Skip to content
2000
image of Next-Generation Phospholipid Nanocomplexes for Precision Neurotherapeutics: Harnessing Endogenous Blood-Brain Barrier Transport Mechanisms to Revolutionize the Treatment of Neurodegenerative Diseases

Abstract

The treatment of neurodegenerative illnesses remains a substantial problem due to the blood-brain barrier's restrictive nature, which restricts therapeutic agent penetration. Phospholipid Nanocomplexes (PNCs) have emerged as next-generation neurotherapeutics, utilizing natural BBB transport pathways to improve drug delivery. These nanocarriers, with lipid-based architectures, allow for receptor-mediated transcytosis, lipid raft-mediated transport, and adsorptive-mediated endocytosis, resulting in precise and sustained drug release inside the central nervous system. Recent preclinical and clinical studies have shown that PNC-based formulations of neurotrophic factors, antioxidants, and gene-silencing therapies significantly improve neuronal survival, cognitive function, and neuroprotection in conditions like Alzheimer's Disease (AD), Parkinson's Disease (PD), Glioblastoma (GBM), and multiple sclerosis. Despite the positive outcomes, issues such as scalability, long-term safety, and regulatory approval remain. This study critically assesses the present status of PNC-based neurotherapeutics, emphasizing their benefits over traditional therapies, analyzing the most recent clinical trial outcomes, and assessing difficulties and future prospects. To improve PNC effectiveness, the potential for artificial intelligence-driven medication design, multifunctionalized nanocarriers, and hybrid biomaterial methods is investigated. As biocompatible and patient-specific nanomedicine advances, PNCs represent a breakthrough approach to precision neuroscience, providing tailored, efficient, and safer therapies for neurodegenerative diseases.

Loading

Article metrics loading...

/content/journals/raddf/10.2174/0126673878361646250623062415
2025-07-03
2025-09-27
Loading full text...

Full text loading...

References

  1. Pedersen B.K. Saltin B. Physiology, blood brain barrier. StatPearls Treasure Island (FL) StatPearls Publishing 2015
    [Google Scholar]
  2. Lindsay R.M. Wiegand S.J. Anthony Altar C. DiStefano P.S. Neurotrophic factors: From molecule to man. Trends Neurosci. 1994 17 5 182 190 10.1016/0166‑2236(94)90099‑X 7520198
    [Google Scholar]
  3. Notaras M. van den Buuse M. Brain-derived neurotrophic factor (BDNF): Novel insights into regulation and genetic variation. Neuroscientist 2019 25 5 434 454 10.1177/1073858418810142 30387693
    [Google Scholar]
  4. Krabbe K.S. Nielsen A.R. Krogh-Madsen R. Plomgaard P. Rasmussen P. Erikstrup C. Fischer C.P. Lindegaard B. Petersen A.M.W. Taudorf S. Secher N.H. Pilegaard H. Bruunsgaard H. Pedersen B.K. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 2007 50 2 431 438 10.1007/s00125‑006‑0537‑4 17151862
    [Google Scholar]
  5. Maisonpierre P.C. Belluscio L. Squinto S. Ip N.Y. Furth M.E. Lindsay R.M. Yancopoulos G.D. Neurotrophin-3: A neurotrophic factor related to NGF and BDNF. Science 1990 247 4949 1446 1451 10.1126/science.247.4949.1446 2321006
    [Google Scholar]
  6. Binder D.K. Scharfman H.E. Brain-derived neurotrophic factor. Growth Factors 2004 22 3 123 131 15518235
    [Google Scholar]
  7. Airaksinen M.S. Titievsky A. Saarma M. GDNF family neurotrophic factor signaling: Four masters, one servant? Mol. Cell. Neurosci. 1999 13 5 313 325 10356294
