Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson's disease

doi:10.1038/s41467-019-11928-w

. 2019 Sep 2;10(1):3945.

doi: 10.1038/s41467-019-11928-w.

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson's disease

Paraskevi Krashia^#^{1

2}, Alberto Cordella^#^{1

3}, Annalisa Nobili^#^{1

2}, Livia La Barbera^{1

3}, Mauro Federici¹, Alessandro Leuti^{1

2}, Federica Campanelli¹, Giuseppina Natale¹, Gioia Marino¹, Valeria Calabrese¹, Francescangelo Vedele^{1

3}, Veronica Ghiglieri^{1

4}, Barbara Picconi¹, Giulia Di Lazzaro³, Tommaso Schirinzi³, Giulia Sancesario⁵, Nicolas Casadei⁶, Olaf Riess⁶, Sergio Bernardini⁷, Antonio Pisani^{1

3}, Paolo Calabresi^{1

8}, Maria Teresa Viscomi⁹, Charles Nicholas Serhan¹⁰, Valerio Chiurchiù^#^{1

2}, Marcello D'Amelio^#^{1

2}, Nicola Biagio Mercuri^#^{11

12}

Affiliations

¹ Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, 00143, Rome, Italy.
² Department of Medicine and Department of Science and Technology for Humans and Environment, University Campus Bio-medico, 00128, Rome, Italy.
³ Department of Systems Medicine, University of Rome 'Tor Vergata', 00133, Rome, Italy.
⁴ Department of Philosophy, Human, Social and Educational Sciences, University of Perugia, 06123, Perugia, Italy.
⁵ Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, 00143, Rome, Italy.
⁶ Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076, Tübingen, Germany.
⁷ Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', 00133, Rome, Italy.
⁸ Neurology Clinic, Department of Medicine, University of Perugia, Santa Maria della Misericordia Hospital, 06156, Perugia, Italy.
⁹ Institute of Histology and Embryology, Università Cattolica del Sacro Cuore, 00168, Rome, Italy.
¹⁰ Center for Experimental Therapeutics and Reperfusion Injury, Department of Anaesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 02115, Boston, MA, USA.
¹¹ Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, 00143, Rome, Italy. mercurin@med.uniroma2.it.
¹² Department of Systems Medicine, University of Rome 'Tor Vergata', 00133, Rome, Italy. mercurin@med.uniroma2.it.

^# Contributed equally.

PMID: 31477726
PMCID: PMC6718379
DOI: 10.1038/s41467-019-11928-w

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson's disease

Paraskevi Krashia et al. Nat Commun. 2019.

. 2019 Sep 2;10(1):3945.

doi: 10.1038/s41467-019-11928-w.

Authors

Affiliations

¹ Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, 00143, Rome, Italy.
² Department of Medicine and Department of Science and Technology for Humans and Environment, University Campus Bio-medico, 00128, Rome, Italy.
³ Department of Systems Medicine, University of Rome 'Tor Vergata', 00133, Rome, Italy.
⁴ Department of Philosophy, Human, Social and Educational Sciences, University of Perugia, 06123, Perugia, Italy.
⁵ Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, 00143, Rome, Italy.
⁶ Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076, Tübingen, Germany.
⁷ Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', 00133, Rome, Italy.
⁸ Neurology Clinic, Department of Medicine, University of Perugia, Santa Maria della Misericordia Hospital, 06156, Perugia, Italy.
⁹ Institute of Histology and Embryology, Università Cattolica del Sacro Cuore, 00168, Rome, Italy.
¹⁰ Center for Experimental Therapeutics and Reperfusion Injury, Department of Anaesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, 02115, Boston, MA, USA.
¹¹ Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, 00143, Rome, Italy. mercurin@med.uniroma2.it.
¹² Department of Systems Medicine, University of Rome 'Tor Vergata', 00133, Rome, Italy. mercurin@med.uniroma2.it.

^# Contributed equally.

PMID: 31477726
PMCID: PMC6718379
DOI: 10.1038/s41467-019-11928-w

Erratum in

Author Correction: Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson's disease.
Krashia P, Cordella A, Nobili A, La Barbera L, Federici M, Leuti A, Campanelli F, Natale G, Marino G, Calabrese V, Vedele F, Ghiglieri V, Picconi B, Di Lazzaro G, Schirinzi T, Sancesario G, Casadei N, Riess O, Bernardini S, Pisani A, Calabresi P, Viscomi MT, Serhan CN, Chiurchiù V, D'Amelio M, Mercuri NB. Krashia P, et al. Nat Commun. 2019 Oct 14;10(1):4725. doi: 10.1038/s41467-019-12538-2. Nat Commun. 2019. PMID: 31611555 Free PMC article.

