Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs)
Abstract
:1. Introduction
2. Pathophysiology of Perinatal Hypoxia-Ischemic Brain Injury
2.1. Initiation of the Pathophysiological Cascade in HIE
2.2. Excitotoxicity
2.3. Oxidative Stress
2.4. Mitochondrial Dysfunction
2.5. Inflammation
3. Current Clinical Treatments: Hypothermia
4. Neuroprotective Peptides and Their Therapeutic Application in HIE
4.1. Peptide Therapeutics
4.2. CARPs Are Intrinsically Neuroprotective
4.3. Cationic Arginine-Rich Cell-Penetrating Peptide Neuroprotective Mechanisms of Actions
4.4. Studies Using CARPs in Animal Models of HIE
4.4.1. TAT-NEMO Binding Domain (NBD)
4.4.2. TAT-mGluR1
4.4.3. c-Jun N-Terminal Kinase (JNK) Inhibitors
4.4.4. TAT-BH4
4.4.5. Osteopontin (OPN) and TAT-Fused OPN Peptide (TAT-OPN)
4.4.6. P5-TAT
4.4.7. D-TAT-GESV
4.4.8. TAT-NR2B9c/NA-1
4.4.9. Poly-Arginine-18 (R18 and R18D)
4.5. Other Peptides Examined in Animal Models of HIE
4.5.1. COG133
4.5.2. Connexin 43 (Cx43) Derived Peptides
4.5.3. Apelin-36
4.5.4. Innate Defense Regulator (IDR) Peptide IDR-1018
5. Do All CARPs Including TAT-Fused Peptides Share a Common Neuroprotective Mechanism of Action?
6. Conclusions
7. Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Peptide/Protein Name; Net Charge a | Proposed Target b | Peptide Sequence c | Injury Model d | Route & Time before/after HI Agent Administered e | Dose | NP f | Study |
---|---|---|---|---|---|---|---|
TAT-NBD; +6 | NFκB | TAT-TALDWSWLQTE | P7 (W): CCAO/8% O2; 120 min | IP: 0 & 3 h, or 0, 3, 6, 9 or 12 h | 6917 nmol/kg | Yes, up to 6 h | [105] |
IP: 0 & 3 h, or 0, 9 & 12 h, or 18 & 21 h | 6817 nmol/kg | Yes, only for 0 & 3 h | [106] | ||||
IP: 0 & 3 h | 6818 nmol.kg | Yes | [107] | ||||
P7 (W): CCAO/10% O2; 90 min + LPS 4 or 72 h before hypoxia | IN; 10 min | 477 nmol/kg | Yes, only for LPS | [108] | |||
TAT-mGluR1; +3 | Calpain | TAT-VIKPLTKSYQGSGK | P7 (SD): CCAO/8% O2; 150 min | IP: −1 h | 58,590 nmol/kg | Yes | [111] |
D-JNKI-1; +4 | JIP | tdqsrpvqpflnlttprkpr-NH2 | P7 (SD): CCAO/8% O2; 120 min | IP, −0.5, 3, 5, 8, 12 and 20 h | 76 nmol/kg | No | [115] |
JNKI-1-TATL; +12 | TAT-PPRPKRPTTLNLFPQVPRSQDT-NH2 | P7 (W): CCAO/8% O2; 120 min | IP: 0 and 3 h, or 3 h or 6 h | 2446 nmol/kg | Yes, except 6 h | [118] | |
JNKI-1-TATD; +12 SabKIM1 +7 | tdqsrpvqpflnlttprkpr-pp-tat-NH2 lpsvfgdvgapsrlpevsls-pp-tat | P7 (W): CCAO/8% O2; 120 min | IP: 0, 3 or 6 h, or 0 & 3 h IP: 0 h | 2616 nmol/kg 2777 or 5555 nmol/kg | Yes except 0 & 3 h Yes | [119] | |
JNKI-1-TATD; +12 | tdqsrpvqpflnlttprkpr-pp-tat-NH2 | P7 (SD): ECA/CCAO/8% O2; 150 min | IP: 0 min | 1000 nmol/kg | No | [22] | |
TAT-BH4; +2.1 | Apoptosis | TAT-RTGYDNREIVMKYIHYKLSQRGYEW | P7 (SD♂): CCAO/8% O2; 150 min | ICV: −0.5 h | 5 µL/20 ng | Yes | [122] |
T-OPN OPN134–153; 0 OPN154–198; −4.9 | αvβ3 integrin receptor | Thrombin cleaved OPN IVPTVDVPNGRGDSLAYR SKSRSFQVSDEQYPDATDEDLTSHMKSGESKESLDVIPVAQLLSM | P5 (C57B6/6J): CCAO/10% O2; 70 min | IN: −70 min IN or ICV: −70 min ICV: −70 min | 1.2 µg IN: 30 µg/ICV: 0.2 µg 0.5 µg | No | [135] |
TAT-OPN; +8 | TAT-IVPTVDVPNGRGDSLAYGLR | P9 (C57BL/6N): CCAO/10% O2; 50 min | IN: 0 h or 0 & 3 h, or 0, 3 h, 1, 2 & 3 d IP: 0 h, or 5, 7, 9, 11, 13, 15 d, or 0, 1, 3, 5, 7, 9, 11, 13, 15 d ICV: 1 h | 350 or 2100 ng 2746 nmol/kg 100 ng | No | [136] | |
P5-TAT; +8.9 | P35 | KEAFWDRCLSVINLMSSKMLQINA-TAT | P7 (SD): CCAO/8% O2; 150 min | IP: −1 h IP: 24 h | 0.23, 2.3, 5.76, or 11.5 nmol/kg 11.5 nmol/kg | Yes, except 0.23 nmol/kg | [143] |
D-TAT-GESV; +7 | NOS | ygrkkrrqrrr-GESV | P7 (SD♂); CCAO/8% O2; 120 min | ICV: −120 min | 100 ng/animal | Yes | [145] |
TAT-NR2B9c; +7 | PSD-95 | TAT-KLSSIESDV | P7 (CD1): CCAO/7.5%; 60 min | IP: −110 or −20 min | 3000 nmol/kg | Yes | [147] |
R18; +18 R18D; +18 | Multiple | RRRRRRRRRRRRRRRRRR rrrrrrrrrrrrrrrrrr | P7 (SD): ECA/CCAO/8% O2; 150 min | IP: 0 h | 30, 100, 300 or 1000 nmol/kg | Yes | [22] |
R18D; +18 | rrrrrrrrrrrrrrrrrr | IP: +0.5 h IP: +1 h IP: +1.5 h | 10, 30, 100, 300 or 1000 nmol/kg 30 or 300 nmol/kg 30 or 300 nmol/kg | Yes, except 100 nmol/kg Yes, except 300 nmol/kg No | [21] | ||
COG133; 5.1 | LDLR | Ac-TEELRVRLASHLRKLRKRLL-NH2 | P7 (W): CCAO/8% O2; 150 min | ICV: −0 h | 40, 200, 300, 400, or 2000 nmol/kg | Yes, except 300 nmol/kg | [151] |
Peptide 5; +1 | Cx43 astrocytic hemichannel | VDKFLSRPTEKT | GD128 (Romney/Suffolk sheep): bilateral tCCAO; 30 min | ICV: 1.5 h | 50,000 nmol/kg/h for 1 h ± 50,000 nmol/kg/24 h for 24 h | Yes | [161] |
ICV: −1 h or 0 h | 50,000 nmol/kg/h: 1 h + 50,000 nmol/kg/24 h for 24 h | Yes, except −1 h | [162] | ||||
ICV: 0 h | 50,000 nmol/kg/h: 1 h + 50,000 nmol/kg/24 h for 24 h 50,000 nmol/kg/h for 25 h | Yes, except high continuous dose | [163] | ||||
ICV: 3 h ± Hypothermia: 32 °C for 72 h; 3 h after tCCAO | 50,000 nmol/kg/h for 1 h + 50,000 nmol/kg/24 h for 24 h | Yes, no additive effect | [165] | ||||
GD103 (Romney/Suffolk sheep): bilateral tCCAO for 25 min | ICV: 1.5 h | 50,000 nmol/kg/h for 1 h + 50,000 nmol/kg/24 h for 24 h | Yes | [164] | |||
Gap 26; +1 Gap 27; +1 | VCYDKSFPISHVR SRPTEKTIFII | P7 (SD): CCAO/8% O2; 150 min | IP: −1 h IP: daily for 1 to 7 d IP: −1 h | 0.64, 3.22, 6.44, 16.1, or 32.2 nmol/kg 32.2 nmol/kg 16.1 nmol/kg | Yes, except 0.64 and 3.22 nmol/kg Yes | [166] | |
Apelin-36; +10.1 | Apelin receptor | LVQPRGSRNGPGPWQGGRRKFRRQRPRLSHKGPMPF | P7 (SD): CCAO8% O2; 150 min | IP: −1 h | 240 nmol/kg | Yes | [172] |
IDR-1018; +5 | Immune modulation | VRLIVAVRIWRR-NH2 | P9 (C57BL/6J): CCAO/10% O2; 20 min + LPS 14 h before hypoxia | IP: −4 h or 3 h | 5208 nmol/kg | Yes | [175] |
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Edwards, A.B.; Anderton, R.S.; Knuckey, N.W.; Meloni, B.P. Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs). Brain Sci. 2018, 8, 147. https://doi.org/10.3390/brainsci8080147
Edwards AB, Anderton RS, Knuckey NW, Meloni BP. Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs). Brain Sciences. 2018; 8(8):147. https://doi.org/10.3390/brainsci8080147
Chicago/Turabian StyleEdwards, Adam B., Ryan S. Anderton, Neville W. Knuckey, and Bruno P. Meloni. 2018. "Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs)" Brain Sciences 8, no. 8: 147. https://doi.org/10.3390/brainsci8080147