PEALut in the Dietary Management of Patients with Acute Ischemic Stroke: A Prospective Randomized Controlled Clinical Trial
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Participants
2.2. Study Design
2.3. Outcome Measures
- (i)
- (ii)
- Independence in activities of daily living and degree of disability were evaluated at T0, T1 and T2 using Barthel Index (BI) [26] and modified Rankin Scale (mRS), respectively [27]. The BI maximal score is 100, indicating that the patient is fully independent in physical functioning, while the mRS scale consists of 6 grades from 0 to 5, with 0 corresponding to no symptoms and 5 corresponding to severe disability [28];
- (iii)
- Cognitive impairment at T1 and T2 was evaluated using Mini-Mental State Examination (MMSE) [29] and Montreal Cognitive Assessment (MoCA) [30]. For MMSE, a perfect score is 30 points, a score of 24 is the recommended score, and a score of 23 or lower indicates dementia. Like the MMSE, the MoCA is a brief 30-point assessment with a proposed cut-off score of 26 and a ≤ 25 score indicative of cognitive impairment [31].
2.4. Safety Assessments
2.5. Sample Size Calculation and Statistical Analysis
3. Results
3.1. Patients Baseline Characteristics
3.2. National Institutes of Health Stroke Scale (NIHSS)
3.3. Barthel Index (BI)
3.4. Modified Rankin Scale (mRS)
3.5. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA)
3.6. Treatment Safety and Tolerability
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Paul, S.; Candelario-Jalil, E. Emerging Neuroprotective Strategies for the Treatment of Ischemic Stroke: An Overview of Clinical and Preclinical Studies. Exp. Neurol. 2021, 335, 113518. [Google Scholar] [CrossRef] [PubMed]
- Ramos-Lima, M.J.M.; Brasileiro, I.d.C.; de Lima, T.L.; Braga-Neto, P. Quality of Life after Stroke: Impact of Clinical and Sociodemographic Factors. Clinics 2018, 73, e418. [Google Scholar] [CrossRef] [PubMed]
- Qiu, Y.M.; Zhang, C.L.; Chen, A.Q.; Wang, H.L.; Zhou, Y.F.; Li, Y.N.; Hu, B. Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy? Front. Immunol. 2021, 12, 678744. [Google Scholar] [CrossRef]
- Zhao, Y.; Zhang, X.; Chen, X.; Wei, Y. Neuronal Injuries in Cerebral Infarction and Ischemic Stroke: From Mechanisms to Treatment (Review). Int. J. Mol. Med. 2022, 49, 15. [Google Scholar] [CrossRef]
- Jin, R.; Yang, G.; Li, G. Inflammatory Mechanisms in Ischemic Stroke: Role of Inflammatory Cells. J. Leukoc. Biol. 2010, 87, 779–789. [Google Scholar] [CrossRef] [PubMed]
- Jayaraj, R.L.; Azimullah, S.; Beiram, R.; Jalal, F.Y.; Rosenberg, G.A. Neuroinflammation: Friend and Foe for Ischemic Stroke. J. Neuroinflamm. 2019, 16, 142. [Google Scholar] [CrossRef]
- Maida, C.D.; Norrito, R.L.; Daidone, M.; Tuttolomondo, A.; Pinto, A. Neuroinflammatory Mechanisms in Ischemic Stroke: Focus on Cardioembolic Stroke, Background, and Therapeutic Approaches. Int. J. Mol. Sci. 2020, 21, 6454. [Google Scholar] [CrossRef]