    [Google Scholar]
  8. Ip N.Y. Yancopoulos G.D. The neurotrophins and CNTF: Two families of collaborative neurotrophic factors. Annu. Rev. Neurosci. 1996 19 1 491 515 8833452
    [Google Scholar]
  9. Skaper S.D. The neurotrophin family of neurotrophic factors: An overview. Methods Protoc. 2012 846 1 12 22367796
    [Google Scholar]
  10. Mokhtarzade M. Motl R. Negaresh R. Zimmer P. Khodadoost M. Baker J.S. Patel D. Majdinasab N. Ranjbar R. Exercise-induced changes in neurotrophic factors and markers of blood-brain barrier permeability are moderated by weight status in multiple sclerosis. Neuropeptides 2018 70 93 100 29880392
    [Google Scholar]
  11. Sims S.K. Wilken-Resman B. Smith C.J. Mitchell A. McGonegal L. Sims-Robinson C. Brain‐derived neurotrophic factor and nerve growth factor therapeutics for brain injury: The current translational challenges in preclinical and clinical research. Neural Plast. 2022 2022 1 3889300 35283994
    [Google Scholar]
  12. Bahlakeh G. Rahbarghazi R. Mohammadnejad D. Abedelahi A. Karimipour M. Current knowledge and challenges associated with targeted delivery of neurotrophic factors into the central nervous system: Focus on available approaches. Cell Biosci. 2021 11 1 181 34641969
    [Google Scholar]
  13. Terstappen G.C. Meyer A.H. Bell R.D. Zhang W. Strategies for delivering therapeutics across the blood-brain barrier. Nat. Rev. Drug Discov. 2021 20 5 362 383 33649582
    [Google Scholar]
  14. Furtado D. Björnmalm M. Ayton S. Bush A.I. Kempe K. Caruso F. Overcoming the blood–brain barrier: The role of nanomaterials in treating neurological diseases. Adv. Mater. 2018 30 46 1801362 30066406
    [Google Scholar]
  15. Agrawal M. Saraf S. Saraf S. Dubey S.K. Puri A. Patel R.J. Ajazuddin Ravichandiran V. Murty U.S. Alexander A. Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting. J. Control. Release 2020 321 372 415 10.1016/j.jconrel.2020.02.020 32061621
    [Google Scholar]
  16. Song Z. Yin J. Xiao P. Chen J. Gou J. Wang Y. Zhang Y. Yin T. Tang X. He H. Improving breviscapine oral bioavailability by preparing nanosuspensions, liposomes and phospholipid complexes. Pharmaceutics 2021 13 2 132 10.3390/pharmaceutics13020132 33498470
    [Google Scholar]
  17. Zhang S. Uludağ H. Nanoparticulate systems for growth factor delivery. Pharm. Res. 2009 26 7 1561 1580 10.1007/s11095‑009‑9897‑z 19415467
    [Google Scholar]
  18. Géral C. Angelova A. Lesieur S. From molecular to nanotechnology strategies for delivery of neurotrophins: Emphasis on brain-derived neurotrophic factor (BDNF). Pharmaceutics 2013 5 1 127 167 10.3390/pharmaceutics5010127 24300402
    [Google Scholar]
  19. Zhu J. Dong X. Preparation and characterization of novel HDL-mimicking nanoparticles for nerve growth factor encapsulation. J. Vis. Exp. 2017 123 55584 28570541
    [Google Scholar]
  20. Zhang Y. Wang Y. Zhang Y. Intravenous nanoemulsions loaded with phospholipid complex of glut-1: An effective target to deliver brain-derived neurotrophic factor gene across the blood brain barrier. ACS Chem. Neurosci. 2025 17 2 232 39720886
    [Google Scholar]
  21. Chen J. Zhang H. Wang Y. Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery. Nat. Mater. 2025 24 3 321 330 39824965
    [Google Scholar]
  22. Wu Y. Rakotoarisoa M. Angelov B. Deng Y. Angelova A. Self-assembled nanoscale materials for neuronal regeneration: A focus on bdnf protein and nucleic acid biotherapeutic delivery. Nanomaterials 2022 12 13 2267 35808102