Abstract

Neuroinflammation is one of the hallmarks of Parkinson's disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD - to modulate disease progression - still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Motor deficits and reduced striatal DA in 4-month-old Syn rats. a Distance travelled during open field test (2-month-old: 15 WT, 13 Syn; 4-month-old: 7 WT, 10 Syn; two-way ANOVA: genotype × age, F_1,41 = 0.10, P = 0.748; genotype, F_1,41 = 6.77, P = 0.013; age, F_1,41 = 4.70, P = 0.037; P > 0.05 with Bonferroni’s) and centre zone entries (2-month-old: 15 WT, 13 Syn; 4-month-old: 6 WT, 7 Syn; two-way ANOVA: genotype × age, F_1,37 = 2.65, P = 0.112; genotype, F_1,37 = 9.66, P = 0.004; age, F_1,37 = 0.06, P = 0.799; WT 4-Syn 4 *P = 0.041 with Bonferroni’s). b Time spent on the accelerating Rotarod (2-month-old: 9 WT, 8 Syn; 4-month-old: 11 WT, 8 Syn; two-way ANOVA: genotype × age, F_1,32 = 3.79, P = 0.061; genotype, F_1,32 = 29.69, P < 1.00 × 10⁻⁴; age, F_1,32 = 5.91, P = 0.021; WT 2 months-Syn 4 months ***P < 1.00 × 10⁻⁴, Syn 2 months-Syn 4 months *P = 0.029, WT 4 months-Syn 4 months ***P < 1.00 × 10⁻⁴ with Bonferroni’s). c Example traces (scale: 50 pA, 500 ms) and evoked DA in the striatum (2-month-old: 24 WT, 21 Syn slices, 4 rats each; 4-month-old: 24 WT, 23 Syn slices, 4 rats each; two-way ANOVA: genotype × age, F_1,88 = 1.72, P = 0.193; genotype, F_1,88 = 19.95, P < 1.00 × 10⁻⁴; age, F_1,88 = 22.50, P < 1.00 × 10⁻⁴; WT 2-Syn 4 ***P < 1.00 × 10⁻⁴, Syn 2-Syn 4 ***P = 4.00 × 10⁻⁴, WT 4-Syn 4 ***P = 5.00 × 10⁻⁴ with Bonferroni’s). d TH labelling in the striatum (scale: 200 μm) and TH levels (5 rats each, 4 sections per animal; Mann–Whitney, P = 0.151). e Striatal DA release by amphetamine (AMPH, 30 µM; scale: 10 pA, 5 min) in 4-month-old rats (8 slices, 4 rats per genotype; Welch’s t-test, P = 0.802). f TH immunoreactivity in a WT rat (scale: 500 μm) and mean TH⁺ and TH⁻ cell numbers (±s.e.m.) in 4-month-old WT (4) and Syn (6) rats (SNpc: two-way ANOVA: genotype × cell number, F_1,16 = 2.38, P = 0.143; genotype, F_1,16 = 1.02, P = 0.327; numbers, F_1,16 = 57^.06, P < 1.00 × 10⁻⁴. WT-Syn for TH⁻: P > 0.05; for TH⁺: P > 0.05 with Bonferroni’s; VTA: two-way ANOVA: genotype × cell numbers, F_1,16 = 0.52, P = 0.483; genotype, F_1,16 = 0.07, P = 0.792; numbers, F_1,16 = 51.19, P < 1.00 × 10⁻⁴. WT-Syn for TH⁻: P > 0.05; for TH⁺: P > 0.05 with Bonferroni’s). In this and all other figures, in box-and-whisker plots the centre lines denote median values, edges are upper and lower quartiles, whiskers show minimum and maximum values and points are individual experiments. Source data are provided as a Source Data file

