digoxin and Alzheimer-Disease

Alzheimer's disease (AD) is by far the most common cause of cognitive impairment in older adults. Current treatments are entirely focused on the symptoms of AD. A complex etiology for AD has been proposed recently, in which AD leads in elevated levels of inflammation. We previously studied digoxin's involvement in the sporadic-AD intracerebroventricular (ICV)-streptozotocin (STZ) animal model due to its anti-inflammatory and neuroprotective characteristics. 18 adult sprague-dawley rats were split into three groups: control (n = 6), STZ + Saline (n = 6), and STZ + Digoxin (n = 6). Twelve AD-induced rats were split into two groups using stereotaxy five days after STZ injection (3 mg/kg) into both lateral ventricles: one group got digoxin (0.1 mg/kg/day, i.p.) for three weeks, while the other group received saline. Following treatment, each subject was subjected to a passive avoidance learning (PAL) test, followed by brain tissue harvesting. The levels of tumor necrosis factor-alpha (TNF-α) and choline acetyl transferase (ChAT) were measured in the brain, and neurons were counted using Cresyl violet staining in cornu ammonis-1 (CA1) and cornu ammonis-3 (CA3) cornu ammonis (CA3). ICV-STZ significantly shortened PAL latency, increased brain TNF-α levels, decreased brain ChAT activity, and decreased hippocampus neuron number. On the other hand, digoxin significantly reduced all of these STZ-induced deleterious effects. Digoxin significantly rescued rats from memory loss caused by ICV-STZ by decreasing hippocampal cell death, neuroinflammation, and cholinergic deficiency. These findings suggest that digoxin may be beneficial in treating cognitive impairment and Alzheimer's disease.

Topics: Alzheimer Disease; Animals; CA1 Region, Hippocampal; Digoxin; Disease Models, Animal; Hippocampus; Maze Learning; Neuroprotective Agents; Rats; Rats, Wistar; Streptozocin

17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme known for its potential role in Alzheimer's Disease (AD). 17β-HSD10, by its oxidative activity, could decrease the concentration of two important neurosteroids, allopregnanolone (ALLOP) and 17β-estradiol (E2), respectively preventing their neurogenesis and neuroprotective effects. Since the inhibition of 17β-HSD10 could lead to a new treatment for AD, we developed two biological assays using labeled ALLOP or E2 as substrates to measure the inhibitory activity of compounds against pure 17β-HSD10 protein. After the optimization of different parameters (time, concentration of enzyme, substrate and cofactor), analogs of the first reported steroidal inhibitor of 17β-HSD10 in intact cells were screened to determine their inhibitory potency for the ALLOP or the E2 oxidation. One compound, androstane derivative 5, possesses the best dual inhibition against both transformations (ALLOP, IC

Topics: 17-Hydroxysteroid Dehydrogenases; 5-alpha-Dihydroprogesterone; Alzheimer Disease; Enzyme Inhibitors; Estradiol; Estrone; HEK293 Cells; Humans; Pregnanolone; Steroids; Structure-Activity Relationship

The purpose of this study was to systematically assess the impact of Alzheimer's disease (AD)-associated blood-brain barrier (BBB) alterations on the uptake of therapeutics into the brain.. The brain uptake of probe compounds was measured in 18-20 month old wild type (WT) and triple transgenic (3×TG) AD mice using an in situ transcardiac perfusion technique. These results were mechanistically correlated with immunohistochemical and molecular studies.. The brain uptake of the paracellular marker, [(14)C] sucrose, did not differ between WT and 3×TG mice. The brain uptake of passively diffusing markers, [(3)H] diazepam and [(3)H] propranolol, decreased 54-60% in 3×TG mice, consistent with a 33.5% increase in the thickness of the cerebrovascular basement membrane in 3×TG mice. Despite a 42.4% reduction in P-gp expression in isolated brain microvessels from a sub-population of 3×TG mice (relative to WT mice), the brain uptake of P-gp substrates ([(3)H] digoxin, [(3)H] loperamide and [(3)H] verapamil) was not different between genotypes, likely due to a compensatory thickening in the cerebrovascular basement membrane counteracting any reduced efflux of these lipophilic substrates.. These studies systematically assessed the impact of AD on BBB drug transport in a relevant animal model, and have demonstrated a reduction in the brain uptake of passively-absorbed molecules in this mouse model of AD.

Topics: Alzheimer Disease; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Brain; Digoxin; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Pharmacokinetics; Propranolol; Sucrose; Transgenes; Vasodilator Agents; Verapamil

This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Alzheimer's disease (AD). The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find the role of cerebral dominance in the genesis of Alzheimer's disease. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol levels, and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while serum tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated in Alzheimer's disease. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid increased. The activity of all free radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in Alzheimer's disease, while the concentration of lipid peroxidation products and NO increased. The hypomagnesemia-related NMDA excitotoxicity, ubiquinone deficiency related mitochondrial dysfunction, and altered glycoconjugates/lysosomal stability could contribute to the pathogenesis of Alzheimer's disease. The biochemical patterns, including hyperdigoxinemia observed in Alzheimer's disease, correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for Alzheimer's disease.

Topics: Aged; Albumins; alpha-Tocopherol; Alzheimer Disease; Ceruloplasmin; Digoxin; Dolichols; Dominance, Cerebral; Erythrocyte Membrane; Female; Free Radicals; Functional Laterality; Glycosaminoglycans; Humans; Hydroxymethylglutaryl CoA Reductases; Hypothalamus; Iron; Lysosomes; Magnesium; Male; Matched-Pair Analysis; Middle Aged; Phosphoprotein Phosphatases; Quinolinic Acid; Serotonin; Sodium-Potassium-Exchanging ATPase; Tryptophan

To document the presence and treatment of selected vascular risk factors in patients with vascular cognitive impairment and elements affecting undertreatment of vascular risk factors.. Secondary analysis of the Canadian Study of Health and Aging database, which is a national, representative, cross-sectional study of the epidemiologic distribution of dementia in elderly people in Canada.. Survey.. Institutionalized and community-dwelling elderly people.. Vascular risk factors, dementia diagnosed by standard methods, and medication use.. Treatable vascular risk factors occurred significantly more often in patients with vascular cognitive impairment (with and without dementia) than in patients with probable Alzheimer disease or normal cognitive function. For example, 76% of patients with vascular dementia and 57% of those with vascular cognitive impairment without dementia had a history of stroke, compared with only 5% of those with probable Alzheimer disease and 7% of those with no cognitive loss. (For hypertension, the comparable figures are 55%, 48%, 24%, and 38%, respectively.) Potential undertreatment of vascular risk factors had little effect on mean control of vascular risk factors. For example, the mean (+/- SD) systolic blood pressure in those being treated was 144 +/- 26 mm Hg, compared with 142 +/- 25 mm Hg in those not receiving pharmacological treatment. In each group (treated vs untreated), the proportion of patients with a systolic blood pressure higher than 160 mm Hg was 20% and 16%, respectively. Potential undertreatment occurred most often in those with severe dementia and those living in nursing homes.. Vascular risk factors occurred more commonly in patients with vascular cognitive impairment compared with other patients, including those with other forms of dementia. When present, such risk factors were often treated pharmacologically, except in patients with severe dementia and those in long-term care institutions. Undertreatment does not, in general, result in worsened risk factor control.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aspirin; Cognition Disorders; Dementia; Diabetes Complications; Diabetes Mellitus; Digoxin; Female; Humans; Hypertension; Male; Risk Factors; Vascular Diseases