Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?
Abstract
:1. Introduction
2. The CNS Barriers: A Protection System
2.1. Organization and Functions of the Normal BBB and BSCB
2.2. The CNS Barriers: A Burden for Brain-Targeted Therapeutics
2.2.1. Mode of Administration
2.2.2. Engineering of Drugs
2.2.3. Permeabilization of the BBB
3. Strategies to Evaluate the BBB Integrity
4. BBB Alterations in ALS and Their Consequences
4.1. Role of Alteration of the BBB in the Pathogenesis of ALS
4.1.1. Findings from Animal Models
4.1.2. Findings from Human Patients
4.1.3. Further Necessary Investigations
4.2. Impact of the BBB Alterations on Drug Pharmacokinetics in ALS
4.2.1. Upregulation of Efflux Transporters
4.2.2. Drugs Diffusion into the Brain after Crossing the Barrier
4.2.3. Limitation of Barrier Bypass Strategies by BBB Alterations
4.2.4. Spatial and Temporal Alterations: A Source of Variability
5. Therapeutic Strategies by Correcting BBB/BSCB Alterations
5.1. Previous Attempts in ALS
5.2. Recent Advances with Direct and Indirect BHE Targeting
5.2.1. Stem-Cell Therapies in Human
5.2.2. Targeting Oxidative Stress and Inflammation
5.2.3. BBB Restoration in Combination of BBB-Opening Strategy
6. Therapeutic Strategies to Overcome BBB in ALS
7. Conclusions: Taking Advantage of BBB/BSCB Alterations or Restoring the Barriers to Optimize Therapy in ALS?
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Method | Advantages | Disadvantages |
---|---|---|
Mode of administration | ||
Intrathecal injection | Clinically applicable, various therapeutics | Highly invasive, distribution limited near the injection site |
Convection-enhanced delivery | Clinically applicable, various therapeutics, pressure-driven delivery | Highly invasive (surgical procedure), distribution limited |
Intranasal administration | Non-invasive | Variability, reduction of efficiency with molecular weight |
Drug modification | ||
Lipidization | Non-invasive | For water-soluble molecules, rapid elimination |
Receptor-mediated transcytosis | Non-invasive, highly specific | Potential toxicity by interference with endogenous ligand |
Carrier-Mediated transcytosis | Non-invasive, highly specific | Limited to small molecules |
Nanoparticles | Non-invasive, variety of carriers, various therapeutics | Technically challenging, rapid degradation |
Neurotropic viruses | Delivery of genes to specific sites in the CNS | Often combined with invasive mode of administration, currently limited to gene therapy, risk of autoimmunity |
Neurotropic cells | Delivery of RNA, peptides, proteins or nanoparticles to specific sites in the CNS | Potential toxicity |
BBB/BSCB modifications | ||
Osmotic disruption | Clinically applicable, various therapeutics | Potential entry of blood neurotoxic compounds |
Tight junction downregulation | Various therapeutics | Potential entry of blood neurotoxic compounds, translation to humans limited |
Efflux transporter downregulation | Non-invasive | Limited to substrates of efflux transporters, potential toxicity |
Focused ultrasounds | Various therapeutics, target of specific sites | Potential entry of blood neurotoxic compounds |
Animal Findings | Human Findings | |||
---|---|---|---|---|
Parameter | Result | References | Result | References |
Ultrastructure | Degeneration of ECs, BM thickening, extracellular edema | [1,2,3] | Degeneration of ECs, BM thickening, collagen IV accumulation, extracellular edema | [17] |
Cells infiltration | Erythrocytes infiltration | [1] | Erythrocytes infiltration | [18] |
Immune cells infiltration | [1,4,5,6,7] | Immunes cells infiltration | [19,20] | |
Entry of blood components | IgG deposits | [4,5,8] | IgG deposits | [17,21,22] |
Hemosiderin deposits | [4,5,8] | Hemosiderin deposits | [18] | |
Fibrin deposits | [2] | Fibrin deposits | [17,18] | |
Hemoglobin deposits | [18,23] | |||
Thrombin deposits | [18] | |||
Astrocytes | Astrocytosis | [5,7,9] | ||
Endfeet degeneration | [3,10,11] | Endfeet degeneration | [11] | |
Microglia | Microgliosis | [1,2,5,6,9] | Microgliosis | [22,24] |
Pericytes | ↑ PDGFRβ | [2,5] | Loss of pericytes | [17,18,25] |
TJs | ↓ mRNA expression | [3] | ↓ mRNA expression | [26] |
↓ protein expression | [2,4,12] | ↓ protein expression | [17] | |
No variation of expression | [23] | |||
Structurally normal (TEM) | [1] | Structurally normal (TEM) | [17] | |
Disruption of TJs (TEM) | [2] | |||
Efflux transporter | ↑ P-gp expression and functionality | [13,14] | ↑ P-gp expression | [13,27] |
↑ BCRP expression | [13] | ↑ BCRP expression | [13,27] | |
No modification BCRP expression | [14] | |||
Aquaporins | ↑AQP4 expression | [6,8,15] | ↑ AQP4 expression | [8] |
Circulant markers | ↑ QAlb, QIgG CSF TP, CSF IgG CSF albumin, CSF hemoglobin in some ALS patients | [23,28,29,30,31,32] | ||
Association with disease progression | [32] | |||
No association with disease progression | [28] | |||
Onset of BBB disruption | Presymptomatic stage | [2,11,12] | ||
After apparition of symptom | [3,9,16] | |||
Tracer leakage | Sodium fluorescein | [16] | ||
Evans blue | [10,15] |
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Alarcan, H.; Al Ojaimi, Y.; Lanznaster, D.; Escoffre, J.-M.; Corcia, P.; Vourc’h, P.; Andres, C.R.; Veyrat-Durebex, C.; Blasco, H. Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS? J. Pers. Med. 2022, 12, 1071. https://doi.org/10.3390/jpm12071071
Alarcan H, Al Ojaimi Y, Lanznaster D, Escoffre J-M, Corcia P, Vourc’h P, Andres CR, Veyrat-Durebex C, Blasco H. Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS? Journal of Personalized Medicine. 2022; 12(7):1071. https://doi.org/10.3390/jpm12071071
Chicago/Turabian StyleAlarcan, Hugo, Yara Al Ojaimi, Debora Lanznaster, Jean-Michel Escoffre, Philippe Corcia, Patrick Vourc’h, Christian R. Andres, Charlotte Veyrat-Durebex, and Hélène Blasco. 2022. "Taking Advantages of Blood–Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?" Journal of Personalized Medicine 12, no. 7: 1071. https://doi.org/10.3390/jpm12071071