**Fig. 2**
Altered DA neuron electrophysiological properties in 4-month-old Syn rats. a Spontaneous firing in SNpc DA neurons from 4-month-old rats (scale: 2 min, 0.2 mV) and plots showing firing frequency (38 cells from 10 WT, 47 cells from 11 Syn; Mann–Whitney test, ***P < 1.00 × 10⁻⁴) and coefficient of variation of interspike interval (35 cells from 10 WT, 45 cells from 11 Syn; Mann–Whitney test, **P = 0.002). b APs induced by depolarization (scale: 100 ms; 20 mV, 100 pA) from DA neurons held at −50 mV and mean (±s.e.m.) AP numbers (11 WT, 10 Syn neurons, 3 rats each; two-way repeated-measures ANOVA: genotype×current, F_4,76 = 9.36, P < 1.00 × 10⁻⁴; current, F_4,76 = 116.6, P < 1.00 × 10⁻⁴; genotype, F_1,19 = 10.76, P = 0.004. WT vs Syn: 200 pA ***P < 1.00 × 10⁻⁴, 150 pA ***P = 4.00 × 10⁻⁴, 100 pA *P = 0.036, 50 pA P = 0.221 with Bonferroni’s). c Sub-threshold responses to hyperpolarization (scale: 100 ms; 10 mV, 100 pA) and current/voltage plots (±s.e.m.; 11 WT, 10 Syn neurons, 3 rats each; two-way repeated-measures ANOVA: genotype×current, F_4,76 = 1.64, P = 0.172; current, F_4,76 = 362.9, P < 1.00 × 10⁻⁴; genotype, F_1,19 = 1.26, P = 0.276. WT vs Syn: 0 pA P > 0.999, −50 pA, P > 0.999, −100 pA, P > 0.999, −150 pA, P = 0.496, −200 pA, P = 0.411 with Bonferroni’s). d Cm (23 WT, 29 Syn neurons, 5 rats each: Welch’s t-test P = 0.638). e I_h currents from DA neurons held at −60 mV and hyperpolarized in 20 mV increments (scale: 200 ms; 50 mV, 200 pA). The activation phase was fitted to 1–2 exponentials (dash line). The plots show I_h amplitude and weighted activation tau after hyperpolarization to −120 mV (24 WT, 22 Syn neurons, 8 rats each; amplitude: Welch’s t-test P = 0.886; tau: Mann–Whitney test P = 0.342). f AHC (scale: 100 ms; 50 mV, 50 pA), induced by depolarization to 0 mV. AHC trace area is designated by red dash lines and deactivation is obtained with exponential fits (12 WT, 21 Syn neurons, 4 rats each; area: Welch’s t-test ***P = 3.00 × 10⁻⁴; tau: Mann–Whitney test *P = 0.013). Source data are provided as a Source Data file

**Fig. 3**
DA sensitivity and intracellular [Ca²⁺] are altered in 4-month-old Syn DA neurons. a Extracellular recordings in SNpc DA neurons from 4-month-old rats and response to 2 min application of 30 µM DA (scale: 1 min, 0.2 mV). Expanded traces (scale: 1 s) show firing in control condition and during DA. The plot shows the firing reduction (% of control) after DA (23 cells from 8 WT, 34 cells from 10 Syn; Mann–Whitney test ***P < 1.00 × 10⁻⁴). b DA currents (30 μM, 2 min) during voltage clamp (−60 mV; scale: 2 min, 20 pA) and mean (±s.e.m.) dose–response curves (18 cells from 8 WT, 18 cells from 7 Syn; two-way ANOVA: genotype × concentration, F_3,29 = 0.66, P = 0.586; concentration, F_3,29 = 6.68, P = 0.001; genotype, F_1,29 = 8.63, P = 0.006; WT vs Syn: 1 µM, P > 0.999, 3 µM P = 0.175, 10 µM, **P = 0.007, 30 µM *P = 0.012 with Bonferroni’s). c Baclofen-mediated currents (10 µM, 3 min; −60 mV; scale: 2 min, 50 pA), and mean (±s.e.m.) current amplitude (11 WT cells, 13 Syn cells, 3 rats each; two-way ANOVA: genotype × concentration, F_1,20 = 4.78, P = 0.041; concentration, F_1,20 = 23.96, P < 1.00 × 10⁻⁴; genotype, F_1,20 = 16.04, P = 7.00 × 10⁻⁴. WT vs Syn: 1 µM, P = 0.337, 10 µM, **P = 0.001 with Bonferroni’s). d Infrared videomicroscopy of a patched DA neuron and a Fura-2 ratiometric image (scale: 10 μm) showing variations in cytosolic [Ca²⁺]. The plot shows cytoplasmic [Ca²⁺] in DA neurons at −60 mV (23 WT, 26 Syn cells, 7 rats each; ***P < 1.00 × 10⁻⁴, Welch’s t-test). e Somatic Ca²⁺ at −60 mV in control conditions and in the presence of Ca²⁺-free bath solution (scale: 2 min). The plot shows the level of [Ca²⁺] reduction (11 WT neurons from 4 rats, 11 Syn neurons from 5 rats; P = 0.338 with Welch’s t-test). f [Ca²⁺] levels in DA neurons from slices incubated with isradipine (200 nM, 1 h; 10 WT, 6 Syn neurons, 3 rats each; ***P = 1.00 × 10⁻⁴ with Welch’s t-test. g Transient rise in fluorescence ratio following CPA application (10 µM; scale: 2 min) and plot showing smaller CPA-induced Ca²⁺ increase in Syn DA neurons (5 WT, 9 Syn neurons, 3 rats each; ***P = 0.001 with Mann–Whitney test). Source data are provided as a Source Data file

