J Korean Neurol Assoc.  2008 Aug;26(3):231-238.

Inhibitory Effect of Tyrphostin AG126 on Brain Synaptosomal Dysfunction Induced by Cholesterol Oxidation Products

• Hong KM
• Han JH
• Kim DE
• Song JH
• Lee CS

Abstract

BACKGROUND
Formation of cholesterol oxidation products is a suggested mechanism of neurodegenerative disorders. Neuronal cell death is mediated by an increased release of excitotoxic glutamate from the presynaptic nerve endings. Tyrosine-specific protein kinases modulate neurotransmitter release at the nerve terminals. Tyrphostin AG126 has anti-inflammatory and cytoprotective effects. However, it remains uncertain whether tyrphostin AG126 has a preventive effect on the alteration of nerve terminal function induced by cholesterol oxidation products.
METHODS
The present study was performed to assess the effect of cholesterol oxidation products against nerve terminal function using synaptosomes isolated from rat cerebrum. We determined the preventive effect of tyrphostin AG126 against oxysterol toxicity by measuring the effects on the glutamate release, depolarization of the membrane potential, changes in Ca2+ levels, and Na+/K+-ATPase activity.
RESULTS
Synaptosomes treated with 7-ketocholesterol or 25-hydroxycholesterol exhibited a sustained release of glutamate, depolarization of membrane potential, early rapid increase in cellular Ca2+ levels and decrease in Na+/K+-ATPase activity. Those responses were concentration-dependent. Treatment of tyrphostin AG126 interfered with alteration of synaptosomal functions and decrease in Na+/K+-ATPase activity induced by 7-ketocholesterol or 25-hydroxycholesterol.
CONCLUSIONS
The results show that 7-ketocholesterol and 25-hydroxycholesterol seem to cause the release of glutamate by inducing depolarization of the membrane potential and early rapid increase in cellular Ca2+ levels and by inactivating Na+/K+-ATPase in the cerebral synaptosomes. Treatment of tyrphostin AG126 may prevent the oxysterol-induced nerve terminal dysfunction.

Keyword

Synaptosomes; Oxysterols; Tyrphostin AG126; Glutamate; Ca2+; Na+/K+-ATPase

MeSH Terms

Animals
Brain
Cell Death
Cerebrum
Cholesterol
Glutamic Acid
Hydroxycholesterols
Ketocholesterols
Membrane Potentials
Neurodegenerative Diseases
Neurons
Neurotransmitter Agents
Presynaptic Terminals
Protein-Tyrosine Kinases
Rats
Synaptosomes
Tyrphostins
Cholesterol
Glutamic Acid
Hydroxycholesterols
Ketocholesterols
Neurotransmitter Agents
Protein-Tyrosine Kinases
Tyrphostins