- Lee, Y.; Lee, S.R.; Choi, S.S.; Yeo, H.G.; Chang, K.T.; Lee, H.J. Therapeutically Targeting Neuroinflammation and Microglia after Acute Ischemic Stroke. Biomed. Res. Int. 2014, 2014, 297241. [Google Scholar] [CrossRef]
- Dabrowska, S.; Andrzejewska, A.; Lukomska, B.; Janowski, M. Neuroinflammation as a Target for Treatment of Stroke Using Mesenchymal Stem Cells and Extracellular Vesicles. J. Neuroinflamm. 2019, 16, 178. [Google Scholar] [CrossRef]
- Skaper, S.D.; Facci, L.; Giusti, P. Glia and Mast Cells as Targets for Palmitoylethanolamide, an Anti-Inflammatory and Neuroprotective Lipid Mediator. Mol. Neurobiol. 2013, 48, 340–352. [Google Scholar] [CrossRef]
- Esposito, E.; Cordaro, M.; Cuzzocrea, S. Roles of Fatty Acid Ethanolamides (FAE) in Traumatic and Ischemic Brain Injury. Pharmacol. Res. 2014, 86, 26–31. [Google Scholar] [CrossRef] [PubMed]
- Parrella, E.; Porrini, V.; Benarese, M.; Pizzi, M. The Role of Mast Cells in Stroke. Cells 2019, 8, 437. [Google Scholar] [CrossRef]
- Esposito, E.; Cuzzocrea, S. Palmitoylethanolamide in Homeostatic and Traumatic Central Nervous System Injuries. CNS Neurol. Disord. 2013, 12, 55–61. [Google Scholar] [CrossRef] [PubMed]
- Petrosino, S.; Di Marzo, V. The Pharmacology of Palmitoylethanolamide and First Data on the Therapeutic Efficacy of Some of Its New Formulations. Br. J. Pharmacol. 2017, 174, 1349–1365. [Google Scholar] [CrossRef] [PubMed]
- Schäbitz, W.R.; Giuffrida, A.; Berger, C.; Aschoff, A.; Schwaninger, M.; Schwab, S.; Piomelli, D. Release of Fatty Acid Amides in a Patient with Hemispheric Stroke: A Microdialysis Study. Stroke 2002, 33, 2112–2114. [Google Scholar] [CrossRef] [PubMed]
- Schomacher, M.; Müller, H.D.; Sommer, C.; Schwab, S.; Schäbitz, W.R. Endocannabinoids Mediate Neuroprotection after Transient Focal Cerebral Ischemia. Brain Res. 2008, 1240, 213–220. [Google Scholar] [CrossRef] [PubMed]
- Garg, P.; Duncan, R.S.; Kaja, S.; Koulen, P. Intracellular Mechanisms of N-Acylethanolamine-Mediated Neuroprotection in a Rat Model of Stroke. Neuroscience 2010, 166, 252–262. [Google Scholar] [CrossRef] [PubMed]
- Impellizzeri, D.; Bruschetta, G.; Cordaro, M.; Crupi, R.; Siracusa, R.; Esposito, E.; Cuzzocrea, S. Micronized/Ultramicronized Palmitoylethanolamide Displays Superior Oral Efficacy Compared to Nonmicronized Palmitoylethanolamide in a Rat Model of Inflammatory Pain. J. Neuroinflamm. 2014, 11, 136. [Google Scholar] [CrossRef]
- Petrosino, S.; Cordaro, M.; Verde, R.; Moriello, A.S.; Marcolongo, G.; Schievano, C.; Siracusa, R.; Piscitelli, F.; Peritore, A.F.; Crupi, R.; et al. Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-Hyperalgesic Effect. Front. Pharmacol. 2018, 9, 249. [Google Scholar] [CrossRef]
- Peritore, A.F.; Siracusa, R.; Crupi, R.; Cuzzocrea, S. Therapeutic Efficacy of Palmitoylethanolamide and Its New Formulations in Synergy with Different Antioxidant Molecules Present in Diets. Nutrients 2019, 11, 2175. [Google Scholar] [CrossRef]