**Fig. 4**
Early neuroinflammatory responses in 4-month-old Syn rats. a GFAP⁺ cell numbers in SNpc and striatum (SNpc: 4 rats each, Mann-Whitney test P = 0.886; striatum: 4 rats each, Welch’s t-test P = 0.837). b Iba1⁺ cell numbers in SNpc and striatum (SNpc: 4 rats each, Welch’s t-test *P = 0.044; striatum: 5 rats each, ***P < 1.00 × 10⁻⁴ with Welch’s t-test). c, d TH/GFAP staining in SNpc (c) and DAPI/GFAP staining in striatum (d) of 4-month-old rats (scale: 10 µm) and representative images of 3D-reconstructed astrocytes. The plots show number of intersections (±s.e.m.) in rats (c: 4 rats each; two-way repeated-measures ANOVA: genotype × radial distance from soma, F_6,36 = 0.583, P = 0.742; genotype, F_1,6 = 0.621, P = 0.461; distance, F_6,36 = 194.8, P < 1.00 × 10⁻⁴; WT vs Syn for 0–60 µm: P > 0.05 with Bonferroni’s; d 4 rats each; two-way repeated-measures ANOVA: genotype×distance, F_6,36 = 0.368, P = 0.895; genotype, F_1,6 = 0.039, P = 0.851; distance, F_6,36 = 253, P < 1.00 × 10⁻⁴; WT vs Syn for 0–60 µm: P > 0.05 with Bonferroni’s). See also Supplementary Fig. 3. e, f TH/Iba1 staining in SNpc (e) and DAPI/Iba1 staining in the striatum (f) of 4-month-old rats (scale: 10 µm) and 3D-reconstructed microglia. The plots show number of intersections (±s.e.m.) (e: 4 rats each; two-way repeated-measures ANOVA: genotype×distance, F_6,36 = 16.58, P < 1.00 × 10⁻⁴; genotype, F_1,6 = 17.05, P = 0.006; distance, F_6,36 = 132.2, P < 1 × 10⁻⁴; 10 μm ***P < 1 × 10⁻⁴, 20 μm ***P < 1 × 10⁻⁴, 30 μm ***P < 8 × 10⁻⁴, with Bonferroni’s; f 4 rats each; two-way repeated-measures ANOVA: genotype×distance, F_6,36 = 11.99, P < 1 × 10⁻⁴; genotype, F_1,6 = 24.0, P = 0.003; distance, F_6,36 = 257.9, P < 1 × 10⁻⁴; 10 μm ***P = 1 × 10⁻⁴, 20 μm ***P < 1 × 10⁻⁴, 30 μm ***P < 1 × 10⁻⁴, with Bonferroni’s). See also Supplementary Fig. 4. g CSF IFN-γ levels in WT and Syn rats at the indicated ages (9 WT and 9 Syn rats per age; two-way ANOVA: genotype × age, F₁,₃₂ = 1.95, P = 0.172; genotype, F_1,32 = 33.44, P < 1.00 × 10⁻⁴; age, F_1,32 = 60.84, P < 1.00 × 10⁻⁴; WT 2-Syn 2 *P = 0.024, WT 2-WT 4 ***P = 5.00 × 10⁻⁴, WT 2-Syn 4 ***P < 1.00 × 10⁻⁴, Syn 2-Syn 4 ***P < 1.00 × 10⁻⁴, WT 4-Syn 4 ***P < 1.00 × 10⁻⁴ with Bonferroni’s). h Percentage of peripheral blood cells gated on live leukocytes or on CD11b⁺ monocytes (5 WT, 4 Syn; granulocytes: P = 0.696; T-lymphocytes: P = 0.827; B-lymphocytes: P = 0.544; monocytes: *P = 0.019, with Welch’s t-test). i Percentage of peripheral monocytes expressing MHC-II and CD68 (5 WT, 4 Syn; MHC-II: **P = 0.007; CD68: **P = 0.004, with Welch’s t-test). Source data are provided as a Source Data file