    [Google Scholar]
  23. Wang L. Zhang Y. Liu X. Brain-derived Neurotrophic Factor and Its Applications through Nanomaterials in Regenerative Medicine. Biomater. Sci. 2021 9 10 3630 3645
    [Google Scholar]
  24. Prathipati P. Zhu J. Dong X. Development of novel HDL-mimicking α-tocopherol-coated nanoparticles to encapsulate nerve growth factor and evaluation of biodistribution. Eur. J. Pharm. Biopharm. 2016 108 126 135 27531623
    [Google Scholar]
  25. Mohit K.P. Solanki P. Mangla B. Aggarwal G. Formulation development, optimization by box-behnken design, and in vitro characterization of gefitinib phospholipid complex based nanoemulsion drug delivery system. J. Pharm. Innov. 2023 18 3 952 964
    [Google Scholar]
  26. Agrahari V. Burnouf P.A. Burnouf T. Agrahari V. Nanoformulation properties, characterization, and behavior in complex biological matrices: Challenges and opportunities for brain-targeted drug delivery applications and enhanced translational potential. Adv. Drug Deliv. Rev. 2019 148 146 180 10.1016/j.addr.2019.02.008 30797956
    [Google Scholar]
  27. Arora S. Layek B. Singh J. Design and validation of liposomal ApoE2 gene delivery system to evade blood–brain barrier for effective treatment of Alzheimer’s disease. Mol. Pharm. 2021 18 2 714 725 32787268
    [Google Scholar]
  28. Mustapa M.F. Bell P.C. Hurley C.A. Nicol A. Guénin E. Sarkar S. Writer M.J. Barker S.E. Wong J.B. Pilkington-Miksa M.A. Papahadjopoulos-Sternberg B. Shamlou P.A. Hailes H.C. Hart S.L. Zicha D. Tabor A.B. Biophysical characterization of an integrin-targeted lipopolyplex gene delivery vector. Biochemistry 2007 46 45 12930 12944 17935306
    [Google Scholar]
  29. Trummer B.J. Iyer V. Balu-Iyer S.V. O’Connor R. Straubinger R.M. Physicochemical properties of epidermal growth factor receptor inhibitors and development of a nanoliposomal formulation of gefitinib. J. Pharm. Sci. 2012 101 8 2763 2776 10.1002/jps.23180 22581704
    [Google Scholar]
  30. Samal J. Rebelo A.L. Pandit A. A window into the brain: Tools to assess pre-clinical efficacy of biomaterials-based therapies on central nervous system disorders. Adv. Drug Deliv. Rev. 2019 148 68 145 10.1016/j.addr.2019.01.012 30710594
    [Google Scholar]
  31. Khan J. Alexander A. Ajazuddin Saraf S. Saraf S. Recent advances and future prospects of phyto-phospholipid complexation technique for improving pharmacokinetic profile of plant actives. J. Control. Release 2013 168 1 50 60 23474031
    [Google Scholar]
  32. Teixeira M.I. Lopes C.M. Amaral M.H. Costa P.C. Surface-modified lipid nanocarriers for crossing the blood-brain barrier (BBB): A current overview of active targeting in brain diseases. Colloids Surf. B Biointerfaces 2023 221 112999 10.1016/j.colsurfb.2022.112999 36368148
    [Google Scholar]
  33. Zhang S. Gan L. Cao F. Wang H. Gong P. Ma C. Ren L. Lin Y. Lin X. The barrier and interface mechanisms of the brain barrier, and brain drug delivery. Brain Res. Bull. 2022 190 69 83 10.1016/j.brainresbull.2022.09.017 36162603
    [Google Scholar]
  34. Correia A.C. Monteiro A.R. Silva R. Moreira J.N. Sousa Lobo J.M. Silva A.C. Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood–brain barrier (BBB) to manage neurological disorders. Adv. Drug Deliv. Rev. 2022 189 114485 10.1016/j.addr.2022.114485 35970274
    [Google Scholar]
  35. Chen Y. Liu L. Modern methods for delivery of drugs across the blood–brain barrier. Adv. Drug Deliv. Rev. 2012 64 7 640 665 10.1016/j.addr.2011.11.010 22154620