- Paterniti, I.; Impellizzeri, D.; Di Paola, R.; Navarra, M.; Cuzzocrea, S.; Esposito, E. A New Co-Ultramicronized Composite Including Palmitoylethanolamide and Luteolin to Prevent Neuroinflammation in Spinal Cord Injury. J. Neuroinflamm. 2013, 10, 91. [Google Scholar] [CrossRef] [PubMed]
- Caltagirone, C.; Cisari, C.; Schievano, C.; Di Paola, R.; Cordaro, M.; Bruschetta, G.; Esposito, E.; Cuzzocrea, S.; Ventura, F.; Casaleggio, M.; et al. Co-Ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: From Rodent to Man. Transl. Stroke Res. 2016, 7, 54–69. [Google Scholar] [CrossRef]
- Assogna, M.; Casula, E.P.; Borghi, I.; Bonnì, S.; Samà, D.; Motta, C.; Di Lorenzo, F.; D’Acunto, A.; Porrazzini, F.; Minei, M.; et al. Effects of Palmitoylethanolamide Combined with Luteoline on Frontal Lobe Functions, High Frequency Oscillations, and GABAergic Transmission in Patients with Frontotemporal Dementia. J. Alzheimer’s Dis. 2020, 76, 1297–1308. [Google Scholar] [CrossRef] [PubMed]
- Rajashekar, D.; Wilms, M.; MacDonald, M.E.; Schimert, S.; Hill, M.D.; Demchuk, A.; Goyal, M.; Dukelow, S.P.; Forkert, N.D. Lesion-Symptom Mapping with NIHSS Sub-Scores in Ischemic Stroke Patients. Stroke Vasc. Neurol. 2022, 7, e001091. [Google Scholar] [CrossRef]
- Chalos, V.; van der Ende, N.A.M.; Lingsma, H.F.; Mulder, M.J.H.L.; Venema, E.; Dijkland, S.A.; Berkhemer, O.A.; Yoo, A.J.; Broderick, J.P.; Palesch, Y.Y.; et al. National Institutes of Health Stroke Scale: An Alternative Primary Outcome Measure for Trials of Acute Treatment for Ischemic Stroke. Stroke 2020, 51, 282–290. [Google Scholar] [CrossRef] [PubMed]
- Ohura, T.; Hase, K.; Nakajima, Y.; Nakayama, T. Validity and Reliability of a Performance Evaluation Tool Based on the Modified Barthel Index for Stroke Patients. BMC Med. Res. Methodol. 2017, 17, 131. [Google Scholar] [CrossRef]
- Haggag, H.; Hodgson, C. Clinimetrics: Modified Rankin Scale (MRS). J. Physiother. 2022, 68, 281. [Google Scholar] [CrossRef]
- Sulter, G.; Steen, C.; De Keyser, J. Use of the Barthel Index and Modified Rankin Scale in Acute Stroke Trials. Stroke 1999, 30, 1538–1541. [Google Scholar] [CrossRef]
- Tombaugh, T.N.; Mclntyre, N.J. The Mini-Mental State Examination: A Comprehensive Review. J. Am. Geriatr. Soc. 1992, 40, 922–935. [Google Scholar] [CrossRef]
- Davis, D.H.J.; Creavin, S.T.; Yip, J.L.Y.; Noel-Storr, A.H.; Brayne, C.; Cullum, S. Montreal Cognitive Assessment for the Detection of Dementia. Cochrane Database Syst. Rev. 2021, 7, CD010775. [Google Scholar] [CrossRef]
- Gluhm, S.; Goldstein, J.; Loc, K.; Colt, A.; Van Liew, C.; Corey-Bloom, J. Cognitive Performance on the Mini-Mental State Examination and the Montreal Cognitive Assessment across the Healthy Adult Lifespan. Cogn. Behav. Neurol. 2013, 26, 1–5. [Google Scholar] [CrossRef] [PubMed]
