Motor Function Efficacy of Pharmacological Treatments Targeting Energy Metabolism, in Parkinson's Patients
Summary
Consistent evidence suggests that mitochondrial dysfunction plays a crucial role in Parkinson¿s disease pathogenesis. Inhibition of complex I of the mitochondrial electron transport chain is sufficient to reproduce biochemical and pathological features of Parkinson¿s Disease in animal models (PD). Alterations of mitochondrial energy metabolism may intervene in PD pathogenesis by inducing inflammation, generation of reactive oxygen species (ROS), and neurodegeneration. The Nuclear factor erythroid 2-related factor 2 (Nrf2) is a regulator both of mitochondrial function and biogenesis, and of cellular resistance to oxidative stress, and may represent a novel target of PD disease-modifying therapies. The aims of the present study are to validate indicators of energy metabolism as biomarkers in PD patients and to evaluate the efficacy of drugs and natural food supplements acting on the Nrf2 pathway in improving motor impairment and Gait in PD patients.
Timeline
- Start
- 2023-12
- Primary completion
- 2026-05
- Completion
- 2026-05
Publications
- Background Amato R, Rossino MG, Cammalleri M, Timperio AM, Fanelli G, Dal Monte M, Pucci L, Casini G. The Potential of Lisosan G as a Possible Treatment for Glaucoma. Front Pharmacol. 2021 Jul 28;12:719951. doi: 10.3389/fphar.2021.719951. eCollection 2021.
- Background Barichella M, Cereda E, Pinelli G, Iorio L, Caroli D, Masiero I, Ferri V, Cassani E, Bolliri C, Caronni S, Maggio M, Ortelli P, Ferrazzoli D, Maras A, Riboldazzi G, Frazzitta G, Pezzoli G. Muscle-targeted nutritional support for rehabilitation in patients with parkinsonian syndrome. Neurology. 2019 Jul 30;93(5):e485-e496. doi: 10.1212/WNL.0000000000007858. Epub 2019 Jul 5.
- Background Belluscio V, Iosa M, Vannozzi G, Paravati S, Peppe A. Auditory Cue Based on the Golden Ratio Can Improve Gait Patterns in People with Parkinson's Disease. Sensors (Basel). 2021 Jan 29;21(3):911. doi: 10.3390/s21030911.
- Background Bonsi P, Ponterio G, Vanni V, Tassone A, Sciamanna G, Migliarini S, Martella G, Meringolo M, Dehay B, Doudnikoff E, Zachariou V, Goodchild RE, Mercuri NB, D'Amelio M, Pasqualetti M, Bezard E, Pisani A. RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models. EMBO Mol Med. 2019 Jan;11(1):e9283. doi: 10.15252/emmm.201809283.
- Background Christiansen CL, Schenkman ML, McFann K, Wolfe P, Kohrt WM. Walking economy in people with Parkinson's disease. Mov Disord. 2009 Jul 30;24(10):1481-7. doi: 10.1002/mds.22621.
- Background Cuadrado A. Brain-Protective Mechanisms of Transcription Factor NRF2: Toward a Common Strategy for Neurodegenerative Diseases. Annu Rev Pharmacol Toxicol. 2022 Jan 6;62:255-277. doi: 10.1146/annurev-pharmtox-052220-103416. Epub 2021 Oct 12.
- Background Giordano N, Iemolo A, Mancini M, Cacace F, De Risi M, Latagliata EC, Ghiglieri V, Bellenchi GC, Puglisi-Allegra S, Calabresi P, Picconi B, De Leonibus E. Motor learning and metaplasticity in striatal neurons: relevance for Parkinson's disease. Brain. 2018 Feb 1;141(2):505-520. doi: 10.1093/brain/awx351.
- Background Gruetter R, Tkac I. Field mapping without reference scan using asymmetric echo-planar techniques. Magn Reson Med. 2000 Feb;43(2):319-23. doi: 10.1002/(sici)1522-2594(200002)43:23.0.co;2-1.
- Background Guatteo E, Yee A, McKearney J, Cucchiaroni ML, Armogida M, Berretta N, Mercuri NB, Lipski J. Dual effects of L-DOPA on nigral dopaminergic neurons. Exp Neurol. 2013 Sep;247:582-94. doi: 10.1016/j.expneurol.2013.02.009. Epub 2013 Feb 26.