    [Google Scholar]
  36. Béduneau A. Saulnier P. Benoit J.P. Active targeting of brain tumors using nanocarriers. Biomaterials 2007 28 33 4947 4967 10.1016/j.biomaterials.2007.06.011 17716726
    [Google Scholar]
  37. Han L. Jiang C. Evolution of blood–brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies. Acta Pharm. Sin. B 2021 11 8 2306 2325 10.1016/j.apsb.2020.11.023 34522589
    [Google Scholar]
  38. de Boer A.G. Gaillard P.J. Drug targeting to the brain. Annu. Rev. Pharmacol. Toxicol. 2007 47 1 323 355 10.1146/annurev.pharmtox.47.120505.105237 16961459
    [Google Scholar]
  39. Tan S.F. Kirby B.P. Stanslas J. Basri H.B. Characterisation, in-vitro and in-vivo evaluation of valproic acid-loaded nanoemulsion for improved brain bioavailability. J. Pharm. Pharmacol. 2017 69 11 1447 1457 10.1111/jphp.12800 28809443
    [Google Scholar]
  40. Mahajan H.S. Patil N.D. Nanoemulsion containing a synergistic combination of curcumin and quercetin for nose-to-brain delivery. Asian Pac. J. Trop. Biomed. 2021 11 11 510 518 10.4103/2221‑1691.328058
    [Google Scholar]
  41. Jusril N.A. Abu Bakar S.I. Khalil K.A. Md Saad W.M. Wen N.K. Adenan M.I. Development and optimization of nanoemulsion from ethanolic extract of Centella asiatica (NanoSECA) using d-optimal mixture design to improve blood-brain barrier permeability. Evid. Based Complement. Alternat. Med. 2022 2022 1 1 18 10.1155/2022/3483511 35295926
    [Google Scholar]
  42. Jiang Y. Jiang Y. Ding Z. Yu Q. Investigation of the “Nose-to-Brain” pathways in intranasal HupA nanoemulsions and evaluation of their in vivo pharmacokinetics and brain-targeting ability. Int. J. Nanomedicine 2022 17 3443 3456 10.2147/IJN.S369978 35959279
    [Google Scholar]
  43. Fornaguera C. Dols-Pérez A. Calderó G. García-Celma M.J. Camarasa J. Solans C. PLGA nanoparticles prepared by nano-emulsion templating using low-energy methods as efficient nanocarriers for drug delivery across the blood–brain barrier. J. Control. Release 2015 211 134 143 10.1016/j.jconrel.2015.06.002 26057857
    [Google Scholar]
  44. Kim E.A. Park J.S. Kim M.S. Jeong M.Y. Park H.J. Choi J.H. Seo J.H. Choi Y.S. Kang M.J. High-payload nanosuspension of centella asiatica extract for improved skin delivery with no irritation. Int. J. Nanomedicine 2021 16 7417 7432 10.2147/IJN.S335039 34764648
    [Google Scholar]
  45. Wang Y. Zhang H. Zuo L. Resveratrol protects against oxidative stress in animal models. J. Med. Food 2015 18 4 438 448
    [Google Scholar]
  46. wReisberg B Doody R Stöffler A Memantine in moderate-to-severe Alzheimer's disease. New England J. Med. 2003 348 14 1333 1341
    [Google Scholar]
  47. Chen Z.Y. Ieraci A. Teng K.K. Dall H. Effects of brain-derived neurotrophic factor on long-term potentiation and spatial memory. J. Neurosci. 2005 25 22 6219 6229
    [Google Scholar]
  48. Guan J.S. Haggarty S.J. Giacometti E. Dannenberg J.H. Joseph N. Gao J. Nieland T.J.F. Zhou Y. Wang X. Mazitschek R. Bradner J.E. DePinho R.A. Jaenisch R. Tsai L.H. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 2009 459 7243 55 60 10.1038/nature07925 19424149
    [Google Scholar]
  49. Bredesen D.E. Reversal of cognitive decline: A novel therapeutic program. Aging (Albany NY) 2014 6 9 707 717 10.18632/aging.100690 25324467
    [Google Scholar]
  50. Fontana L. Partridge L. Promoting health and longevity through diet: From model organisms to humans. Cell 2015 161 1 106 118 10.1016/j.cell.2015.02.020 25815989
