Oxysterols in Central and Peripheral Synaptic Communication

Cholesterol is a key molecule for synaptic transmission, and both central and peripheral synapses are cholesterol rich. During intense neuronal activity, a substantial portion of synaptic cholesterol can be oxidized by either enzymatic or non-enzymatic pathways to form oxysterols, which in turn modulate the activities of neurotransmitter receptors (e.g., NMDA and adrenergic receptors), signaling molecules (nitric oxide synthases, protein kinase C, liver X receptors), and synaptic vesicle cycling involved in neurotransmitters release. 24-Hydroxycholesterol, produced by neurons in the brain, could directly affect neighboring synapses and change neurotransmission. 27-Hydroxycholesterol, which can cross the blood-brain barrier, can alter both synaptogenesis and synaptic plasticity. Increased generation of 25-hydroxycholesterol by activated microglia and macrophages could link inflammatory processes to learning and neuronal regulation. Amyloids and oxidative stress can lead to an increase in the levels of ring-oxidized sterols and some of these oxysterols (4-cholesten-3-one, 5α-cholestan-3-one, 7β-hydroxycholesterol, 7-ketocholesterol) have a high potency to disturb or modulate neurotransmission at both the presynaptic and postsynaptic levels. Overall, oxysterols could be used as "molecular prototypes" for therapeutic approaches. Analogs of 24-hydroxycholesterol (SGE-301, SGE-550, SAGE718) can be used for correction of NMDA receptor hypofunction-related states, whereas inhibitors of cholesterol 24-hydroxylase, cholestane-3β,5α,6β-triol, and cholest-4-en-3-one oxime (olesoxime) can be utilized as potential anti-epileptic drugs and (or) protectors from excitotoxicity.