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Hydrogen sulfide-releasing cyclooxygenase inhibitor ATB-346 enhances motor function and reduces cortical lesion volume following traumatic brain injury in mice.

Campolo M, Esposito E, Ahmad A, Di Paola R, Paterniti I, Cordaro M, Bruschetta G, Wallace JL, Cuzzocrea S - J Neuroinflammation (2014)

Bottom Line: We recently reported that administration of ATB-346 (2-(6-methoxynapthalen- 2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester), a hydrogen sulfide-releasing cyclooxygenase inhibitor, showed marked beneficial effects in an animal model of spinal cord injury, significantly enhancing recovery of motor function and reducing the secondary inflammation and tissue injury.Moreover, the aim of the present study was to carefully investigate molecular pathways and subtypes of glial cells involved in the protective effect of ATB-346 on inflammatory reaction associated with an experimental model of TBI.ATB-346 also significantly reduced the severity of inflammation and restored neurotrophic factors that characterized the secondary events of TBI.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31-98166, Messina, Italy. campolom@unime.it.

ABSTRACT

Background: Traumatic brain injury (TBI) induces secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. We recently reported that administration of ATB-346 (2-(6-methoxynapthalen- 2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester), a hydrogen sulfide-releasing cyclooxygenase inhibitor, showed marked beneficial effects in an animal model of spinal cord injury, significantly enhancing recovery of motor function and reducing the secondary inflammation and tissue injury.

Methods: Here we evaluated the neuroprotective potential of ATB-346, a hydrogen sulfide-releasing derivative of naproxen, using the controlled cortical impact (CCI) injury model in mice, one of the most common models of TBI. Moreover, the aim of the present study was to carefully investigate molecular pathways and subtypes of glial cells involved in the protective effect of ATB-346 on inflammatory reaction associated with an experimental model of TBI. In these studies, TBI was induced in mice by CCI and mice were orally administered ATB-346, naproxen (both at 30 μmol/kg) or vehicle (dimethylsulfoxide:1% carboxymethylcellulose [5:95] suspension) one and six hours after brain trauma and once daily for 10 days.

Results: Results revealed that ATB-346 attenuated TBI-induced brain edema, suppressed TBI-induced neural cell death and improved neurological function. ATB-346 also significantly reduced the severity of inflammation and restored neurotrophic factors that characterized the secondary events of TBI.

Conclusions: These data demonstrate that ATB-346 can be efficacious in a TBI animal model by reducing the secondary inflammation and tissue injury. Therefore, ATB-346 could represent an interesting approach for the management of secondary damage following CNS diseases, counteracting behavioral changes and inflammatory process.

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RT–PCR analysis forGDNF,NGFandVEGF(A, B and C, respectively). ATB-346 treatment significantly increased both GDNF and NGF mRNA expression compared to TBI (A and B, respectively). ATB-346 determined an important increase in VEGF mRNA expression (C). β-actin was used as an internal control. mRNA was extracted and reverse-transcribed as described in the Methods section. Similar results were obtained in four additional separate experiments. No bands were observed in the absence of cDNA. Western blot analysis showed that eNOS expression in TBI mice was increased compared with sham mice (D), while ATB-346 upregulated its expression (D). A representative blot of homogenates obtained from five animals per group is shown, and densitometry analysis of all animals is reported (A1 to D1). A P value of less than 0.05 was considered significant. *P < 0.05, **P <0.01, ***P <0.001 versus sham, #P <0.05 versus TBI.
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Fig6: RT–PCR analysis forGDNF,NGFandVEGF(A, B and C, respectively). ATB-346 treatment significantly increased both GDNF and NGF mRNA expression compared to TBI (A and B, respectively). ATB-346 determined an important increase in VEGF mRNA expression (C). β-actin was used as an internal control. mRNA was extracted and reverse-transcribed as described in the Methods section. Similar results were obtained in four additional separate experiments. No bands were observed in the absence of cDNA. Western blot analysis showed that eNOS expression in TBI mice was increased compared with sham mice (D), while ATB-346 upregulated its expression (D). A representative blot of homogenates obtained from five animals per group is shown, and densitometry analysis of all animals is reported (A1 to D1). A P value of less than 0.05 was considered significant. *P < 0.05, **P <0.01, ***P <0.001 versus sham, #P <0.05 versus TBI.

Mentions: To test whether ATB-346 modulates the levels of the neurotrophic factors, we studied GDNF and NGF levels in brain tissue using semi-quantitative RT–PCR analysis. A significant decrease in GDNF (470 bp) and NGF (318 bp) mRNA expression following TBI and TBZ administration was evident. Moreover, ATB-346 significantly increased mRNA levels of both neurotrophic factors examined (Figure 6A and B respectively, see densitometry analysis A1 and B1 respectively).Figure 6


Hydrogen sulfide-releasing cyclooxygenase inhibitor ATB-346 enhances motor function and reduces cortical lesion volume following traumatic brain injury in mice.