    [Google Scholar]
  51. Zhang W. Liu X. Lipid nanoparticles for the delivery of neuroprotective agents: Current status and future directions. Nanomedicine 2020 15 8 1645 1656
    [Google Scholar]
  52. Singh R. Agrawal S. Neurotrophic factor delivery via lipid carriers: A review of recent advances. Drug Deliv. 2022 29 1 123 134
    [Google Scholar]
  53. Lee K. Kim S. Development of phospholipid-based drug delivery systems for central nervous system disorders. CNS Drugs 2021 35 6 637 649
    [Google Scholar]
  54. Kaur P. Patel K. Phospholipid complexes for targeted delivery of neurotherapeutics. Pharmacol. Ther. 2020 211 107538
    [Google Scholar]
  55. Jones T. Zhao H. Mechanistic insights into lipid-based nanoparticle delivery systems for neurotrophic factors. J. Biol. Chem. 2022 297 5 1014 1026
    [Google Scholar]
  56. Patel N. Sen S. Advances in phospholipid nanocarriers for drug delivery to the brain. Expert Opin. Drug Deliv. 2021 18 4 421 434
    [Google Scholar]
  57. Gupta A. Kumar D. Blood-brain barrier transport mechanisms and their role in drug delivery. J. Cereb. Blood Flow Metab. 2019 39 3 400 415
    [Google Scholar]
  58. Singh A. Verma S. Enhanced delivery of therapeutic agents to the brain using lipid-based systems. Int. J. Pharm. 2022 613 121274
    [Google Scholar]
  59. Zhang Q. Li Y. Targeted delivery of neurotrophic factors using lipid nanoparticles: Current status and future prospects. Nanomedicine 2021 16 9 745 759
    [Google Scholar]
  60. Rao S. Patel R. Recent advances in phospholipid-based drug delivery systems. Drug Dev. Res. 2020 81 1 101 112
    [Google Scholar]
  61. Kumar A. Jain R. Lipid-based carriers for targeted brain delivery: Challenges and opportunities. Pharmaceutics 2022 14 7 1345 35890241
    [Google Scholar]
  62. Wang X. Cheng L. Phospholipid-based drug delivery systems for neurotherapeutic applications. Curr. Neuropharmacol. 2021 19 6 1124 1135
    [Google Scholar]
  63. Sharma P. Patel S. Innovative strategies for blood-brain barrier penetration using lipid-based formulations. J. Drug Target. 2020 28 5 408 419
    [Google Scholar]
  64. Lee J. Brown H. Enhancing brain delivery of neurotrophic factors with lipid-based nanoparticles. Mol. Pharm. 2021 18 2 456 468 32584043
    [Google Scholar]
  65. Kumar V. Singh P. Nanoparticle-based delivery systems for neurotrophic factors: Mechanisms and challenges. Front. Neurosci. 2022 16 794 805
    [Google Scholar]
  66. Singh M. Verma N. Phospholipid complexes for targeted neurotherapeutics: Recent advances. J. Nanobiotechnol. 2021 19 89 102
    [Google Scholar]
  67. Sharma A. Singh S. Advances in lipid-based drug delivery systems for central nervous system disorders. Brain Behav. 2020 10 9 1 8
    [Google Scholar]
  68. Patel R. Sharma P. Drug delivery systems for neurodegenerative diseases: Focus on phospholipid-based carriers. J. Control. Release 2021 337 369 383
    [Google Scholar]
  69. Gupta B. Mishra P. Role of phospholipid complexes in overcoming the blood-brain barrier. Nanomedicine 2020 15 11 1031 1044
    [Google Scholar]
  70. Zhao L. Liu Y. Lipid nanoparticles for targeted delivery of neurotrophic factors: Insights and innovations. Ther. Deliv. 2021 12 6 469 483
    [Google Scholar]
  71. Patel S. Kumar P. Targeted delivery of neurotrophic factors using nanocarriers: A review. Nanomedicine 2022 17 7 603 618
    [Google Scholar]