**Fig. 5**
Region-specific aggregation of pathological α-syn in Syn rats. a Representative dot blot of midbrain, pontine nuclei, cortex, hippocampus and striatum homogenates from 4-month-old WT and Syn rats, immunostained with the conformation-specific α-syn antibody [MJFR-14-6-4-2], and densitometric quantification. The plot shows the levels of α-syn aggregates (expressed as % of WT). (Midbrain: 6 WT rats and 7 Syn rats, Welch’s t-test **P = 0.004; Pontine nuclei: 3 rats per genotype, Welch’s t-test P = 0.926; Cortex: 5 rats per genotype, Welch’s t-test *P = 0.030; Hippocampus: 5 rats per genotype, Mann–Whitney test **P = 0.008; Striatum: 5 rats per genotype, Welch’s t-test ***P = 0.001). The full blot and raw data are provided as a Source Data file

**Fig. 6**
Age-dependent changes in central and peripheral RvD1 levels in Syn rats. a Chemical structure of RvD1 and RvD2, derived from docosahexaenoic acid (DHA) metabolism. b Quantification with ELISA of RvD1 in the CSF (left) and plasma (right) of WT and Syn rats at 2 and 4 months of age (CSF: 6 WT, 6 Syn rats per age; two-way ANOVA: genotype × age, F_1,20 = 6.38, P = 0.020; genotype, F_1,20 = 9.61, P = 0.006; age, F_1,20 = 22.36, P = 1.00 × 10⁻⁴; WT 2 -Syn 4 ***P = 1.00 × 10⁻⁴, Syn 2 -Syn 4 ***P = 3.00 × 10⁻⁴, WT 4-Syn 4 **P = 0.004 with Bonferroni’s; plasma: 6 WT, 6 Syn for each age; two-way ANOVA: genotype × age, F_1,20 = 46.44, P < 1.00 × 10⁻⁴; genotype, F_1,20 = 4.99, P = 0.037; age, F_1,20 = 24.64, P < 1.00 × 10⁻⁴; WT 2-Syn 2 *P = 0.025, WT 2-Syn 4 ***P = 3.00 × 10⁻⁴, Syn 2-Syn 4 ***P < 1.00 × 10⁻⁴, WT 4 -Syn 4 ***P < 1.00 × 10⁻⁴ with Bonferroni’s). c ELISA quantifications of CSF and plasma RvD2 from 2- and 4-month-old rats (6 WT and 6 Syn per age; two-way ANOVA for CSF: genotype × age, F_1,20 = 0.26, P = 0.613; genotype, F_1,20 = 0.94, P = 0.343; age, F_1,20 = 3.66, P = 0.070; two-way ANOVA for plasma: genotype × age, F_1,20 = 4.03, P = 0.059; genotype, F_1,20 = 0.339, P = 0.567; age, F_1,20 = 12.43, P = 0.002; Syn 2-Syn 4 **P = 0.005 with Bonferroni’s). d, e CSF and plasma RvD1 (d) and RvD2 (e) from 18-month-old rats (d: CSF: 6 WT and 3 Syn rats, **P = 0.002; plasma: 8 WT and 6 Syn rats, *P = 0.039 with Welch’s t-test; e: CSF: 5 rats per genotype, P = 0.379; plasma: 4 per genotype, P = 0.818 with Welch’s t-test). Source data are provided as a Source Data file