- Liu, R.; Pan, M.-X.; Tang, J.-C.; Zhang, Y.; Liao, H.-B.; Zhuang, Y.; Zhao, D.; Wan, Q. Role of Neuroinflammation in Ischemic Stroke. Neuroimmunol. Neuroinflamm. 2017, 4, 158–166. [Google Scholar] [CrossRef]
- Saver, J.L.; Altman, H. Relationship between Neurologic Deficit Severity and Final Functional Outcome Shifts and Strengthens during First Hours after Onset. Stroke 2012, 43, 1537–1541. [Google Scholar] [CrossRef]
- Kristensen, D.V.; Johnsen, N.T.; Amthor, K.-F.; Lunde, L.; Strømmen, L.B.; Vestby, E.M.; Hagberg, G. Culturally Adapted Translation of the NIHSS. Sykepl. Forsk. 2020, 15, e82736. [Google Scholar] [CrossRef]
- Lee, E.Y.; Sohn, M.K.; Lee, J.M.; Kim, D.Y.; Shin, Y.I.; Oh, G.J.; Lee, Y.S.; Lee, S.Y.; Song, M.K.; Han, J.H.; et al. Changes in Long-Term Functional Independence in Patients with Moderate and Severe Ischemic Stroke: Comparison of the Responsiveness of the Modified Barthel Index and the Functional Independence Measure. Int. J. Environ. Res. Public. Health 2022, 19, 9612. [Google Scholar] [CrossRef]
- Yang, H.; Chen, Y.; Wang, J.; Wei, H.; Chen, Y.; Jin, J. Activities of Daily Living Measurement after Ischemic Stroke: Rasch Analysis of the Modified Barthel Index. Medicine 2021, 100, e24926. [Google Scholar] [CrossRef]
- Faig-Martí, J. Palmitoylethanolamide for Neurological Disorders. OBM Neurobiol. 2020, 4, 76. [Google Scholar] [CrossRef]
- Colizzi, M.; Bortoletto, R.; Colli, C.; Bonomo, E.; Pagliaro, D.; Maso, E.; Di Gennaro, G.; Balestrieri, M. Therapeutic Effect of Palmitoylethanolamide in Cognitive Decline: A Systematic Review and Preliminary Meta-Analysis of Preclinical and Clinical Evidence. Front. Psychiatry 2022, 13, 1038122. [Google Scholar] [CrossRef]
- Landolfo, E.; Cutuli, D.; Petrosini, L.; Caltagirone, C. Effects of Palmitoylethanolamide on Neurodegenerative Diseases: A Review from Rodents to Humans. Biomolecules 2022, 12, 667. [Google Scholar] [CrossRef]
- Ahmad, A.; Genovese, T.; Impellizzeri, D.; Crupi, R.; Velardi, E.; Marino, A.; Esposito, E.; Cuzzocrea, S. Reduction of Ischemic Brain Injury by Administration of Palmitoylethanolamide after Transient Middle Cerebral Artery Occlusion in Rats. Brain Res. 2012, 1477, 45–58. [Google Scholar] [CrossRef]
- Parrella, E.; Porrini, V.; Iorio, R.; Benarese, M.; Lanzillotta, A.; Mota, M.; Fusco, M.; Tonin, P.; Spano, P.F.; Pizzi, M. PEA and Luteolin Synergistically Reduce Mast Cell-Mediated Toxicity and Elicit Neuroprotection in Cell-Based Models of Brain Ischemia. Brain Res. 2016, 1648, 409–417. [Google Scholar] [CrossRef] [PubMed]
- Cordaro, M.; Impellizzeri, D.; Paterniti, I.; Bruschetta, G.; Siracusa, R.; De Stefano, D.; Cuzzocrea, S.; Esposito, E. Neuroprotective Effects of Co-UltraPEALut on Secondary Inflammatory Process and Autophagy Involved in Traumatic Brain Injury. J. Neurotrauma 2016, 33, 132–146. [Google Scholar] [CrossRef] [PubMed]
