A Combination of Three Repurposed Drugs Administered at Reperfusion as a Promising Therapy for Postischemic Brain Injury.

Cerebral ischemia leads to multifaceted injury to the brain. A polytherapeutic drug that can be administered immediately after reperfusion may increase protection to the brain by simultaneously targeting multiple deleterious cascades. This study evaluated efficacy of the combination of three clinically approved drugs: lamotrigine, minocycline, and lovastatin, using two mouse models: global and focal cerebral ischemia induced by transient occlusion of the common carotid arteries or the middle cerebral artery, respectively. In vitro, the combination drug, but not single drug, protected neurons against oxygen-glucose deprivation (OGD)-induced cell death. The combination drug simultaneously targeted cell apoptosis and DNA damage induced by ischemia. Besides acting on neurons, the combination drug suppressed inflammatory processes in microglia and brain endothelial cells induced by ischemia. In a transient global ischemia model, the combination drug, but not single drug, suppressed microglial activation and inflammatory cytokine production, and reduced neuronal damage. In a transient focal ischemia model, the combination drug, but not single drug, attenuated brain infarction, suppressed infiltration of peripheral neutrophils, and reduced neurological deficits following ischemic stroke. In summary, the combination drug confers a broad-spectrum protection against ischemia/reperfusion (I/R) injury and could be a promising approach for early neuroprotection after out-of-hospital cardiac arrest or ischemic stroke.

Estrogen receptors alpha and beta in choroid plexus epithelial cells in Alzheimer's disease.

Estrogen replacement therapy (ERT) may reduce the risks of Alzheimer's disease (AD). One of the potential actions of estrogen is through its effect on beta-amyloid elimination into the cerebrospinal fluid (CSF) compartment from the brain parenchyma. CSF secretion is controlled largely by the choroid plexus (CP) epithelial cells. In this study, we evaluated the status of estrogen receptor (ER) alpha and beta subtypes in CP epithelial cells. Tissue from 49 AD and 12 non-AD patients were studied using immunohistochemistry with anti-ER antibodies. ER alpha and ER beta were present in CP epithelial cells in both cytosolic and nuclear compartments. Male and female AD patients had lower ER alpha and beta densities in CP compared to non-AD patients. We further stratified the female AD patients into four groups according to their hormonal status. Among the female AD patients, those without hysterectomy and with ERT had the highest ER alpha density. In contrast, those with hysterectomy and without ERT had the lowest ER alpha density. The effects of hysterectomy and ERT were additive. For ER beta, ERT but not the status of hysterectomy was associated with higher receptor density. The lower ER density in CP epithelial cells of AD patients supports a potential role of estrogen in the regulation of CSF secretion of beta-amyloid protein, which may affect the accumulation of beta-amyloid in the brain parenchyma. Among AD patients, the association of ER alpha density with status of hysterectomy and ERT supports estrogen effects through receptor-mediated mechanisms.