Eight-hydroxy-2'-deoxyguanosine (8-OHdG) is increased in the brain in late-stage Alzheimer's disease (LAD) and mild cognitive impairment (MCI). To determine if decreased base-excision repair contributes to these elevations, we measured oxoguanine glycosylase 1 (OGG1) protein and incision activities in nuclear and mitochondrial fractions from frontal (FL), temporal (TL), and parietal (PL) lobes from 8 MCI and 7 LAD patients, and 6 age-matched normal control (NC) subjects. OGG1 activity was significantly (P<0.05) decreased in nuclear specimens of FL, TL, and PL in MCI and LAD and in mitochondria from LAD FL and TL and MCI TL. Nuclear OGG1 protein was significantly decreased in LAD FL and MCI and LAD PL. No differences in mitochondrial OGG1 protein levels were found. Overall, our results suggest that decreased OGG1 activity occurs early in the progression of AD, possibly mediated by 4-hydroxynonenal inactivation and may contribute to elevated 8-OHdG in the brain in MCI and LAD.
The objective was to assess the impact of larger than conventional amounts of 14 commonly used excipients on Biopharmaceutics Classification System (BCS) class 3 drug absorption in humans. Cimetidine and acyclovir were used as model class 3 drugs across three separate four-way crossover bioequivalence (BE) studies (n = 24 each) in healthy human volunteers, denoted as study 1A, 1B, and 2. In study 1A and 1B, three capsule formulations of each drug were manufactured, collectively involving 14 common excipients. Capsule formulations that incorporated hydroxypropyl methylcellulose (HPMC) or magnesium stearate exhibited lower absorption. The cimetidine commercial solution contained sorbitol and also resulted in lower absorption. Hence, in study 2, two capsule formulations with lower amounts of HPMC and magnesium stearate, the sorbitol-containing commercial solution, and a sorbitol-free solution were assessed for BE. Overall, 12 common excipients were found in large amounts to not impact BCS class 3 drug absorption in humans, such that these excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather simply be not more than the quantities studied here. Meanwhile, for each HPMC and microcrystalline cellulose, BCS class 3 biowaivers require these two excipients to be qualitatively the same and quantitatively very similar to the reference.
Increasing evidence suggests a role for oxidative stress in several neurodegenerative diseases, including Alzheimer's disease (AD), and that selenium compounds may function as antioxidants. To evaluate the antioxidant mechanism of selenium, primary rat hippocampal neurons were pretreated with seleno-L-methionine (SeMet) for 16 h prior to treatment with iron/hydrogen peroxide (Fe(2+)/H(2)O(2)) or amyloid beta peptide (Abeta(2535)); free radical generation was assessed using laser confocal microscopy and CM-H(2)DCFDA and APF. Treatment with Fe(2+)/H(2)O(2) or Abeta significantly decreased cell survival and increased free radical generation compared to cultures treated with vehicle alone. In contrast, cultures pretreated with SeMet showed significantly (p < 0.05) increased survival and significantly lower CM-H(2)DCFDA and APF fluorescence compared to Fe(2+)/H(2)O(2) or Abeta treated cultures. To determine if SeMet protection was mediated by glutathione peroxidase (GPx), levels of GPx protein and activity were measured using confocal microscopy and a selenium-dependent GPx specific antibody and an activity assay. Pretreatment with SeMet significantly (p < 0.05) increased GPx protein and activity in Fe(2+)/H(2)O(2)- and Abeta-treated cultures compared to cultures treated with Fe(2+)/H(2)O(2) or Abeta alone. These data suggest that SeMet can decrease free radical generation induced by Fe(2+)/H(2)O(2) or Abeta through modulation of GPx and may be suitable as a potential therapeutic agent in neurodegenerative diseases where there is increased oxidative stress.
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