**Fig. 7**
RvD1 resolves neuroinflammation in 4-month-old Syn rats. a RvD1 treatment scheme (0.2 μg kg⁻¹). Injections were performed twice a week for 2 months, starting from 2- and until 4 months of age. b, c Iba1⁺ numbers in SNpc (b) and striatum (c). (b: 6 WT/saline, 4 WT/RvD1; 6 Syn/saline, 4 Syn/RvD1; ANOVA: genotype × treatment, F_1,17 = 5.25, P = 0.035; treatment, F_1,17 = 5.33, P = 0.034; genotype, F_1,17 = 2.69, P = 0.119; WT/saline-Syn/saline *P = 0.047, Syn/saline-Syn/RvD1 *P = 0.022 with Bonferroni’s; c: 4 WT/saline, 4 WT/RvD1; 4 Syn/saline, 6 Syn/RvD1; ANOVA: genotype × treatment, F_1,14 = 9.36, P = 0.009; treatment, F_1,14 = 4.59, P = 0.050; genotype, F_1,14 = 12.72, P = 0.003; WT/saline-Syn/saline **P = 0.003, WT/RvD1-Syn/saline *P = 0.010, Syn/saline-Syn/RvD1 *P = 0.010 with Bonferroni’s). d, e TH/Iba1 staining in SNpc (d) and DAPI/Iba1 staining in striatum (e; scale, 10 µm) and 3D-reconstructed microglia. Number of intersections (±s.e.m.) in SNpc (d: 4 rats each; repeated-measures ANOVA for WT: treatment×distance, F_6,36 = 0.36, P = 0.898; treatment, F_1,6 = 0.71, P = 0.431; distance, F_6,36 = 283.9, P < 1.00 × 10⁻⁴; 0–60 μm P > 0.05 with Bonferroni’s; for Syn: treatment × distance, F_6,36 = 18.9, P < 1.00 × 10⁻⁴; treatment, F_1,6 = 27.1, P = 0.002; distance, F_6,36 = 130.7, P < 1.00 × 10⁻⁴; 10 μm ***P < 1.00 × 10⁻⁴, 20 μm ***P < 1.00 × 10⁻⁴, 30 μm **P = 0.003, with Bonferroni’s) and striatum (e: 4 rats each; repeated-measures ANOVA for WT: treatment × distance, F_6,36 = 0.26, P = 0.951; treatment, F_1,6 = 0.21, P = 0.667; distance, F_6,36 = 94.82, P < 1.00 × 10⁻⁴; 0–60 μm P > 0.05 with Bonferroni’s; for Syn: treatment× distance, F_6,36 = 5.72, P = 3.00 × 10⁻⁴; treatment, F_1,6 = 6.94, P = 0.039; distance, F_6,36 = 180.9, P < 1.00 × 10⁻⁴; 10 μm **P = 0.006, 20 μm ***P < 1.00 × 10⁻⁴, with Bonferroni’s). See also Supplementary Fig. 7. f CSF IFN-γ levels (7 rats each; ANOVA: genotype×treatment, F_1,24 = 26.81, P < 1.00 × 10⁻⁴; treatment, F_1,24 = 177.2, P < 1.00 × 10⁻⁴; genotype, F_1,24 = 58.79, P < 1.00 × 10⁻⁴; WT/saline-WT/RvD1 ***P < 1.00 × 10⁻⁴, WT/saline-Syn/saline ***P < 1.00 × 10⁻⁴, WT/saline-Syn/RvD1 **P = 0.003, WT/RvD1-Syn/saline ***P < 1.00 × 10⁻⁴, Syn/saline-Syn/RvD1 ***P < 1.00 × 10⁻⁴ with Bonferroni’s). g Monocyte (% of total blood cells) following treatment (4 WT/saline, 4 WT/RvD1; 3 Syn/saline, 3 Syn/RvD1; ANOVA: genotype×treatment, F_1,10 = 8.58, P = 0.015; genotype, F_1,10 = 3.65, P = 0.085; treatment, F_1,10 = 4.69, P = 0.056; WT/saline-Syn/saline *P = 0.039, Syn/saline-Syn/RvD1 *P = 0.043 with Bonferroni’s). h Percentage of MHC-II and CD68-expressing monocytes (4 WT/saline, 4 WT/RvD1; 3 Syn/saline, 3 Syn/RvD1; MHC-II: ANOVA: genotype × treatment, F_1,10 = 6.20, P = 0.032; genotype, F_1,10 = 18.69, P = 0.002; treatment, F_1,10 = 9.653, P = 0.011; WT/saline-Syn/saline **P = 0.004, WT/RvD1-Syn/saline **P = 0.002, Syn/saline-Syn/RvD1 *P = 0.025 with Bonferroni’s; CD68: ANOVA for genotype × treatment, F_1,10 = 7.05, P = 0.024; genotype, F_1,10 = 4.51, P = 0.060; treatment, F_1,10 = 9.651, P = 0.011; WT/saline-Syn/saline *P = 0.042, WT/RvD1-Syn/saline *P = 0.025, Syn/saline-Syn/RvD1 *P = 0.021 with Bonferroni’s). Source data are provided as a Source Data file

