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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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Sulfasalazine prevents the development of tactile allodynia in experimentally diabetic rats. A: Experimental diabetes in Lewis rats was induced by a single injection of streptozotocin as described in research design and methods. Diabetic rats (D) exhibited early signs of allodynia 4–7 days after streptozotocin injection, as indicated by the values shown at 0 time (representative of an independent evaluation of two separate sets comprising a total of 52 diabetic and 16 normal rats). Streptozotocin-induced diabetic rats were either left untreated or subjected to treatment with sulfasalazine (starting 6–10 days after streptozotocin injection) for up to 9 months (D+SFZ). B: Streptozotocin-induced diabetic animals were treated for 3 months with sulfasalazine, sodium salicylate (SAL), acetylsalicylic acid (aspirin), or PJ34. The presence of tactile allodynia was investigated at different time points (A) or after 3 months (B) by comparison with responses in normal animals (N) (n = 6–8 animals per group were used). Results are means ± SE of the averages of the 50% withdrawal thresholds measured on the left and right paw of each animal (see research design and methods). Significantly different from diabetic animals at *P < 0.05 and **P < 0.01. ††Significantly different from normal animals at P < 0.01, as calculated by Kruskal-Wallis’ test followed by Dunn's test.
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f1: Sulfasalazine prevents the development of tactile allodynia in experimentally diabetic rats. A: Experimental diabetes in Lewis rats was induced by a single injection of streptozotocin as described in research design and methods. Diabetic rats (D) exhibited early signs of allodynia 4–7 days after streptozotocin injection, as indicated by the values shown at 0 time (representative of an independent evaluation of two separate sets comprising a total of 52 diabetic and 16 normal rats). Streptozotocin-induced diabetic rats were either left untreated or subjected to treatment with sulfasalazine (starting 6–10 days after streptozotocin injection) for up to 9 months (D+SFZ). B: Streptozotocin-induced diabetic animals were treated for 3 months with sulfasalazine, sodium salicylate (SAL), acetylsalicylic acid (aspirin), or PJ34. The presence of tactile allodynia was investigated at different time points (A) or after 3 months (B) by comparison with responses in normal animals (N) (n = 6–8 animals per group were used). Results are means ± SE of the averages of the 50% withdrawal thresholds measured on the left and right paw of each animal (see research design and methods). Significantly different from diabetic animals at *P < 0.05 and **P < 0.01. ††Significantly different from normal animals at P < 0.01, as calculated by Kruskal-Wallis’ test followed by Dunn's test.

Mentions: Consistent with previous observations (18), experimentally diabetic rats exhibited signs of tactile allodynia (i.e., pain in response to nonpainful, low-intensity stimuli) 4–7 days after streptozotocin injection, as evidenced by a significant decrease in the 50% withdrawal thresholds to von Frey filaments (0 time in Fig. 1A). The tactile allodynia in the diabetic animals persisted during the 9-month experimental period. Importantly, treatment with sulfasalazine completely blocked the development of tactile allodynia in diabetic rats (Fig. 1A). The effectiveness of sulfasalazine was also evident when the percentage of animals exhibiting a 50% withdrawal threshold higher than a reference value (set at 8 g) was calculated: responsiveness was observed in 50% of the diabetic rats after 1 month and in 100% after 3 months of therapy. We compared the effect of sulfasalazine on diabetic tactile allodynia with those of other salicylates and the PARP-1 inhibitor PJ34. In contrast to sulfasalazine treatment, administration of sodium salicylate, acetylsalicylic acid, or PJ34 only resulted in a partial, statistically nonsignificant, amelioration of tactile allodynia (Fig. 1B). The higher effectiveness of sulfasalazine was also evident when the percentage of animals exhibiting a 50% withdrawal threshold >8 g was calculated: responsiveness was observed in 90% of diabetic rats treated for 3 months with sulfasalazine compared with only 38, 38, and 25% of those treated with sodium salicylate, acetylsalicylic acid, or PJ34, respectively. Interestingly, although daily insulin administration to 4-month diabetic rats for 4 months corrected the rate of body weight gain and GHb levels, it only partially ameliorated tactile allodynia (Table 2).


