Hormone replacement therapy to treat or prevent Alzheimer Disease (AD) in postmenopausal women is controversial because it may pose other health risks such as cancer and thromboembolism. ApoE status is thought to influence the nootropic efficacy of hormone therapy, but findings are neither consistent nor well understood. We used a known in vitro memory model (long-term potentiation, LTP) in aged (24-27 month) female targeted replacement mice expressing human apoE3 or E4 to compare the effects of exogenous estradiol. Recording medial perforant path evoked field potentials in dentate gyrus of hippocampal slices, we found that both strains exhibited comparable basal synaptic transmission as assessed by input/output functions and paired pulse depression, and that these measures were not affected by estradiol. Vehicle-treated groups from both strains showed comparable LTP. Estradiol had no effect on LTP in apoE3-TR, but selectively increased LTP magnitude in apoE4-TR. The estradiol induced enhancement of LTP in aged female apoE4-TR is consistent with recent clinical observations that estrogen replacement decreases AD risk in some women with apoE4. Elucidating the mechanism of this selective enhancement may lead to more informed treatment decisions as well as to the development of safer alternatives to hormone therapy.

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Continuous exercise and bright light affect brain function, particularly in seasonal affective disorders. However, the underlying mechanism of action remains unclear. In this study, we examined whether low-intensity treadmill exercise and 4 weeks of bright light exposure change the expression of brain-derived neurotrophic factor (BDNF), phosphoinositide 3-kinase/AKT (PI3K/AKT) pathway, protein kinase C (PKC), extracellular signalregulated kinases (ERK1/2), cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), vascular endothelial growth factor (VEGF), and glycogen synthase kinase-3β (GSK-3β) in the brain of 5-week old Sprague-Dawley male rats by performing western blot analysis. We demonstrated that BDNF expression significantly increased with exercise and light exposure compared to a control group. Moreover, we found that the expression levels of PI3K, PKC, p-ERK1/2, p-CREB, p-AKT, and VEGF increased significantly in the hippocampus and cortex with exercise and light exposure compared to the levels from a control group. However, phosphorylated GSK-3β level was unchanged, and even slightly decreased with exercise and light exposure. These results suggest that low-intensity treadmill exercise and bright light exposure induce BDNF expression and activate its downstream kinase signaling pathway, which in turn activate CREB-mediated transcription of neurotrophic factors and may stimulate neurogenesis and improve neuronal functions.

Sildenafil exerts cardioprotective effects by activating the opening of mitochondrial ATP-sensitive potassium channels to attenuate ischaemia-reperfusion (IR) injury. In the present study, we used atomic force microscopy (AFM) to investigate changes in mitochondrial morphology and properties to assess sildenafil-mediated cardioprotection in a rat myocardial infarction model. To investigate the cardioprotective effects of sildenafil, we used an in vivo Sprague-Dawley rat model of IR. Rats were randomly divided into three groups: (i) sham-operated rats (control; n = 5); (ii) IR-injured rats treated with vehicle (normal saline; IR; n = 10); and (iii) IR-injured rats treated with 0.75 mg/kg, i.p., sildenafil (IR + Sil; n = 10). Morphological and mechanical changes to mitochondria were analysed by AFM. Infarct areas were significantly reduced in sildenafil-treated rats (7.8 ± 3.9% vs 20.4 ± 7.0% in the sildenafil-treated and untreated IR groups, respectively; relative reduction 62%; P < 0.001). Analysis of mitochondria by AFM showed that IR injury significantly increased the areas of isolated mitochondria compared with control (24 150 ± 18 289 vs 1495 ± 1139 nm(2) , respectively; P < 0.001), indicative of mitochondrial swelling. Pretreatment with sildenafil before IR injury reduced the mitochondrial areas (7428 ± 3682 nm(2) ; P < 0.001; relative reduction 69.2% compared with the IR group) and ameliorated the adhesion force of mitochondrial surfaces. Together, these results suggest that sildenafil has cardioprotective effects against IR injury in a rat model by improving the morphological and mechanical characteristics of mitochondria.

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