γ agonist, was neuroprotective in a mouse model of Parkinson’s disease (PD) and assessed possible mechanisms of action. LSN (3, 10, or 30？mg/kg) or vehicle was orally administered daily to C57BL/6 and antioxidant response element-human placental alkaline phosphatase (ARE-hPAP) reporter mice 3 days prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30？mg/kg, i.p. ×？？5 days) or PBS administration. LSN elicited a dose-dependent preservation of dopaminergic nigrostriatal innervation that was not associated with inhibition of MPTP metabolism or activation of Nrf2-ARE, although changes in NQO1 and SOD2 mRNA were observed. A significant dose-dependent downregulation in MAC-1 and GFAP positive cells was observed in MPTP + LSN-treated mice as well as significant downregulation of mRNA expression levels of these inflammatory markers. MPTP-induced increases in PPAR-γ and PGC1α expression were ameliorated by LSN dosing. Our results demonstrate that oral administration of LSN is neuroprotective against MPTP-induced neurodegeneration, and this effect is associated with downregulation of neuroinflammation, decreased oxidative stress, and modulation of PPAR-γ and PGC1α expression. These results suggest that LSN can be a candidate alternative non-thiazoledinedione partial PPAR-γ agonist for neuroprotective treatment of PD. 1. Introduction Neuroinflammation plays a key role in nigral dopaminergic (DA) cell loss in Parkinson’s disease (PD; [1]). Microglia serve as resident immune cells of the nervous system, and under normal conditions they monitor the environment of the brain in a resting state. However, in response to trauma or insult, microglia become activated, exhibiting phagocytic morphology and upregulation of CD1 and cell adhesion molecules such as MAC-1 (CD11b) and CD54 [1]. When activated for a prolonged period of time, microglia release a cascade of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, which may lead to mitochondrial dysfunction and cell death [1]. Activated microglia are present at a high density in the substantia nigra of patients with PD [2, 3]. Nigral DA neurons seem to be particularly susceptible to inflammation due to a number of factors including decreased glutathione levels (reducing antioxidant ability [4], diminished redox activity [5], high density of neuromelanin [6], and elevated
References
[1]
M. Tansey, M. McCoy, and T. Frank-Cannon, “Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention,” Experimental Neurology, vol. 208, no. 1, pp. 1–25, 2007.
[2]
I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990.
[3]
P. L. McGeer, S. Itagaki, B. E. Boyes, and E. G. McGeer, “Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains,” Neurology, vol. 38, no. 8, pp. 1285–1291, 1988.
[4]
D. A. Loeffler, A. J. DeMaggio, P. L. Juneau, M. K. Havaich, and P. A. LeWitt, “Effects of enhanced striatal dopamine turnover in vivo on glutathione oxidation,” Clinical Neuropharmacology, vol. 17, no. 4, pp. 370–379, 1994.
[5]
M. J. Zigmond, T. G. Hastings, and R. G. Perez, “Increased dopamine turnover after partial loss of dopaminergic neurons: compensation or toxicity?” Parkinsonism and Related Disorders, vol. 8, no. 6, pp. 389–393, 2002.
[6]
L. Zecca, F. A. Zucca, H. Wilms, and D. Sulzer, “Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics,” Trends in Neurosciences, vol. 26, no. 11, pp. 578–580, 2003.
[7]
L. Zecca, M. B. H. Youdim, P. Riederer, J. R. Connor, and R. R. Crichton, “Iron, brain ageing and neurodegenerative disorders,” Nature Reviews Neuroscience, vol. 5, no. 11, pp. 863–873, 2004.
[8]
G. T. Liberatore, V. Jackson-Lewis, S. Vukosavic et al., “Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease,” Nature Medicine, vol. 5, no. 12, pp. 1403–1409, 1999.
[9]
D. C. Wu, V. Jackson-Lewis, M. Vila et al., “Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease,” Journal of Neuroscience, vol. 22, no. 5, pp. 1763–1771, 2002.
[10]
D. L. Feinstein, E. Galea, V. Gavrilyuk et al., “Peroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitis,” Annals of Neurology, vol. 51, no. 6, pp. 694–702, 2002.
[11]
S. W. Park, J. H. Yi, G. Miranpuri et al., “Thiazolidinedione class of peroxisome proliferator-activated receptor γ agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats,” Journal of Pharmacology and Experimental Therapeutics, vol. 320, no. 3, pp. 1002–1012, 2007.
[12]
N. K. Phulwani, D. L. Feinstein, V. Gavrilyuk, C. Akar, and T. Kielian, “15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone modulate Staphylococcus aureus-dependent astrocyte activation primarily through a PPAR-γ-independent pathway,” Journal of Neurochemistry, vol. 99, no. 5, pp. 1389–1402, 2006.