- Background Guatteo E, Rizzo FR, Federici M, Cordella A, Ledonne A, Latini L, Nobili A, Viscomi MT, Biamonte F, Landrock KK, Martini A, Aversa D, Schepisi C, D'Amelio M, Berretta N, Mercuri NB. Functional alterations of the dopaminergic and glutamatergic systems in spontaneous alpha-synuclein overexpressing rats. Exp Neurol. 2017 Jan;287(Pt 1):21-33. doi: 10.1016/j.expneurol.2016.10.009. Epub 2016 Oct 20.
- Background Heger LM, Wise RM, Hees JT, Harbauer AB, Burbulla LF. Mitochondrial Phenotypes in Parkinson's Diseases-A Focus on Human iPSC-Derived Dopaminergic Neurons. Cells. 2021 Dec 7;10(12):3436. doi: 10.3390/cells10123436.
- Background Imbriani P, Tassone A, Meringolo M, Ponterio G, Madeo G, Pisani A, Bonsi P, Martella G. Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson's Disease. Int J Mol Sci. 2019 Jul 11;20(14):3407. doi: 10.3390/ijms20143407.
- Background Imbriani P, D'Angelo V, Platania P, Di Lazzaro G, Scalise S, Salimei C, El Atiallah I, Colona VL, Mercuri NB, Bonsi P, Pisani A, Schirinzi T, Martella G. Ischemic injury precipitates neuronal vulnerability in Parkinson's disease: Insights from PINK1 mouse model study and clinical retrospective data. Parkinsonism Relat Disord. 2020 May;74:57-63. doi: 10.1016/j.parkreldis.2020.04.004. Epub 2020 Apr 20.
- Background Iosa M, Morone G, Fusco A, Marchetti F, Caltagirone C, Paolucci S, Peppe A. Loss of fractal gait harmony in Parkinson's Disease. Clin Neurophysiol. 2016 Feb;127(2):1540-1546. doi: 10.1016/j.clinph.2015.11.016. Epub 2015 Dec 2.
- Background Jeng B, Cederberg KLJ, Lai B, Sasaki JE, Bamman MM, Motl RW. Oxygen cost of over-ground walking in persons with mild-to-moderate Parkinson's disease. Gait Posture. 2020 Oct;82:1-5. doi: 10.1016/j.gaitpost.2020.08.108. Epub 2020 Aug 11.
- Background Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos EN, Shen J. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11441-6. doi: 10.1073/pnas.0702717104. Epub 2007 Jun 11.
- Background La Marca M, Beffy P, Pugliese A, Longo V. Fermented wheat powder induces the antioxidant and detoxifying system in primary rat hepatocytes. PLoS One. 2013 Dec 31;8(12):e83538. doi: 10.1371/journal.pone.0083538. eCollection 2013.
- Background Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL. Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968-73. doi: 10.1073/pnas.132197599.
- Background Liang J, Zhang XY, Zhen YF, Chen C, Tan H, Hu J, Tan MS. PGK1 depletion activates Nrf2 signaling to protect human osteoblasts from dexamethasone. Cell Death Dis. 2019 Nov 26;10(12):888. doi: 10.1038/s41419-019-2112-1.
- Background Liu W, Wang C, He T, Su M, Lu Y, Zhang G, Munte TF, Jin L, Ye Z. Substantia Nigra Integrity Correlates with Sequential Working Memory in Parkinson's Disease. J Neurosci. 2021 Jul 21;41(29):6304-6313. doi: 10.1523/JNEUROSCI.0242-21.2021.
- Background Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401-26. doi: 10.1146/annurev-pharmtox-011112-140320.
- Background Martella G, Madeo G, Maltese M, Vanni V, Puglisi F, Ferraro E, Schirinzi T, Valente EM, Bonanni L, Shen J, Mandolesi G, Mercuri NB, Bonsi P, Pisani A. Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice. Neurobiol Dis. 2016 Jul;91:21-36. doi: 10.1016/j.nbd.2015.12.020. Epub 2016 Feb 23.
- Background Padmanabhan P, Sreekanth Rao K, Gonzalez AJ, Pantelyat AY, Chib VS, Roemmich RT. The Cost of Gait Slowness: Can Persons with Parkinson's Disease Save Energy by Walking Faster? J Parkinsons Dis. 2021;11(4):2073-2084. doi: 10.3233/JPD-212613.
