Novel Synthetic PEGylated Conjugate of α-Lipoic Acid and Tempol Reduces Cell Death in a Neuronal PC12 Clonal Line Subjected to Ischemia.

Abstract

α-Lipoic acid (α-LA), a natural thiol antioxidant, and Tempol, a synthetic free radical scavenger, are known to confer neuroprotection following ischemic insults in both in vivo and in vitro models. The aim of this study was to synthesize and characterize a conjugate of α-LA and Tempol linked by polyethylene glycol (PEG) in order to generate a more efficacious neuroprotectant molecule. AD3 (α-Tempol ester-ω-lipo ester PEG) was synthesized, purified, and characterized by flash chromatography and reverse phase high pressure liquid chromatography and by 1H nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry. AD3 conferred neuroprotection in a PC12 pheochromocytoma cell line of dopaminergic origin, exposed to oxygen and glucose deprivation (OGD) insult measured by LDH release. AD3 exhibited EC50 at 10 μM and showed a 2-3-fold higher efficacy compared to the precursor moieties, indicating an intrinsic potent neuroprotective activity. AD3 attenuated by 25% the intracellular redox potential, by 54% lipid peroxidation and prevented phosphorylation of ERK, JNK, and p38 by 57%, 22%, and 21%, respectively. Cumulatively, these findings indicate that AD3 is a novel conjugate that confers neuroprotection by attenuation of MAPK phosphorylation and by modulation of the redox potential of the cells.

• Authors: Adi Lahiani, Adel Hidmi, Jehoshua Katzhendler, Ephraim Yavin, Philip Lazarovici
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 7 Issue 10 Pg. 1452-1462 (10 19 2016) ISSN: 1948-7193 [Electronic] United States
• PMID: 27499112 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Cyclic N-Oxides
• Free Radical Scavengers
• Neuroprotective Agents
• Spin Labels
• Polyethylene Glycols
• Thioctic Acid
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Glucose
• tempol

Topics

• Animals
• Antioxidants (chemistry)
• Cell Death (drug effects, physiology)
• Cell Hypoxia (drug effects, physiology)
• Cyclic N-Oxides (chemical synthesis, chemistry, pharmacology, toxicity)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Free Radical Scavengers (chemistry)
• Glucose (deficiency)
• Lipid Peroxidation (drug effects)
• MAP Kinase Kinase 4 (metabolism)
• Neuroprotective Agents (chemical synthesis, pharmacology, toxicity)
• Oxidative Stress (drug effects, physiology)
• PC12 Cells
• Phosphorylation (drug effects)
• Polyethylene Glycols (chemical synthesis, chemistry, pharmacology, toxicity)
• Rats
• Spin Labels
• Thioctic Acid (analogs & derivatives, chemical synthesis, chemistry, pharmacology, toxicity)
• p38 Mitogen-Activated Protein Kinases (metabolism)