Delayed neurological deterioration (DND) is a major cause of death and disability due to aneurismal subarachnoid hemorrhage (SAH). In humans, this complication occurs seven to ten days after the rupture. Although great efforts have been made for preventing this neurological condition, many patients remain unresponsive to the currently recommended treatments. This exploratory project will test our hypothesis that combination of betaine (trimethylglycine) and fenofibrate may be a potential candidate for this neurological disease. Betaine and fenofibrate have been prescribed for homocystinuria and dyslipidemia, respectively. In invertebrates, betaine drives organisms into cryptobiosis, an ametabolic state of cells, in response to adverse environment such as desiccation, freezing, and oxygen deficiency. Betaine has also been shown protective in mammalian cells against stressful conditions;however, little is known about the influence of betaine on the nervous system subjected to stress. We previously reported that the lipid normalizing drug fenofibrate significantly reduced infarct size in mice subjected to ischemic stroke. This neuroprotection was accompanied by improved cerebral microcirculation, attenuation of oxidative stress, and inhibition of cellular adhesion molecules expression, all of which are crucial factors to DND after SAH. Our recent preliminary studies showed that combination of betaine and fenofibrate reduced infarct volume although fenofibrate alone at that dose was not effective. These findings suggest at least two possibilities: (1) betaine alone might be protective;(2) betaine might counteract an adverse effect of fenofibrate.
Aim 1 will test post-SAH treatment of betaine alone against DND in a mouse SAH model.
Aim 2 will measure the effect of combination of betaine and fenofibrate (post-SAH) in mice after SAH. Cortical perfusion, behavioral outcome, microthrombosis formation in the brain, and plasma homocysteine will also be measured.
Delayed neurological deterioration is a major cause of death and disability due to aneurismal subarachnoid hemorrhage. We propose to test our hypothesis that the combination therapy of betaine and fenofibrate may be effective to prevent this devastating neurological disease. Both betaine and fenofibrate are FDA-approved drugs for homocysfinuria and dyslipidemia, respectively.
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