Optimized liposomes with transactivator of transcription peptide and anti-apoptotic drugs to target hippocampal neurons and prevent tau-hyperphosphorylated neurodegeneration.

Abstract

Liposomes (lip) carrying pharmaceuticals have shown promise in their ability to advance the therapy for neurodegenerative diseases. However, the low nerve-targeting capacity and poor penetration rate of lip through the blood-brain barrier (BBB) are major hurdles to achieving successful treatment. Herein, we developed lip incorporating cardiolipin (CL) and phosphatidic acid (PA) to promote their capability against hyperphosphorylation of tau protein, and a transactivator of transcription (TAT) peptide to permeate the BBB for delivering nerve growth factor (NGF), rosmarinic acid (RA), curcumin (CURC) and quercetin (QU). We derived an optimization method to assess a better composition of phospholipids in the lip loaded with the four medicines. Experimental results revealed that this optimized lip increased the viability of SK-N-MC cells insulted with β-amyloid peptide (Aβ) fibrils and prevented Wistar rat brain from producing hyperphosphorylated tau. CL and PA and the grafted TAT peptide on the carrier surface improved the rescue efficiency by inhibiting Aβ deposition and reducing the expressions of phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), c-Jun N-terminal protein kinase, p38, tau at serine 202 and caspase-3. The lip also enhanced the expressions of p-ERK5 and p-cyclic adenosine monophosphate response element-binding protein. The amalgamated activity of NGF, RA, CURC and QU, and the effect of charged CL/PA on Aβ deposits supported the therapeutic efficacy of lip. The optimized TAT-NGF-RA-CURC-QU-CL/PA-lip can be a capable drug delivery system to cross the BBB and protect Alzheimer's disease brains from tau hyperphosphorylation. STATEMENTS OF SIGNIFICANCE: The therapeutic efficiency of liposomes (lip) against neurodegenerative disorder depends on their nerve-targeting capacity and ability to permeate the blood-brain barrier (BBB). Lip was developed incorporating cardiolipin (CL) and phosphatidic acid (PA) to promote their target specificity against hyperphosphorylation of tau protein, and a transactivator of transcription (TAT) peptide to permeate the BBB. We have successfully derived an optimization method using a new mathematical expression for the first time to assess a better composition of phospholipids in lip loaded with nerve growth factor (NGF), rosmarinic acid (RA), curcumin (CURC) and quercetin (QU). The optimized TAT-NGF-RA-CURC-QU-CL/PA-lip efficaciously down-regulated the expressions of phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), c-Jun N-terminal protein kinase, p38, tau at serine 202 and caspase-3, and up-regulated the expressions of p-ERK5 and p-cyclic adenosine monophosphate response element-binding protein in Alzheimer's disease Wistar rat model.

• Authors: Yung-Chih Kuo, Chang-Li Chen, Rajendiran Rajesh
• Journal: Acta biomaterialia (Acta Biomater) Vol. 87 Pg. 207-222 (03 15 2019) ISSN: 1878-7568 [Electronic] England
• PMID: 30716553 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Liposomes
• NGF protein, human
• Trans-Activators
• tau Proteins
• Nerve Growth Factor
• Quercetin
• Curcumin

Topics

• Alzheimer Disease (drug therapy, metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Apoptosis (drug effects)
• Blood-Brain Barrier (metabolism, pathology)
• Curcumin (chemistry, pharmacokinetics, pharmacology)
• Hippocampus (metabolism, pathology)
• Humans
• Liposomes
• Nerve Growth Factor (chemistry, pharmacokinetics, pharmacology)
• Neurons (metabolism, pathology)
• Quercetin (chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Wistar
• Trans-Activators (chemistry, pharmacokinetics, pharmacology)
• tau Proteins (metabolism)