- Cordaro, M.; Cuzzocrea, S.; Crupi, R. An Update of Palmitoylethanolamide and Luteolin Effects in Preclinical and Clinical Studies of Neuroinflammatory Events. Antioxidants 2020, 9, 216. [Google Scholar] [CrossRef] [PubMed]
- Campolo, M.; Crupi, R.; Cordaro, M.; Cardali, S.M.; Ardizzone, A.; Casili, G.; Scuderi, S.A.; Siracusa, R.; Esposito, E.; Conti, A.; et al. Co-Ultra PEALut Enhances Endogenous Repair Response Following Moderate Traumatic Brain Injury. Int. J. Mol. Sci. 2021, 22, 8717. [Google Scholar] [CrossRef] [PubMed]
- Chiti, G.; Pantoni, L. Use of Montreal Cognitive Assessment in Patients with Stroke. Stroke 2014, 44, 3135–3140. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Y.; Zhao, S.; Fan, Z.; Li, Z.; He, F.; Lin, C.; Topatana, W.; Yan, Y.; Liu, Z.; Chen, Y.; et al. Evaluation of the Mini-Mental State Examination and the Montreal Cognitive Assessment for Predicting Post-Stroke Cognitive Impairment During the Acute Phase in Chinese Minor Stroke Patients. Front. Aging Neurosci. 2020, 12, 236. [Google Scholar] [CrossRef] [PubMed]
- Wong, G.K.C.; Mak, J.S.Y.; Wong, A.; Zheng, V.Z.Y.; Poon, W.S.; Abrigo, J.; Mok, V.C.T. Minimum Clinically Important Difference of Montreal Cognitive Assessment in Aneurysmal Subarachnoid Hemorrhage Patients. J. Clin. Neurosci. 2017, 46, 41–44. [Google Scholar] [CrossRef]
- Gibson, E.; Koh, C.L.; Eames, S.; Bennett, S.; Scott, A.M.; Hoffmann, T.C. Occupational Therapy for Cognitive Impairment in Stroke Patients. Cochrane Database Syst. Rev. 2010, 2010, CD006430. [Google Scholar] [CrossRef]
- Wu, C.Y.; Hung, S.J.; Lin, K.C.; Chen, K.H.; Chen, P.; Tsay, P.K. Responsiveness, Minimal Clinically Important Difference, and Validity of the MoCA in Stroke Rehabilitation. Occup. Ther. Int. 2019, 2019, 2517658. [Google Scholar] [CrossRef]
- Beggiato, S.; Tomasini, M.C.; Cassano, T.; Ferraro, L. Chronic Oral Palmitoylethanolamide Administration Rescues Cognitive Deficit and Reduces Neuroinflammation, Oxidative Stress, and Glutamate Levels in a Transgenic Murine Model of Alzheimer’s Disease. J. Clin. Med. 2020, 9, 428. [Google Scholar] [CrossRef]
- Scuderi, C.; Bronzuoli, M.R.; Facchinetti, R.; Pace, L.; Ferraro, L.; Broad, K.D.; Serviddio, G.; Bellanti, F.; Palombelli, G.; Carpinelli, G.; et al. Ultramicronized Palmitoylethanolamide Rescues Learning and Memory Impairments in a Triple Transgenic Mouse Model of Alzheimer’s Disease by Exerting Anti-Inflammatory and Neuroprotective Effects. Transl. Psychiatry 2018, 8, 32. [Google Scholar] [CrossRef]
- Calabrò, R.S.; Naro, A.; De Luca, R.; Leonardi, S.; Russo, M.; Marra, A.; Bramanti, P. PEALut Efficacy in Mild Cognitive Impairment: Evidence from a SPECT Case Study! Aging Clin. Exp. Res. 2016, 28, 1279–1282. [Google Scholar] [CrossRef]
- Manni, B.; Federzoni, L.; Zucchi, P.; Fabbo, A. Co-UltraPEALut Effect on Mild Cognitive Impairment: A Retrospective Observational Study. Acta Sci. Neurol. 2021, 4, 8–14. [Google Scholar] [CrossRef]
