Simvastatin is the statin that most efficiently protects against kainate-induced excitotoxicity and memory impairment.

Statins have recently been shown to act as protectants against several neuropathological conditions. They have received special attention in the field of Alzheimer's disease (AD), where epidemiological studies indicating a lower prevalence of AD/dementia in statin-prescribed populations. Excitotoxicity, which derives from the overstimulation of glutamate receptors, is a major cause of neuron death in several neurological diseases, including AD and epilepsy. We have carried out a comparative study to investigate the effects of all the commercially available statins (simvastatin, lovastatin, fluvastatin, pravastatin, and atorvastatin) on neuron damage and memory impairment. To this end, we studied neurodegeneration in a mouse model by systemic administration of kainate. Simvastatin was the most effective statin in reducing the deleterious effects caused by kainate, including the severity of seizures, excitotoxicity, oxidative damage, neuritic dystrophy and apoptosis in the hippocampus and other limbic structures of the brain cortex. Lovastatin was the second most efficient statin in preventing seizures and histopathological signs of excitotoxicity, whilst fluvastatin, pravastatin, and atorvastatin showed neither antiepileptic nor neuroprotective effects. Only simvastatin enhanced episodic-like memory. To the best of our knowledge this is the first in vivo study to analyze the neuroprotective effect of all the commercially available statins. Our results suggest that both simvastatin and lovastatin (but especially simvastatin) may well have therapeutic potential in the treatment of neurodegenerative diseases involving excitotoxicity and memory impairment, including AD.

ApoB100/LDLR-/- hypercholesterolaemic mice as a model for mild cognitive impairment and neuronal damage.

Recent clinical findings support the notion that the progressive deterioration of cholesterol homeostasis is a central player in Alzheimer's disease (AD). Epidemiological studies suggest that high midlife plasma total cholesterol levels are associated with an increased risk of AD. This paper reports the plasma cholesterol concentrations, cognitive performance, locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR]) of human familial hypercholesterolaemia (FH). From birth, these animals have markedly elevated LDL-cholesterol and apolipoprotein B100 (apoB100) levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showed cholesterol (total and fractions) concentrations considerably higher than those of 18-month-old wild-type mice. The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing) and impairment of the episodic-like memory (determined by the integrated memory test). This decline in locomotor activity and cognitive status was associated with neuritic dystrophy and/or the disorganization of the neuronal microtubule network, plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype, while cerebral ß-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline.