Abstract
Lipophilic statins which are blood brain barrier (BBB) permeable are speculated to affect the cholesterol synthesis and neural functions in the central nervous system. However, whether these statins can affect cholesterol levels and synaptic plasticity in hippocampus and the in vivo consequence remain unclear. Here, we report that long-term subcutaneous treatments of simvastatin significantly impair mouse hippocampal synaptic plasticity, reflected by the attenuated long-term potentiation of field excitatory postsynaptic potentials. The simvastatin administration causes a deficiency in recognition and spatial memory but fails to affect motor ability and anxiety behaviors in the mice. Mass spectrometry imaging indicates a significant decrease in cholesterol intensity in hippocampus of the mice receiving chronic simvastatin treatments. Such effects of simvastatin are transient because drug discontinuation can restore the hippocampal cholesterol level and synaptic plasticity and the memory function. These findings may provide further clues to elucidate the mechanisms of neurological side effects, especially the brain cognitive function impairment, caused by long-term usage of BBB-permeable statins.
Highlights
Statins are the most effective low density lipoprotein-cholesterol lowering medications by targeting 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in blood and liver [1, 2]
Hippocampal long-term potentiation (LTP) is inhibited in simvastatin‐treated mice First, we examined the LTP, a main form of synaptic plasticity that underlies synaptic information storage within the central nervous system (CNS) [27], in the hippocampal slices of mice receiving chronic subcutaneous (S.C.) simvastatin administration (30 mg/kg/day, 26 days)
We examined whether the basal synaptic field responses in the hippocampus were altered by simvastatin, by comparing input–output curves constructed from the stimulation intensity vs Field excitatory postsynaptic potentials (fEPSPs) slope
Summary
Statins are the most effective low density lipoprotein-cholesterol lowering medications by targeting 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in blood and liver [1, 2]. Various types of statins including atorvastatin, lovastatin, rosuvastatin and simvastatin have been approved by the U.S Food and Drug Administration (FDA) [5]. According to their capacity to cross the blood–brain barrier (BBB), statins are classified as lipophilic statins including atorvastatin, simvastatin and lovastatin which. Accurate maintenance of brain cholesterol level is essential for normal brain function including signaling and synaptic plasticity [10, 11]. Human studies have demonstrated that low levels of total cholesterol are associated with poor performance on cognitive function [15]. Animal studies indicated that animals with cholesterol synthesis deficiency suffer severe declines
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