Baseline Characteristics | Control (N = 30) | PEALut (N = 30) | p |
---|---|---|---|
Days in Stroke Unit | 10.2 ± 1.29 | 9.0 ± 1.27 | 0.3423 a |
NIHSS | 10.8 ± 0.88 | 8.4 ± 0.61 | 0.5464 b |
BI | 21.3 ± 3.06 | 27.8 ± 2.96 | 1.0000 b |
mRS | 4.4 ± 0.12 | 3.9 ± 0.14 | 0.6819 b |
AIS site, n (%) | 0.7413 c | ||
Posterior circulation | 2 (7) | 3 (10) | |
Anterior circulation | 28 (93) | 27 (90) | |
Previous stroke (without sequelae), n (%) | 4 (13) | 3 (10) | 1.0000 c |
Previous TIA, n (%) | 7 (23) | 7 (23) | 1.0000 c |
Thrombophilia, n (%) | 1 (3) | 0 (0) | 1.0000 c |
Heart failure, n (%) | 2 (7) | 5 (17) | 0.4238 c |
Ongoing neoplastic disease, n (%) | 6 (20) | 4 (13) | 0.7306 c |
Ischemic heart disease, n (%) | 5 (17) | 7 (23) | 0.7480 c |
Hypertension, n (%) | 21 (70) | 26 (87) | 0.2092 c |
Non-ischemic heart disease, n (%) | 0.0382 c | ||
Hypertensive | 11 (37) | 20 (67) | |
Valve | 0 (0) | 0 (0) | |
Dilative | 0 (0) | 0 (0) | |
Other | 4 (13) | 4 (13) | |
Presence of prosthesis valve COPD, n (%) | 3 (10) | 2 (7) | 1.0000 c |
Epilepsy, n (%) | 2 (7) | 1 (3) | 1.0000 c |
Current infections, n (%) | 1 (3) | 1 (3) | 1.0000 c |
Chronic kidney disease, n (%) | 0 (0) | 0 (0) | 1.0000 c |
Diabetes, n (%) | 0.6130 c | ||
Insulin dependence | 2 (7) | 4 (13) | |
NIDDM | 5 (17) | 3 (10) |
NIHSS Score | T0 | T1 | T2 | p |
---|---|---|---|---|
Control | 10.8 ± 0.88 | 6.3 ± 0.87 | 4.7 ± 0.74 | 0.7134 |
PEALut | 8.4 ± 0.61 | 3.9 ± 0.64 | 2.3 ± 0.41 |
BI Score | T0 | T1 | T2 | p |
---|---|---|---|---|
Control | 21.3 ± 3.06 | 50.2 ± 4.72 | 64.6 ± 4.81 | 0.0020 |
PEALut | 27.8 ± 2.96 | 64.2 ± 3.62 | 86.0 ± 3.06 |
mRS Score | T0 | T1 | T2 | p |
---|---|---|---|---|
Control | 4.4 ± 0.12 | 3.3 ± 0.24 | 2.9 ± 0.29 | 0.0001 |
PEALut | 3.9 ± 0.14 | 3.0 ± 0.20 | 1.3 ± 0.23 |
Control | PEALut | |||
---|---|---|---|---|
T1 (N = 30) | T2 (N = 26) | T1 (N = 29) | T2 (N = 28) | |
MMSE | 30% | 19.2% | 69% | 75% |
MoCA | 26.7% | 11.5% | 65.5% | 64.3% |
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Bonzanino, M.; Riolo, M.; Battaglini, I.; Perna, M.; De Mattei, M. PEALut in the Dietary Management of Patients with Acute Ischemic Stroke: A Prospective Randomized Controlled Clinical Trial. J. Clin. Med. 2024, 13, 509. https://doi.org/10.3390/jcm13020509
Bonzanino M, Riolo M, Battaglini I, Perna M, De Mattei M. PEALut in the Dietary Management of Patients with Acute Ischemic Stroke: A Prospective Randomized Controlled Clinical Trial. Journal of Clinical Medicine. 2024; 13(2):509. https://doi.org/10.3390/jcm13020509
Chicago/Turabian StyleBonzanino, Massimo, Marianna Riolo, Iacopo Battaglini, Marilisa Perna, and Marco De Mattei. 2024. "PEALut in the Dietary Management of Patients with Acute Ischemic Stroke: A Prospective Randomized Controlled Clinical Trial" Journal of Clinical Medicine 13, no. 2: 509. https://doi.org/10.3390/jcm13020509