Campolo M, Esposito E, Ahmad A, Di Paola R, Paterniti I, Cordaro M, Bruschetta G, Wallace JL, Cuzzocrea S - J Neuroinflammation (2014)

RT–PCR analysis forGDNF,NGFandVEGF(A, B and C, respectively). ATB-346 treatment significantly increased both GDNF and NGF mRNA expression compared to TBI (A and B, respectively). ATB-346 determined an important increase in VEGF mRNA expression (C). β-actin was used as an internal control. mRNA was extracted and reverse-transcribed as described in the Methods section. Similar results were obtained in four additional separate experiments. No bands were observed in the absence of cDNA. Western blot analysis showed that eNOS expression in TBI mice was increased compared with sham mice (D), while ATB-346 upregulated its expression (D). A representative blot of homogenates obtained from five animals per group is shown, and densitometry analysis of all animals is reported (A1 to D1). A P value of less than 0.05 was considered significant. *P < 0.05, **P <0.01, ***P <0.001 versus sham, #P <0.05 versus TBI.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4265354&req=5

Fig6: RT–PCR analysis forGDNF,NGFandVEGF(A, B and C, respectively). ATB-346 treatment significantly increased both GDNF and NGF mRNA expression compared to TBI (A and B, respectively). ATB-346 determined an important increase in VEGF mRNA expression (C). β-actin was used as an internal control. mRNA was extracted and reverse-transcribed as described in the Methods section. Similar results were obtained in four additional separate experiments. No bands were observed in the absence of cDNA. Western blot analysis showed that eNOS expression in TBI mice was increased compared with sham mice (D), while ATB-346 upregulated its expression (D). A representative blot of homogenates obtained from five animals per group is shown, and densitometry analysis of all animals is reported (A1 to D1). A P value of less than 0.05 was considered significant. *P < 0.05, **P <0.01, ***P <0.001 versus sham, #P <0.05 versus TBI.
Mentions: To test whether ATB-346 modulates the levels of the neurotrophic factors, we studied GDNF and NGF levels in brain tissue using semi-quantitative RT–PCR analysis. A significant decrease in GDNF (470 bp) and NGF (318 bp) mRNA expression following TBI and TBZ administration was evident. Moreover, ATB-346 significantly increased mRNA levels of both neurotrophic factors examined (Figure 6A and B respectively, see densitometry analysis A1 and B1 respectively).Figure 6

Bottom Line: We recently reported that administration of ATB-346 (2-(6-methoxynapthalen- 2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester), a hydrogen sulfide-releasing cyclooxygenase inhibitor, showed marked beneficial effects in an animal model of spinal cord injury, significantly enhancing recovery of motor function and reducing the secondary inflammation and tissue injury.Moreover, the aim of the present study was to carefully investigate molecular pathways and subtypes of glial cells involved in the protective effect of ATB-346 on inflammatory reaction associated with an experimental model of TBI.ATB-346 also significantly reduced the severity of inflammation and restored neurotrophic factors that characterized the secondary events of TBI.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31-98166, Messina, Italy. campolom@unime.it.

ABSTRACT

Background: Traumatic brain injury (TBI) induces secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory and cytotoxic processes. We recently reported that administration of ATB-346 (2-(6-methoxynapthalen- 2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester), a hydrogen sulfide-releasing cyclooxygenase inhibitor, showed marked beneficial effects in an animal model of spinal cord injury, significantly enhancing recovery of motor function and reducing the secondary inflammation and tissue injury.

Methods: Here we evaluated the neuroprotective potential of ATB-346, a hydrogen sulfide-releasing derivative of naproxen, using the controlled cortical impact (CCI) injury model in mice, one of the most common models of TBI. Moreover, the aim of the present study was to carefully investigate molecular pathways and subtypes of glial cells involved in the protective effect of ATB-346 on inflammatory reaction associated with an experimental model of TBI. In these studies, TBI was induced in mice by CCI and mice were orally administered ATB-346, naproxen (both at 30 μmol/kg) or vehicle (dimethylsulfoxide:1% carboxymethylcellulose [5:95] suspension) one and six hours after brain trauma and once daily for 10 days.

Results: Results revealed that ATB-346 attenuated TBI-induced brain edema, suppressed TBI-induced neural cell death and improved neurological function. ATB-346 also significantly reduced the severity of inflammation and restored neurotrophic factors that characterized the secondary events of TBI.

Conclusions: These data demonstrate that ATB-346 can be efficacious in a TBI animal model by reducing the secondary inflammation and tissue injury. Therefore, ATB-346 could represent an interesting approach for the management of secondary damage following CNS diseases, counteracting behavioral changes and inflammatory process.

Show MeSH
Related in: MedlinePlus