[13]
J. Clark and D. K. Simon, “Transcribe to survive: transcriptional control of antioxidant defense programs for neuroprotection in parkinson's disease,” Antioxidants and Redox Signaling, vol. 11, no. 3, pp. 509–528, 2009.
[14]
H. J. Kim, K. G. Park, E. K. Yoo et al., “Effects of PGC-1α on TNF-α-induced MCP-1 and VCAM-1 expression and NF-κB activation in human aortic smooth muscle and endothelial cells,” Antioxidants and Redox Signaling, vol. 9, no. 3, pp. 301–307, 2007.
[15]
N. Schintu, L. Frau, M. Ibba et al., “PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's disease,” European Journal of Neuroscience, vol. 29, no. 5, pp. 954–963, 2009.
[16]
T. Dehmer, M. T. Heneka, M. Sastre, J. Dichgans, and J. B. Schulz, “Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with IκBα induction and block of NFκB and iNOS activation,” Journal of Neurochemistry, vol. 88, no. 2, pp. 494–501, 2004.
[17]
T. Breidert, J. Callebert, M. T. Heneka, G. Landreth, J. M. Launay, and E. C. Hirsch, “Protective action of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in a mouse model of Parkinson's disease,” Journal of Neurochemistry, vol. 82, no. 3, pp. 615–624, 2002.
[18]
C. R. Swanson, V. Joers, V. Bondarenko et al., “The PPAR-γ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys,” Journal of Neuroinflammation, vol. 8, article 91, 2011.
[19]
L. P. Quinn, B. Crook, M. E. Hows et al., “The PPARγ agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B,” British Journal of Pharmacology, vol. 154, no. 1, pp. 226–233, 2008.
[20]
E. Y. Park, I. J. Cho, and S. G. Kim, “Transactivation of the PPAR-responsive enhancer module in chemopreventive glutathione S-transferase gene by the peroxisome proliferator-activated receptor-γ and retinoid X receptor heterodimer,” Cancer Research, vol. 64, no. 10, pp. 3701–3713, 2004.
[21]
Y. K. Loke, C. S. Kwok, and S. Singh, “Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies,” BMJ, vol. 342, article d1309, 2011.
[22]
C. M. Gerrits, M. Bhattacharya, S. Manthena, R. Baran, A. Perez, and S. Kupfer, “A comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes,” Pharmacoepidemiology and Drug Safety, vol. 16, no. 10, pp. 1065–1071, 2007.
[23]
S. E. Nissen, “Perspective: effect of rosiglitazone on cardiovascular outcomes,” Current Cardiology Reports, vol. 9, no. 5, pp. 343–344, 2007.
[24]
A. M. Lincoff, K. Wolski, S. J. Nicholls, and S. E. Nissen, “Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials,” Journal of the American Medical Association, vol. 298, no. 10, pp. 1180–1188, 2007.
[25]
A. Reifel-Miller, K. Otto, E. Hawkins et al., “A peroxisome proliferator-activated receptor α/γ dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia,” Molecular Endocrinology, vol. 19, no. 6, pp. 1593–1605, 2005.
[26]
E. Esposito, D. Impellizzeri, E. Mazzon, I. Paterniti, and S. Cuzzocrea, “Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson's disease,” PLoS ONE, vol. 7, no. 8, Article ID e41880, 2012.
[27]
D. A. Johnson, G. K. Andrews, W. Xu, and J. A. Johnson, “Activation of the antioxidant response element in primary cortical neuronal cultures derived from transgenic reporter mice,” Journal of Neurochemistry, vol. 81, no. 6, pp. 1233–1241, 2002.
[28]
M. E. Emborg, J. Moirano, J. Raschke et al., “Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF,” Neurobiology of Disease, vol. 36, no. 2, pp. 303–311, 2009.
[29]
Z. C. Baquet, D. Williams, J. Brody, and R. J. Smeyne, “A comparison of model-based (2D) and design-based (3D) stereological methods for estimating cell number in the substantia nigra pars compacta (SNpc) of the C57BL/6J mouse,” Neuroscience, vol. 161, no. 4, pp. 1082–1090, 2009.
[30]
C. Schmitz and P. R. Hof, “Design-based stereology in neuroscience,” Neuroscience, vol. 130, no. 4, pp. 813–831, 2005.
[31]
M. E. Emborg, S. Y. Ma, E. J. Mufson et al., “Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys,” Journal of Comparative Neurology, vol. 401, no. 2, pp. 253–265, 1998.
[32]
M. J. West, L. Slomianka, and H. J. Gundersen, “Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator,” Anatomical Record, vol. 231, no. 4, pp. 482–497, 1991.