Sulfasalazine blocks the development of tactile allodynia in diabetic rats.

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

Sulfasalazine prevents the development of tactile allodynia in experimentally diabetic rats. A: Experimental diabetes in Lewis rats was induced by a single injection of streptozotocin as described in research design and methods. Diabetic rats (D) exhibited early signs of allodynia 4–7 days after streptozotocin injection, as indicated by the values shown at 0 time (representative of an independent evaluation of two separate sets comprising a total of 52 diabetic and 16 normal rats). Streptozotocin-induced diabetic rats were either left untreated or subjected to treatment with sulfasalazine (starting 6–10 days after streptozotocin injection) for up to 9 months (D+SFZ). B: Streptozotocin-induced diabetic animals were treated for 3 months with sulfasalazine, sodium salicylate (SAL), acetylsalicylic acid (aspirin), or PJ34. The presence of tactile allodynia was investigated at different time points (A) or after 3 months (B) by comparison with responses in normal animals (N) (n = 6–8 animals per group were used). Results are means ± SE of the averages of the 50% withdrawal thresholds measured on the left and right paw of each animal (see research design and methods). Significantly different from diabetic animals at *P < 0.05 and **P < 0.01. ††Significantly different from normal animals at P < 0.01, as calculated by Kruskal-Wallis’ test followed by Dunn's test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Sulfasalazine prevents the development of tactile allodynia in experimentally diabetic rats. A: Experimental diabetes in Lewis rats was induced by a single injection of streptozotocin as described in research design and methods. Diabetic rats (D) exhibited early signs of allodynia 4–7 days after streptozotocin injection, as indicated by the values shown at 0 time (representative of an independent evaluation of two separate sets comprising a total of 52 diabetic and 16 normal rats). Streptozotocin-induced diabetic rats were either left untreated or subjected to treatment with sulfasalazine (starting 6–10 days after streptozotocin injection) for up to 9 months (D+SFZ). B: Streptozotocin-induced diabetic animals were treated for 3 months with sulfasalazine, sodium salicylate (SAL), acetylsalicylic acid (aspirin), or PJ34. The presence of tactile allodynia was investigated at different time points (A) or after 3 months (B) by comparison with responses in normal animals (N) (n = 6–8 animals per group were used). Results are means ± SE of the averages of the 50% withdrawal thresholds measured on the left and right paw of each animal (see research design and methods). Significantly different from diabetic animals at *P < 0.05 and **P < 0.01. ††Significantly different from normal animals at P < 0.01, as calculated by Kruskal-Wallis’ test followed by Dunn's test.
Mentions: Consistent with previous observations (18), experimentally diabetic rats exhibited signs of tactile allodynia (i.e., pain in response to nonpainful, low-intensity stimuli) 4–7 days after streptozotocin injection, as evidenced by a significant decrease in the 50% withdrawal thresholds to von Frey filaments (0 time in Fig. 1A). The tactile allodynia in the diabetic animals persisted during the 9-month experimental period. Importantly, treatment with sulfasalazine completely blocked the development of tactile allodynia in diabetic rats (Fig. 1A). The effectiveness of sulfasalazine was also evident when the percentage of animals exhibiting a 50% withdrawal threshold higher than a reference value (set at 8 g) was calculated: responsiveness was observed in 50% of the diabetic rats after 1 month and in 100% after 3 months of therapy. We compared the effect of sulfasalazine on diabetic tactile allodynia with those of other salicylates and the PARP-1 inhibitor PJ34. In contrast to sulfasalazine treatment, administration of sodium salicylate, acetylsalicylic acid, or PJ34 only resulted in a partial, statistically nonsignificant, amelioration of tactile allodynia (Fig. 1B). The higher effectiveness of sulfasalazine was also evident when the percentage of animals exhibiting a 50% withdrawal threshold >8 g was calculated: responsiveness was observed in 90% of diabetic rats treated for 3 months with sulfasalazine compared with only 38, 38, and 25% of those treated with sodium salicylate, acetylsalicylic acid, or PJ34, respectively. Interestingly, although daily insulin administration to 4-month diabetic rats for 4 months corrected the rate of body weight gain and GHb levels, it only partially ameliorated tactile allodynia (Table 2).

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