**Fig. 8**
RvD1 treatment prevents neuronal and motor deficits in 4-month-old Syn rats. a DA neuron firing in treated rats (scale: 2 s, 0.2 mV) and firing frequency plots (14 WT/saline, 14 WT/RvD1 cells from 3 rats; 27 Syn/saline and 27 Syn/RvD1 cells from 4 rats; ANOVA for genotype × treatment, F_1,78 = 16.34, P = 1.00 × 10⁻⁴; genotype, F_1,78 = 10.04, P = 0.002; treatment, F_1,78 = 7.43, P = 0.008; WT/saline-Syn/saline ***P < 1.00 × 10⁻⁴, WT/RvD1-Syn/saline ***P = 5.00 × 10⁻⁴, Syn/saline⁻Syn/RvD1 ***P < 1.00 × 10⁻⁴, with Bonferroni’s) and CV-ISI (14 WT/saline, 14 WT/RvD1 cells from 3 rats; 29 Syn/saline and 27 Syn/RvD1 cells from 4 rats; ANOVA for genotype × treatment, F_1,80 = 12.58, P = 7.00 × 10⁻⁴; genotype, F_1,80 = 10.10, P = 0.002; treatment, F_1,80 = 8.40, P = 0.005; WT/saline-Syn/saline *** P < 1.00 × 10⁻⁴, WT/RvD1-Syn/saline ***P = 3.00 × 10⁻⁴, Syn/saline-Syn/RvD1 ***P < 1.00 × 10⁻⁴, with Bonferroni’s). b DA neuron firing (scale: 1 s, 0.2 mV) from treated rats before (CTRL) and during DA (30 µM, 2 min) and plot showing % inhibition by DA (14 WT/saline, 14 WT/RvD1 cells from 3 rats; 22 Syn/saline and 26 Syn/RvD1 cells from 4 rats; ANOVA for genotype × treatment, F_1,72 = 5.06, P = 0.028; genotype, F_1,72 = 4.38, P = 0.040; treatment, F_1,72 = 3.93, P = 0.051; WT/saline-Syn/saline *P = 0.021, WT/RvD1-Syn/saline *P = 0.035, Syn/saline-Syn/RvD1 **P = 0.005, with Bonferroni’s). c Cytoplasmic [Ca²⁺] in DA neurons at −60 mV (11 WT/saline, 6 WT/RvD1 cells from 3 rats; 10 Syn/saline, 7 Syn/RvD1 cells from 4 rats; ANOVA: genotype×treatment, F_1,30 = 21.5, P < 1.00 × 10⁻⁴; genotype, F_1,30 = 12.82, P = 0.001; treatment, F_1,30 = 19.08, P = 1.00 × 10⁻⁴; WT/saline-Syn/saline ***P < 1.00 × 10⁻⁴, WT/RvD1-Syn/saline ***P < 1.00 × 10⁻⁴, Syn/saline-Syn/RvD1 ***P < 1.00 × 10⁻⁴, with Bonferroni’s). d Amperometric traces (scale: 500 ms, 50 pA) and striatal DA release (49 WT/saline, 71 WT/RvD1 slices from 4 rats; 49 Syn/saline, 77 Syn/RvD1 slices from 4 rats; ANOVA: genotype×treatment, F_1,242 = 36.43, P < 1.00 × 10⁻⁴; genotype, F_1,242 = 90.56, P < 1.00 × 10⁻⁴; treatment, F_1,242 = 35.29, P < 1.00 × 10⁻⁴; WT/saline-Syn/saline ***P < 1.00 × 10⁻⁴, WT/RvD1-Syn/saline ***P < 1.00 × 10⁻⁴, Syn/saline-Syn/RvD1 ***P < 1.00 × 10⁻⁴, WT/RvD1-Syn/RvD1 *P = 0.038 with Bonferroni’s). e Entries in centre zone during open field test in treated rats (16 WT/saline, 7 WT/RvD1, 15 Syn/saline and 7 Syn/RvD1 rats; two-way ANOVA for genotype×treatment, F_1,41 = 4.75, P = 0.035; genotype, F_1,41 = 0.85, P = 0.362; treatment, F_1,41 = 4.59, P = 0.038; WT/saline-Syn/saline *P = 0.048, Syn/saline-Syn/RvD1 *P = 0.025, with Bonferroni’s). f Time performance in the accelerating rotarod (11 WT/saline, 9 WT/RvD1, 12 Syn/saline, 9 Syn/RvD1 rats; ANOVA: genotype × treatment, F_1,37 = 4.34, P = 0.044; genotype, F_1,37 = 43.04, P < 1.00 × 10⁻⁴; treatment, F_1,37 = 3.64, P = 0.064; WT/saline-Syn/saline ***P < 1.00 × 10⁻⁴, WT/saline-Syn/RvD1 *P = 0.014, WT/RvD1-Syn/saline ***P < 1.00 × 10⁻⁴_, WT/RvD1-Syn/RvD1 *P = 0.030, Syn/saline-Syn/RvD1 *P = 0.043). Source data are provided as a Source Data file