[33]
M. R. Vargas, D. A. Johnson, D. W. Sirkis, A. Messing, and J. A. Johnson, “Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis,” Journal of Neuroscience, vol. 28, no. 50, pp. 13574–13581, 2008.
[34]
V. Jackson-Lewis and S. Przedborski, “Protocol for the MPTP mouse model of Parkinson's disease,” Nature Protocols, vol. 2, no. 1, pp. 141–151, 2007.
[35]
V. Jackson-Lewis, M. Jakowec, R. E. Burke, and S. Przedborski, “Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,” Neurodegeneration, vol. 4, no. 3, pp. 257–269, 1995.
[36]
N. A. Tatton and S. J. Kish, “In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal Deoxynucleotidyl transferase labelling and acridine orange staining,” Neuroscience, vol. 77, no. 4, pp. 1037–1048, 1997.
[37]
W. Dauer and S. Przedborski, “Parkinson's disease: mechanisms and models,” Neuron, vol. 39, no. 6, pp. 889–909, 2003.
[38]
M. E. Emborg, “Evaluation of animal models of Parkinson's disease for neuroprotective strategies,” Journal of Neuroscience Methods, vol. 139, no. 2, pp. 121–143, 2004.
[39]
Y. Du, Z. Ma, S. Lin et al., “Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 25, pp. 14669–14674, 2001.
[40]
J. N. Joyce, C. Woolsey, H. Ryoo, S. Borwege, and D. Hagner, “Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D3 receptor,” BMC Biology, vol. 2, article 22, 2004.
[41]
R. E. Heikkila, L. Manzino, F. S. Cabbat, and R. C. Duvoisin, “Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors,” Nature, vol. 311, no. 5985, pp. 467–469, 1984.
[42]
H. Y. Cho, W. Gladwell, X. Wang et al., “Nrf2-regulated PPARγ expression is critical to protection against acute lung injury in mice,” American Journal of Respiratory and Critical Care Medicine, vol. 182, no. 2, pp. 170–182, 2010.
[43]
P. Gong, D. Stewart, B. Hu et al., “Activation of the mouse heme oxygenase-1 gene by 15-Deoxy-Δ(12,14)-prostaglandin J(2) is mediated by the stress response elements and transcription factor Nrf2,” Antioxidants and Redox Signaling, vol. 4, no. 2, pp. 249–257, 2002.
[44]
A. R. Carta, L. Frau, A. Pisanu, J. Wardas, S. Spiga, and E. Carboni, “Rosiglitazone decreases peroxisome proliferator receptor-gamma levels in microglia and inhibits TNF-alpha production: new evidences on neuroprotection in a progressive Parkinson's disease model,” Neuroscience, vol. 194, pp. 250–261, 2011.
[45]
R. L. Hunter, D. Y. Choi, S. A. Ross, and G. Bing, “Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague-Dawley rats,” Neuroscience Letters, vol. 432, no. 3, pp. 198–201, 2008.
[46]
G. Walsh and R. Jefferis, “Post-translational modifications in the context of therapeutic proteins,” Nature Biotechnology, vol. 24, no. 10, pp. 1241–1252, 2006.
[47]
N. Dana, D. M. Fathallah, and M. A. Arnaout, “Expression of a soluble and functional form of the human β2 integrin CD11b/CD18,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 8, pp. 3106–3110, 1991.
[48]
S. M. Abaraviciene, I. Lundquist, and A. Salehi, “Rosiglitazone counteracts palmitate-induced β-cell dysfunction by suppression of MAP kinase, inducible nitric oxide synthase and caspase 3 activities,” Cellular and Molecular Life Sciences, vol. 65, no. 14, pp. 2256–2265, 2008.
[49]
M. Kiaei, K. Kipiani, J. Chen, N. Y. Calingasan, and M. F. Beal, “Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis,” Experimental Neurology, vol. 191, no. 2, pp. 331–336, 2005.
[50]
S. Moreno, S. Farioli-vecchioli, and M. P. Cerù, “Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS,” Neuroscience, vol. 123, no. 1, pp. 131–145, 2004.
[51]
T. E. Cullingford, K. Bhakoo, S. Peuchen, C. T. Dolphin, R. Patel, and J. B. Clark, “Distribution of mRNAs encoding the peroxisome proliferator-activated receptor α, β, and γ and the retinoid X receptor α, β, and γ in rat central nervous system,” Journal of Neurochemistry, vol. 70, no. 4, pp. 1366–1375, 1998.
[52]
W. J. Lee, M. Kim, H. S. Park et al., “AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARα and PGC-1,” Biochemical and Biophysical Research Communications, vol. 340, no. 1, pp. 291–295, 2006.
[53]
C. Cantó and J. Auwerx, “PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure,” Current Opinion in Lipidology, vol. 20, no. 2, pp. 98–105, 2009.
