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2.
Figure 6

Figure 6. From: Early intervention with a small molecule inhibitor for tumor nefosis factor-? prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

Tumor necrosis factor-α protein from splenocytes isolated from Non-Tg and 3 × Tg mice. Splenocytes isolated from Non-Tg and 3 × Tg mice were cultured for 24 hours and TNFα levels measured by ELISA. 3,6′-DT-treated 3 × Tg mice had significantly reduced TNFα secretion compared with vehicle-treated 3 × Tg mice. One-way analysis of variance: P = 0.0184. *P < 0.05 versus 3 × Tg (vehicle). ELISA: enzyme-linked immunosorbent assay; 3,6′-DT: 3,6′-dithiothalidomide; Thal: thalidomide; TNFα: tumor necrosis factor-α.

S Prasad Gabbita, et al. J Neuroinflammation. 2012;9:99-99.
3.
Figure 9

Figure 9. From: Early intervention with a small molecule inhibitor for tumor nefosis factor-? prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

3,6-dithiothalidomide reduces central nervous system-infiltrating peripheral blood leukocytes. Mononuclear cells were isolated from the whole brains of Non-Tg and 3 × Tg mice (vehicle-, Thal- and 3,6′-DT-treated; n = 3 to 4 per group) following 2.5 months of treatment and counted using a hemocytometer. One-way analysis of variance: P < 0.0001; *P < 0.001 versus Non-Tg, **P < 0.001 versus 3 × Tg (Thal). Thal: thalidomide; 3,6′-DT: 3,6’-dithiothalidomide.

S Prasad Gabbita, et al. J Neuroinflammation. 2012;9:99-99.
4.
Figure 2

Figure 2. From: Early intervention with a small molecule inhibitor for tumor nefosis factor-? prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

Thalidomide and 3,6-dithiothalidomide attenuate lipopolysaccharide-induced increase in tumor necrosis factor-α. BV2 cells were treated with 1 ng/mL LPS ± Thal or 3,6′-DT for 24 h. Initial studies in BV2 cells demonstrate that both Thal and 3,6′-DT are effective at attenuating LPS-induced TNFα release into culture media. 3,6′-DT has an IC50 value of approximately 1 μM whereas the IC50 for Thal is > 10 μM. n = 6 per group. One-way analysis of variance: P < 0.0001; *P < 0.001 versus both drugs, both doses. LPS: lipopolysaccharide; Thal: thalidomide; TNFα: tumor necrosis factor-α; 3,6′-DT: 3,6′-dithiothalidomide.

S Prasad Gabbita, et al. J Neuroinflammation. 2012;9:99-99.
5.
Figure 8

Figure 8. From: Early intervention with a small molecule inhibitor for tumor nefosis factor-? prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

Amyloid precursor protein/amyloid beta peptide staining is not changed in 3 × Tg mice by 3,6-dithiothalidomide or thalidomide treatment. 6E10 immunohistochemistry was stereologically analyzed in the hippocampal CA1 to CA2 regions (left graph; n = 5 to 6 mice per treatment). There were no statistically significant differences in 6E10+ cell counts between treatment groups. Representative photomicrographs of each treatment group are shown. The same regions were also analyzed for optical density (right graph) and show that there were no differences between treatment groups.

S Prasad Gabbita, et al. J Neuroinflammation. 2012;9:99-99.
6.
Figure 3

Figure 3. From: Early intervention with a small molecule inhibitor for tumor nefosis factor-? prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

3,6-dithiothalidomide and thalidomide inhibited lipopolysaccharide-stimulated tumor necrosis factor-α gene and protein expression in C57 mice. Mice were treated peripherally (intraperitoneal injection) with a single equivalent dose (100 mg/kg) of 3,6′-DT or Thal 30 min prior to a peripheral 5 mg/kg dose of LPS (intraperitoneal injection). Cortical tissue was harvested 4 hours after LPS injection. n = 6 per group. One-way analysis of variance: P < 0.001; *P < 0.001 versus all other groups. LPS: lipopolysaccharide; Thal: thalidomide; TNFα: tumor necrosis factor-α; 3,6′-DT: 3,6′-dithiothalidomide.