- Background Petrillo S, Schirinzi T, Di Lazzaro G, D'Amico J, Colona VL, Bertini E, Pierantozzi M, Mari L, Mercuri NB, Piemonte F, Pisani A. Systemic activation of Nrf2 pathway in Parkinson's disease. Mov Disord. 2020 Jan;35(1):180-184. doi: 10.1002/mds.27878. Epub 2019 Nov 4.
- Background Ponterio G, Tassone A, Sciamanna G, Vanni V, Meringolo M, Santoro M, Mercuri NB, Bonsi P, Pisani A. Enhanced mu opioid receptor-dependent opioidergic modulation of striatal cholinergic transmission in DYT1 dystonia. Mov Disord. 2018 Feb;33(2):310-320. doi: 10.1002/mds.27212. Epub 2017 Nov 18.
- Background Rothman DL, Dienel GA, Behar KL, Hyder F, DiNuzzo M, Giove F, Mangia S. Glucose sparing by glycogenolysis (GSG) determines the relationship between brain metabolism and neurotransmission. J Cereb Blood Flow Metab. 2022 May;42(5):844-860. doi: 10.1177/0271678X211064399. Epub 2022 Jan 7.
- Background Sciamanna G, Ponterio G, Vanni V, Laricchiuta D, Martella G, Bonsi P, Meringolo M, Tassone A, Mercuri NB, Pisani A. Optogenetic Activation of Striatopallidal Neurons Reveals Altered HCN Gating in DYT1 Dystonia. Cell Rep. 2020 May 19;31(7):107644. doi: 10.1016/j.celrep.2020.107644.
- Background Spolaor F, Romanato M, Annamaria G, Peppe A, Bakdounes L, To DK, Volpe D, Sawacha Z. Relationship between Muscular Activity and Postural Control Changes after Proprioceptive Focal Stimulation (Equistasi(R)) in Middle-Moderate Parkinson's Disease Patients: An Explorative Study. Sensors (Basel). 2021 Jan 14;21(2):560. doi: 10.3390/s21020560.
- Background Storm FA, Cesareo A, Reni G, Biffi E. Wearable Inertial Sensors to Assess Gait during the 6-Minute Walk Test: A Systematic Review. Sensors (Basel). 2020 May 6;20(9):2660. doi: 10.3390/s20092660.
- Background Tassone A, Martella G, Meringolo M, Vanni V, Sciamanna G, Ponterio G, Imbriani P, Bonsi P, Pisani A. Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia. Mov Disord. 2021 Dec;36(12):2768-2779. doi: 10.1002/mds.28698. Epub 2021 Jun 26.
- Background Tyrrell DJ, Bharadwaj MS, Van Horn CG, Marsh AP, Nicklas BJ, Molina AJ. Blood-cell bioenergetics are associated with physical function and inflammation in overweight/obese older adults. Exp Gerontol. 2015 Oct;70:84-91. doi: 10.1016/j.exger.2015.07.015. Epub 2015 Jul 29.
- Background Valdinocci D, Simoes RF, Kovarova J, Cunha-Oliveira T, Neuzil J, Pountney DL. Intracellular and Intercellular Mitochondrial Dynamics in Parkinson's Disease. Front Neurosci. 2019 Sep 18;13:930. doi: 10.3389/fnins.2019.00930. eCollection 2019.
- Background Wang Y, Gao L, Chen J, Li Q, Huo L, Wang Y, Wang H, Du J. Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson's Disease. Front Pharmacol. 2021 Nov 23;12:757161. doi: 10.3389/fphar.2021.757161. eCollection 2021.
- Background Wertman V, Gromova A, La Spada AR, Cortes CJ. Low-Cost Gait Analysis for Behavioral Phenotyping of Mouse Models of Neuromuscular Disease. J Vis Exp. 2019 Jul 18;(149):10.3791/59878. doi: 10.3791/59878.
- Background Zampese E, Surmeier DJ. Calcium, Bioenergetics, and Parkinson's Disease. Cells. 2020 Sep 8;9(9):2045. doi: 10.3390/cells9092045.
- Background Zane AC, Reiter DA, Shardell M, Cameron D, Simonsick EM, Fishbein KW, Studenski SA, Spencer RG, Ferrucci L. Muscle strength mediates the relationship between mitochondrial energetics and walking performance. Aging Cell. 2017 Jun;16(3):461-468. doi: 10.1111/acel.12568. Epub 2017 Feb 9.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Terazosin | Small molecule | 2 mg | — |