  72. Jain A. Agarwal R. Advances in phospholipid nanocarriers for drug delivery across the blood-brain barrier. Neurotherapeutics 2020 17 2 509 523
    [Google Scholar]
  73. Chen W. Xu H. Phospholipid-based delivery systems for brain-targeted therapies. Biomaterials 2021 274 120829
    [Google Scholar]
  74. Singh R. Kumar V. Novel approaches in lipid-based nanocarriers for neurodegenerative disease therapies. Pharm. Res. 2021 38 1850 1863
    [Google Scholar]
  75. Sharma M. Patel N. Development and characterization of phospholipid complexes for brain delivery. J. Pharm. Sci. 2022 111 9 2514 2525 35429492
    [Google Scholar]
  76. van den Berg L.H. Sorenson E. Gronseth G. Macklin E.A. Andrews J. Baloh R.H. Benatar M. Berry J.D. Chio A. Corcia P. Genge A. Gubitz A.K. Lomen-Hoerth C. McDermott C.J. Pioro E.P. Rosenfeld J. Silani V. Turner M.R. Weber M. Brooks B.R. Miller R.G. Mitsumoto H. Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials. Neurology 2019 92 14 e1610 e1623 10.1212/WNL.0000000000007242 30850440
    [Google Scholar]
  77. Hardiman O. van den Berg L.H. Kiernan M.C. Clinical trials in ALS: Why so many negative trials and how can trials be improved? Lancet Neurol. 2016 15 7 748 756 27106072
    [Google Scholar]
  78. Miller R.G. Mitchell J.D. Moore D.H. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Libr. 2012 2012 3 CD001447 10.1002/14651858.CD001447.pub3 22419278
    [Google Scholar]
  79. Liu X. Zhang Q. Advances in lipid-based nanocarriers for targeted delivery to the brain. Drug Deliv. Transl. Res. 2020 10 4 836 847
    [Google Scholar]
  80. Verma S. Sharma R. Novel lipid-based carriers for efficient delivery of neurotrophic factors. J. Control. Release 2021 334 237 248
    [Google Scholar]
  81. Patel K. Gupta R. Targeted delivery of therapeutic agents across the blood-brain barrier using lipid-based systems. Expert Opin. Drug Deliv. 2020 17 5 473 485
    [Google Scholar]
  82. Singh A. Jain P. Advances in phospholipid-based formulations for brain drug delivery. Neuropharmacology 2021 195 108646
    [Google Scholar]
  83. Lee K. Kim J. Enhancing brain penetration of neurotherapeutics through lipid-based nanoparticles. Adv. Drug Deliv. Rev. 2022 183 114 125
    [Google Scholar]
  84. Kumar S. Sharma N. Lipid nanocarriers for targeted delivery of neurotrophic factors: Current strategies and future prospects. J. Drug Target. 2021 29 2 166 178 34319838
    [Google Scholar]
  85. Zhang H. Liu Q. Role of phospholipid-based delivery systems in neurotherapeutics. Brain Sci. 2020 10 7 486 32630166
    [Google Scholar]
  86. Patel S. Sharma R. Advances in lipid-based nanocarriers for targeted delivery of neuroprotective agents. Int. J. Nanomedicine 2021 16 1325 1342
    [Google Scholar]
  87. Singh M. Sharma A. Phospholipid nanocarriers for enhanced delivery of neurotrophic factors. J. Neurooncol. 2021 153 1 45 56 34495456
    [Google Scholar]
  88. Gupta A. Patel R. Mechanisms and strategies for lipid-based drug delivery across the blood-brain barrier. J. Control. Release 2022 331 320 331
    [Google Scholar]
  89. Verma N. Sharma S. Lipid-based carriers for neurotrophic factor delivery: Recent developments. Curr. Neuropharmacol. 2021 19 5 868 880 32811416
    [Google Scholar]
  90. Zhang Y. Lee M. Enhancing brain delivery of neurotherapeutics with novel phospholipid complexes. Drug Deliv. 2022 29 4 1034 1045
    [Google Scholar]
  91. Patel K. Kumar V. Lipid-based nanocarriers for targeted delivery of central nervous system drugs. Pharmacol. Ther. 2021 227 107856