S Prasad Gabbita, et al. J Neuroinflammation. 2012;9:99-99.
7.
Figure 7

Figure 7. From: Early intervention with a small molecule inhibitor for tumor nefosis factor-? prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

Stereological analysis of ionized calcium-binding adapter molecule 1 staining in the hippocampus. Unbiased stereological methods were used to analyze 35 μm sections, every fifth section through the hippocampus (total of eight sections per mouse; n = 3 to 4 per group). The top panel shows the morphological criteria used for designating resting versus activated Iba-1 positive microglia. Middle Panel: (Aa) Non-Tg; (Bb) 3 × Tg (vehicle); (Cc) 3 × Tg (Thal); (Dd) 3 × Tg (3,6′-DT) mice. Bottom panel: total, resting and activated cell counts. Bonferroni post hoc testing: *P < 0.05, **P < 0.01, ***P < 0.001. Bar equals 40 μm (A), 10 μm (a). 3,6′-DT: 3,6′-dithiothalidomide; Iba-1: ionized calcium-binding adapter molecule 1; Thal: thalidomide.

S Prasad Gabbita, et al. J Neuroinflammation. 2012;9:99-99.
8.
Figure 5

Figure 5. From: Early intervention with a small molecule inhibitor for tumor nefosis factor-? prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

Tumor necrosis factor-α gene and protein expression in the 3 × Tg mouse. (A) Fold-change (2^(− δ δCt)) is the normalized gene expression (2^(−δ Ct)) in the test sample (3 × Tg treated with Thal or 3,6′-DT) divided by the normalized gene expression (2^(−δ Ct)) in the control sample (vehicle-treated 3 × Tg). Fold-change values of less than one indicate a negative- or downregulation. Both Thal and 3,6′-DT downregulated TNFα gene expression but the value was significant only in the 3,6′-DT group (P = 0.033). (B) TNFα protein levels are doubled in the cortex of 3 × Tg mice compared with Non-Tg mice. 3,6′-DT, but not Thal, reduced TNFα protein levels near to Non-Tg levels in 3 × Tg mice. n = 5 to 8 per group. One-way analysis of variance (P = 0.062, *P < 0.05). Thal: thalidomide; TNFα: tumor necrosis factor-α; 3,6′-DT: 3,6’-dithiothalidomide.

S Prasad Gabbita, et al. J Neuroinflammation. 2012;9:99-99.
9.
Figure 10

Figure 10. From: Early intervention with a small molecule inhibitor for tumor nefosis factor-? prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

3,6-dithiothalidomide reduces tumor necrosis factor-α in central nervous system-infiltrating myelomonocytic/granulocytic leukocytes. (A) Non-Tg mice; (B) 3 × Tg mice; (C) 3,6′-DT mice. CNS-infiltrating leukocytes from whole mouse brains (n = 3 to 4 per group) were isolated and evaluated for the presence of CD45hi and myelomonocytes/granulocytes (CD45hi/Gr1+/Ly6Ghi) by cell surface staining and flow cytometric analyses. There was a trend towards an increased percentage of CD45hi cells and CD45hi/Gr1+/Ly6Ghi (not significant) in 3 × Tg mice (B) relative to Non-Tg (A) mice. 3,6′-DT (C) did not alter the percentages of these cell populations. TNFα expression in the total CD45hi population and in the granulocyte population was increased in 3 × Tg mice relative to Non-Tg mice. 3,6′-DT treatment did not reduce TNFα expression in the total CD45 hi population but specifically reduced TNFα expression in the CD45hi/Gr1+/Ly6Ghi population (P = 0.031). Flow cytometry results were quantified and are presented in Table 1.

S Prasad Gabbita, et al. J Neuroinflammation. 2012;9:99-99.
10.
Figure 4

Figure 4. From: Early intervention with a small molecule inhibitor for tumor nefosis factor-? prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

3,6-dithiothalidomide improves cognitive performance as assessed using the eight-arm radial arm maze in 3 × Tg mice. (A) 6.5-month-old 3 × Tg mice demonstrate a significant working memory deficit relative to age-matched Non-Tg mice (n = 15). Daily intraperitoneal administration of 50 mg/kg, 3,6′-DT for 2.5 months (4 to 6.5 months of age) significantly improved working memory errors (WME) in 3 × Tg mice (n = 11) compared with vehicle-treated (n = 14) or Thal-treated (50 mg/kg intraperitoneal injection; n = 11) 3 × Tg mice. No difference in WME was observed between 3, 6′-DT-treated 3 × Tg mice and age-matched Non-Tg mice. One-way analysis of variance: P = 0.0076. *P < 0.05. (B) Reference memory errors and (C) time to complete the radial arm maze on the last day of testing were not significantly different between groups. Thal: thalidomide; TNFα: tumor necrosis factor-α; 3,6′-DT: 3,6’-dithiothalidomide; WME: working memory errors.

S Prasad Gabbita, et al. J Neuroinflammation. 2012;9:99-99.

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