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Sulfasalazine blocks the development of tactile allodynia in diabetic rats.

Berti-Mattera LN, Kern TS, Siegel RE, Nemet I, Mitchell R - Diabetes (2008)

Bottom Line: Importantly, the absence of tactile allodynia in diabetic NF-kappaB p50(-/-) mice supported a role for NF-kappaB in diabetic neuropathy.The complete inhibition of tactile allodynia in experimental diabetes by sulfasalazine may stem from its ability to regulate both NF-kappaB and inosine.Sulfasalazine might be useful in the treatment of nociceptive alterations in diabetic patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. lnb@case.edu

ABSTRACT

Objective: Diabetic neuropathy is manifested either by loss of nociception (painless syndrome) or by mechanical hyperalgesia and tactile allodynia (pain in response to nonpainful stimuli). While therapies with vasodilators or neurotrophins reverse some functional and metabolic abnormalities in diabetic nerves, they only partially ameliorate neuropathic pain. The reported link between nociception and targets of the anti-inflammatory drug sulfasalazine prompted us to investigate its effect on neuropathic pain in diabetes.

Research design and methods: We examined the effects of sulfasalazine, salicylates, and the poly(ADP-ribose) polymerase-1 inhibitor PJ34 on altered nociception in streptozotocin-induced diabetic rats. We also evaluated the levels of sulfasalazine targets in sciatic nerves and dorsal root ganglia (DRG) of treated animals. Finally, we analyzed the development of tactile allodynia in diabetic mice lacking expression of the sulfasalazine target nuclear factor-kappaB (NF-kappaB) p50.

Results: Sulfasalazine completely blocked the development of tactile allodynia in diabetic rats, whereas relatively minor effects were observed with other salicylates and PJ34. Along with the behavioral findings, sciatic nerves and DRG from sulfasalazine-treated diabetic rats displayed a decrease in NF-kappaB p50 expression compared with untreated diabetic animals. Importantly, the absence of tactile allodynia in diabetic NF-kappaB p50(-/-) mice supported a role for NF-kappaB in diabetic neuropathy. Sulfasalazine treatment also increased inosine levels in sciatic nerves of diabetic rats.

Conclusions: The complete inhibition of tactile allodynia in experimental diabetes by sulfasalazine may stem from its ability to regulate both NF-kappaB and inosine. Sulfasalazine might be useful in the treatment of nociceptive alterations in diabetic patients.

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Expression of NF-κB p50, phospho-p65 (P-p65), and p65 subunits in nuclear-enriched fractions (NEF) of sciatic nerves from normal (N), 3-month diabetic (D), and sulfasalazine-treated 3-month diabetic (S) rats. A: Immunoreactivity of sciatic nerve nuclear-enriched fractions from three individual animals in each group. Blots were also incubated with anti-ERK2 to control for differences in sample loading. Numbers at the left of each panel depict the position of molecular mass markers (in kDa). B: Specificity of the signals was confirmed by immunoblotting of sciatic nerve extracts with dilutions of anti–NF-κB p50 or anti–NF-κB p65 antisera previously incubated in the presence (+P) or absence (−) of immunogenic peptides. C: Densitometry of immunoreactivity of NF-κB subunits relative to ERK2 for all animals analyzed in each group (n = 5–7) (Significantly different from **normal and ∧∧untreated diabetics at P < 0.01 as calculated by ANOVA followed by Dunnett's test).
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f2: Expression of NF-κB p50, phospho-p65 (P-p65), and p65 subunits in nuclear-enriched fractions (NEF) of sciatic nerves from normal (N), 3-month diabetic (D), and sulfasalazine-treated 3-month diabetic (S) rats. A: Immunoreactivity of sciatic nerve nuclear-enriched fractions from three individual animals in each group. Blots were also incubated with anti-ERK2 to control for differences in sample loading. Numbers at the left of each panel depict the position of molecular mass markers (in kDa). B: Specificity of the signals was confirmed by immunoblotting of sciatic nerve extracts with dilutions of anti–NF-κB p50 or anti–NF-κB p65 antisera previously incubated in the presence (+P) or absence (−) of immunogenic peptides. C: Densitometry of immunoreactivity of NF-κB subunits relative to ERK2 for all animals analyzed in each group (n = 5–7) (Significantly different from **normal and ∧∧untreated diabetics at P < 0.01 as calculated by ANOVA followed by Dunnett's test).

Mentions: We examined the steady-state levels of NF-κB subunits in nuclear-enriched fractions of sciatic nerves and DRG. Although the expression of NF-κB p50 was similar in sciatic nerves and DRG from normal and diabetic rats, a significant decrease was observed after sulfasalazine treatment (Figs. 2 and 3). A different pattern was observed for NF-κB p65. Sciatic nerve extracts from diabetic rats displayed increased levels of NF-κB p65 when compared with normal samples that were corrected by sulfasalazine treatment (Fig. 2). In contrast, diabetic DRG displayed a ∼30% decrease in NF-κB p65 compared with normal samples that was not significantly altered after treatment with sulfasalazine (Fig. 3). Finally, a similar pattern, decreased levels in diabetic compared with normal samples that were not corrected by sulfasalazine treatment, was observed for NF-κB phospho-p65 (P-p65) in sciatic nerves and DRG nuclear-enriched fractions (Figs. 2 and 3).