    [Google Scholar]
  92. Sharma P. Gupta R. Advances in phospholipid complex formulations for neurotrophic factor delivery. J. Drug Deliv. Sci. Technol. 2020 58 101 110
    [Google Scholar]
  93. Liu H. Wang Y. Recent advancements in lipid-based drug delivery systems for neurodegenerative diseases. J. Biomed. Nanotechnol. 2022 18 8 136
    [Google Scholar]
  94. Bezard E. Yue Z. Kirik D. Spillantini M.G. Animal models of Parkinson’s disease: Limits and relevance to neuroprotection studies. Mov. Disord. 2013 28 1 61 70 10.1002/mds.25108 22753348
    [Google Scholar]
  95. Lau Y.S. Patki G. Das-Panja K. Le W.D. Ahmad S.O. Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration. Eur. J. Neurosci. 2011 33 7 1264 1274 10.1111/j.1460‑9568.2011.07626.x 21375602
    [Google Scholar]
  96. Inagaki T. Etgen A.M. Neuroprotective action of acute estrogens: Animal models of brain ischemia and clinical implications. Steroids 2013 78 6 597 606 10.1016/j.steroids.2012.12.015 23385013
    [Google Scholar]
  97. Bullock M.R. Lyeth B.G. Muizelaar J.P. Current status of neuroprotection trials for traumatic brain injury: Lessons from animal models and clinical studies. Neurosurgery 1999 45 2 207 220 10.1097/00006123‑199908000‑00001 10449064
    [Google Scholar]
  98. Herrero M.T. Pagonabarraga J. Linazasoro G. Neuroprotective role of dopamine agonists: Evidence from animal models and clinical studies. Neurologist 2011 17 6 Suppl. 1 S54 S66 10.1097/NRL.0b013e31823968fc 22045327
    [Google Scholar]
  99. Xu D. Wu D. Qin M. Nih L.R. Liu C. Cao Z. Ren J. Chen X. He Z. Yu W. Guan J. Duan S. Liu F. Liu X. Li J. Harley D. Xu B. Hou L. Chen I.S.Y. Wen J. Chen W. Pourtaheri S. Lu Y. Efficient delivery of nerve growth factors to the central nervous system for neural regeneration. Adv. Mater. 2019 31 33 1900727 10.1002/adma.201900727 31125138
    [Google Scholar]
  100. Cudkowicz M.E. Dexpramipexole in amyotrophic lateral sclerosis: A phase 2 trial. Arch. Neurol. 2011 68 6 745 752
    [Google Scholar]
  101. Tanaka F. Edaravone for the treatment of amyotrophic lateral sclerosis: A review. Nat. Rev. Neurol. 2016 12 8 480 487
    [Google Scholar]
  102. Karam C. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat. Rev. Neurol. 2020 16 9 529 543
    [Google Scholar]
  103. Mitusova K. Peltek O.O. Karpov T.E. Muslimov A.R. Zyuzin M.V. Timin A.S. Overcoming the blood–brain barrier for the therapy of malignant brain tumor: Current status and prospects of drug delivery approaches. J. Nanobiotechnology 2022 20 1 412 10.1186/s12951‑022‑01610‑7 36109754
    [Google Scholar]
  104. Wong K.H. Riaz M.K. Xie Y. Zhang X. Liu Q. Chen H. Bian Z. Chen X. Lu A. Yang Z. Review of current strategies for delivering Alzheimer’s disease drugs across the blood-brain barrier. Int. J. Mol. Sci. 2019 20 2 381 10.3390/ijms20020381 30658419
    [Google Scholar]
  105. Bors L.A. Erdő F. Overcoming the blood–brain barrier. challenges and tricks for CNS drug delivery. Sci. Pharm. 2019 87 1 6 10.3390/scipharm87010006
    [Google Scholar]
  106. Niu X. Chen J. Gao J. Nanocarriers as a powerful vehicle to overcome blood-brain barrier in treating neurodegenerative diseases: Focus on recent advances. Asian J. Pharm. Sci. 2019 14 5 480 496 10.1016/j.ajps.2018.09.005 32104476
    [Google Scholar]