[54]
D. G. Hardie, “AMPK: a key regulator of energy balance in the single cell and the whole organism,” International Journal of Obesity, vol. 32, no. 4, pp. S7–S12, 2008.
[55]
H. Bromage, P. Tempst, B. M. Spiegelman et al., “Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1α: modulation by p38 MAPK,” Genes and Development, vol. 18, no. 3, pp. 278–289, 2004.
[56]
E. Burgermeister and R. Seger, “MAPK kinases as nucleo-cytoplasmic shuttles for PPARγ,” Cell Cycle, vol. 6, no. 13, pp. 1539–1548, 2007.
[57]
J. H. Shin, H. S. Ko, H. Kang et al., “PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease,” Cell, vol. 144, no. 5, pp. 689–702, 2011.
[58]
H. L. Martin, R. B. Mounsey, S. Mustafa, K. Sathe, and P. Teismann, “Pharmacological manipulation of peroxisome proliferator-activated receptor γ (PPARγ) reveals a role for anti-oxidant protection in a model of Parkinson's disease,” Experimental Neurology, vol. 235, no. 2, pp. 528–538, 2012.
[59]
J. St-Pierre, S. Drori, M. Uldry et al., “Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators,” Cell, vol. 127, no. 2, pp. 397–408, 2006.
[60]
C. Ciron, S. Lengacher, J. Dusonchet, P. Aebischer, and B. L. Schneider, “Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function,” Human Molecular Genetics, vol. 21, no. 8, Article ID ddr618, pp. 1861–1876, 2012.
[61]
D. L. Feinstein, A. Spagnolo, C. Akar et al., “Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key?” Biochemical Pharmacology, vol. 70, no. 2, pp. 177–188, 2005.
[62]
S. Giri, R. Rattan, A. K. Singh, and I. Singh, “The 15-Deoxy-Δ12,14-prostaglandin J2 inhibits the inflammatory response in primary rat astrocytes via down-regulating multiple steps in phosphatidylinositol 3-kinase-akt-NF-κB-p300 pathway independent of peroxisome proliferator-activated receptor γ,” Journal of Immunology, vol. 173, no. 8, pp. 5196–5208, 2004.
[63]
S. Boyault, M. A. Simonin, A. Bianchi et al., “15-Deoxy-Δ12,14-PGJ2, but not troglitazone, modulates IL-1β effects in human chondrocytes by inhibiting NF-κB and AP-1 activation pathways,” FEBS Letters, vol. 501, no. 1, pp. 24–30, 2001.
[64]
P. A. Ruiz, S. C. Kim, R. B. Sartor, and D. Haller, “15-Deoxy-Δ12,14-prostaglandin J2-mediated ERK signaling inhibits gram-negative bacteria-induced RelA phosphorylation and interleukin-6 gene expression in intestinal epithelial cells through modulation of protein phosphatase 2A activity,” The Journal of Biological Chemistry, vol. 279, no. 34, pp. 36103–36111, 2004.
[65]
S. Eligini, C. Banfi, M. Brambilla et al., “15-Deoxy-Δ12,14-Prostaglandin J2 inhibits tissue factor expression in human macrophages and endothelial cells: evidence for ERK1/2 signaling pathway blockade,” Thrombosis and Haemostasis, vol. 88, no. 3, pp. 524–532, 2002.
[66]
H. Sawano, M. Haneda, T. Sugimoto, K. Inoki, D. Koya, and R. Kikkawa, “15-Deoxy-δ12,14-prostaglandin J2 inhibits IL-1β-induced cyclooxygenase-2 expression in mesangial cells,” Kidney International, vol. 61, no. 6, pp. 1957–1967, 2002.
[67]
P. Garrido-Gil, B. Joglar, A. I. Rodriguez-Perez, M. J. Guerra, and J. L. Labandeira-Garcia, “Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease,” Journal of Neuroinflammation, vol. 9, article 38, 2012.
[68]
T. Hosono, H. Mizuguchi, K. Katayama et al., “RNA interference of PPARγ using fiber-modified adenovirus vector efficiently suppresses preadipocyte-to-adipocyte differentiation in 3T3-L1 cells,” Gene, vol. 348, no. 1-2, pp. 157–165, 2005.
[69]
A. Neumann, A. Weill, P. Ricordeau, J. P. Fagot, F. Alla, and H. Allemand, “Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study,” Diabetologia, no. 7, pp. 1953–1962, 2012.
[70]
J. D. Lewis, A. Ferrara, T. Peng et al., “Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study,” Diabetes Care, vol. 34, no. 4, pp. 916–922, 2011.
[71]
M. Mitka, “Panel recommends easing restrictions on rosiglitazone despite concerns about cardiovascular safety,” JAMA, vol. 310, no. 3, pp. 246–247, 2013.