**Fig. 9**
CSF and plasma cytokines and resolvins in PD patients and control subjects. a Quantification with ELISA of CSF levels of pro- and anti-inflammatory cytokines in control subjects (CTRL) and PD patients (IFN-γ: 8 CTRL and 7 PD, P = 0.183; IL-1β: 6 CTRL and 7 PD, P > 0.999; IL-6: 8 CTRL and 7 PD, P = 0.467; TNF-α: 8 CTRL and 7 PD, P = 0.200; IL-4: 8 CTRL and 7 PD, **P = 0. 004; IL-10: 8 CTRL and 7 PD, P = 0. 294; IL-13: 8 CTRL and 7 PD, P = 0.436, all with Mann–Whitney test). b Quantification with ELISA of plasma levels of cytokines in CTRL and PD patients (IFN-γ: 8 CTRL and 7 PD, *P = 0.013; IL-1β: 6 CTRL and 7 PD, P = 0.169; IL-6: 8 CTRL and 7 PD, P > 0.999; TNF-α: 8 CTRL and 7 PD, P = 0.200; IL-4: 8 CTRL and 7 PD, P = 0.121; IL-10: 8 CTRL and 7 PD, *P = 0. 013; IL-13: 8 CTRL and 7 PD, P = 0.515, all with Mann–Whitney test). c Quantification of CSF and plasma levels of RvD1 in CTRL and PD patients (7 CTRL and 6 PD patients; CSF: *P = 0.049; Plasma: **P = 0.007, with two-tailed Welch’s t-test). d Quantification of CSF and plasma levels of RvD2 in PD and CTRL patients. No differences were detected between the two groups (CSF: 8 CTRL and 8 PD patients; P = 0.936; Plasma: 8 CTRL and 7 PD patients P = 0.667, with two-tailed Welch’s t-test). Source data are provided as a Source Data file

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References

1. Schapira AHV, Tolosa E. Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nat. Rev. Neurol. 2010;6:309–317. - PubMed
1. Lee VM-Y, Trojanowski JQ. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron. 2006;52:33–38. - PubMed
1. Polymeropoulos MH, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–2047. - PubMed
1. Spillantini MG, et al. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–840. - PubMed
1. Singleton AB, et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science. 2003;302:841. - PubMed

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[1] Schapira AHV, Tolosa E. Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nat. Rev. Neurol. 2010;6:309–317. - PubMed

[2] Schapira AHV, Tolosa E. Molecular and clinical prodrome of Parkinson disease: implications for treatment. Nat. Rev. Neurol. 2010;6:309–317. - PubMed

[3] Lee VM-Y, Trojanowski JQ. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron. 2006;52:33–38. - PubMed

[4] Lee VM-Y, Trojanowski JQ. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron. 2006;52:33–38. - PubMed

[5] Polymeropoulos MH, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–2047. - PubMed

[6] Polymeropoulos MH, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–2047. - PubMed

[7] Spillantini MG, et al. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–840. - PubMed

[8] Spillantini MG, et al. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–840. - PubMed

[9] Singleton AB, et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science. 2003;302:841. - PubMed

[10] Singleton AB, et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science. 2003;302:841. - PubMed

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Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson's disease

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