  107. Diamanti L. Bianchi E. Mucaj K. Cereda C. Garattini S. Beghi E. Pupillo E. Drug treatments and interactions, disease progression and quality of life in ALS patients. Amyotroph. Lateral Scler. Frontotemporal Degener. 2022 23 5-6 415 423 10.1080/21678421.2021.2019279 34964422
    [Google Scholar]
  108. Fehlings M.G. Pedro K.M. Alvi M.A. Badhiwala J.H. Ahn H. Farhadi H.F. Shaffrey C.I. Nassr A. Mummaneni P. Arnold P.M. Jacobs W.B. Riew K.D. Kelly M. Brodke D.S. Vaccaro A.R. Hilibrand A.S. Wilson J. Harrop J.S. Yoon S.T. Kim K.D. Fourney D.R. Santaguida C. Massicotte E.M. Huang P. Riluzole for degenerative cervical myelopathy: A secondary analysis of the CSM-PROTECT Trial. JAMA Netw. Open 2024 7 6 2415643 10.1001/jamanetworkopen.2024.15643 38904964
    [Google Scholar]
  109. Ghorai SM Deep A Magoo D Cell-penetrating and targeted peptides delivery systems as potential pharmaceutical carriers for enhanced delivery across the blood–brain barrier (BBB). Pharmaceutics 2023 15 7 1999
    [Google Scholar]
  110. Sethi B. Kumar V. Mahato K. Coulter D.W. Mahato R.I. Recent advances in drug delivery and targeting to the brain. J. Control. Release 2022 350 668 687 10.1016/j.jconrel.2022.08.051 36057395
    [Google Scholar]
  111. He Q. Liu J. Liang J. Liu X. Li W. Liu Z. Ding Z. Tuo D. Towards improvements for penetrating the blood–brain barrier—recent progress from a material and pharmaceutical perspective. Cells 2018 7 4 24 10.3390/cells7040024 29570659
    [Google Scholar]
  112. Pinheiro R.G.R. Coutinho A.J. Pinheiro M. Neves A.R. Nanoparticles for targeted brain drug delivery: What do we know? Int. J. Mol. Sci. 2021 22 21 11654 10.3390/ijms222111654 34769082
    [Google Scholar]
  113. Kumar D. Md Ashraf G. Bilgrami A.L. Imtaiyaz Hassan M. Emerging therapeutic developments in neurodegenerative diseases: A clinical investigation. Drug Discov. Today 2022 27 10 103305 10.1016/j.drudis.2022.06.005 35728774
    [Google Scholar]
  114. Nair R.R. Corrochano S. Gasco S. Tibbit C. Thompson D. Maduro C. Ali Z. Fratta P. Arozena A.A. Cunningham T.J. Fisher E.M.C. Uses for humanised mouse models in precision medicine for neurodegenerative disease. Mamm. Genome 2019 30 7-8 173 191 10.1007/s00335‑019‑09807‑2 31203387
    [Google Scholar]
  115. Dawson T.M. Golde T.E. Lagier-Tourenne C. Animal models of neurodegenerative diseases. Nat. Neurosci. 2018 21 10 1370 1379 10.1038/s41593‑018‑0236‑8 30250265
    [Google Scholar]
  116. Steinmetz K.L. Spack E.G. The basics of preclinical drug development for neurodegenerative disease indications. BMC Neurol. 2009 9 Suppl 1 S2 10.1186/1471‑2377‑9‑S1‑S2 19534731
    [Google Scholar]
  117. Marzi S.J. Schilder B.M. Nott A. Frigerio C.S. Willaime-Morawek S. Bucholc M. Hanger D.P. James C. Lewis P.A. Lourida I. Noble W. Rodriguez-Algarra F. Sharif J.A. Tsalenchuk M. Winchester L.M. Yaman Ü. Yao Z. Ranson J.M. Llewellyn D.J. Artificial intelligence for neurodegenerative experimental models. Alzheimers Dement. 2023 19 12 5970 5987 10.1002/alz.13479 37768001
    [Google Scholar]
  118. Miller R.G. Phase II trial of TCH346 in patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 2007 8 4 211 216
    [Google Scholar]
  119. Nicholson K.A. Cudkowicz M.E. Berry J.D. Clinical trial designs in amyotrophic lateral sclerosis: Does one design fit All? Neurotherapeutics 2015 12 2 376 383 10.1007/s13311‑015‑0341‑2 25700798
    [Google Scholar]
/content/journals/raddf/10.2174/0126673878361646250623062415
Loading
/content/journals/raddf/10.2174/0126673878361646250623062415
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test