Sulfasalazine blocks the development of tactile allodynia in diabetic rats.

Berti-Mattera LN, Kern TS, Siegel RE, Nemet I, Mitchell R - Diabetes (2008)

Expression of NF-κB p50, phospho-p65 (P-p65), and p65 subunits in nuclear-enriched fractions (NEF) of sciatic nerves from normal (N), 3-month diabetic (D), and sulfasalazine-treated 3-month diabetic (S) rats. A: Immunoreactivity of sciatic nerve nuclear-enriched fractions from three individual animals in each group. Blots were also incubated with anti-ERK2 to control for differences in sample loading. Numbers at the left of each panel depict the position of molecular mass markers (in kDa). B: Specificity of the signals was confirmed by immunoblotting of sciatic nerve extracts with dilutions of anti–NF-κB p50 or anti–NF-κB p65 antisera previously incubated in the presence (+P) or absence (−) of immunogenic peptides. C: Densitometry of immunoreactivity of NF-κB subunits relative to ERK2 for all animals analyzed in each group (n = 5–7) (Significantly different from **normal and ∧∧untreated diabetics at P < 0.01 as calculated by ANOVA followed by Dunnett's test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551692&req=5

f2: Expression of NF-κB p50, phospho-p65 (P-p65), and p65 subunits in nuclear-enriched fractions (NEF) of sciatic nerves from normal (N), 3-month diabetic (D), and sulfasalazine-treated 3-month diabetic (S) rats. A: Immunoreactivity of sciatic nerve nuclear-enriched fractions from three individual animals in each group. Blots were also incubated with anti-ERK2 to control for differences in sample loading. Numbers at the left of each panel depict the position of molecular mass markers (in kDa). B: Specificity of the signals was confirmed by immunoblotting of sciatic nerve extracts with dilutions of anti–NF-κB p50 or anti–NF-κB p65 antisera previously incubated in the presence (+P) or absence (−) of immunogenic peptides. C: Densitometry of immunoreactivity of NF-κB subunits relative to ERK2 for all animals analyzed in each group (n = 5–7) (Significantly different from **normal and ∧∧untreated diabetics at P < 0.01 as calculated by ANOVA followed by Dunnett's test).
Mentions: We examined the steady-state levels of NF-κB subunits in nuclear-enriched fractions of sciatic nerves and DRG. Although the expression of NF-κB p50 was similar in sciatic nerves and DRG from normal and diabetic rats, a significant decrease was observed after sulfasalazine treatment (Figs. 2 and 3). A different pattern was observed for NF-κB p65. Sciatic nerve extracts from diabetic rats displayed increased levels of NF-κB p65 when compared with normal samples that were corrected by sulfasalazine treatment (Fig. 2). In contrast, diabetic DRG displayed a ∼30% decrease in NF-κB p65 compared with normal samples that was not significantly altered after treatment with sulfasalazine (Fig. 3). Finally, a similar pattern, decreased levels in diabetic compared with normal samples that were not corrected by sulfasalazine treatment, was observed for NF-κB phospho-p65 (P-p65) in sciatic nerves and DRG nuclear-enriched fractions (Figs. 2 and 3).

Bottom Line: Importantly, the absence of tactile allodynia in diabetic NF-kappaB p50(-/-) mice supported a role for NF-kappaB in diabetic neuropathy.The complete inhibition of tactile allodynia in experimental diabetes by sulfasalazine may stem from its ability to regulate both NF-kappaB and inosine.Sulfasalazine might be useful in the treatment of nociceptive alterations in diabetic patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. lnb@case.edu

ABSTRACT

Objective: Diabetic neuropathy is manifested either by loss of nociception (painless syndrome) or by mechanical hyperalgesia and tactile allodynia (pain in response to nonpainful stimuli). While therapies with vasodilators or neurotrophins reverse some functional and metabolic abnormalities in diabetic nerves, they only partially ameliorate neuropathic pain. The reported link between nociception and targets of the anti-inflammatory drug sulfasalazine prompted us to investigate its effect on neuropathic pain in diabetes.

Research design and methods: We examined the effects of sulfasalazine, salicylates, and the poly(ADP-ribose) polymerase-1 inhibitor PJ34 on altered nociception in streptozotocin-induced diabetic rats. We also evaluated the levels of sulfasalazine targets in sciatic nerves and dorsal root ganglia (DRG) of treated animals. Finally, we analyzed the development of tactile allodynia in diabetic mice lacking expression of the sulfasalazine target nuclear factor-kappaB (NF-kappaB) p50.

Results: Sulfasalazine completely blocked the development of tactile allodynia in diabetic rats, whereas relatively minor effects were observed with other salicylates and PJ34. Along with the behavioral findings, sciatic nerves and DRG from sulfasalazine-treated diabetic rats displayed a decrease in NF-kappaB p50 expression compared with untreated diabetic animals. Importantly, the absence of tactile allodynia in diabetic NF-kappaB p50(-/-) mice supported a role for NF-kappaB in diabetic neuropathy. Sulfasalazine treatment also increased inosine levels in sciatic nerves of diabetic rats.

Conclusions: The complete inhibition of tactile allodynia in experimental diabetes by sulfasalazine may stem from its ability to regulate both NF-kappaB and inosine. Sulfasalazine might be useful in the treatment of nociceptive alterations in diabetic patients.

Show MeSH
Related in: MedlinePlus