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Inhibition of cathepsin S produces neuroprotective effects after traumatic brain injury in mice.

Xu J, Wang H, Ding K, Lu X, Li T, Wang J, Wang C, Wang J - Mediators Inflamm. (2013)

Bottom Line: The increased expression was detected in microglia and neurons.Inhibition of CatS significantly reduced the level of TBI-induced inflammatory factors in brain tissue and alleviated brain edema.Additionally, administration of LHVS led to a decrease in neuronal degeneration and improved neurobehavioral function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu 210002, China.

ABSTRACT
Cathepsin S (CatS) is a cysteine protease normally present in lysosomes. It has long been regarded as an enzyme that is primarily involved in general protein degradation. More recently, mounting evidence has shown that it is involved in Alzheimer disease, seizures, age-related inflammatory processes, and neuropathic pain. In this study, we investigated the time course of CatS protein and mRNA expression and the cellular distribution of CatS in a mouse model of traumatic brain injury (TBI). To clarify the roles of CatS in TBI, we injected the mice intraventricularly with LHVS, a nonbrain penetrant, irreversible CatS inhibitor, and examined the effect on inflammation and neurobehavioral function. We found that expression of CatS was increased as early as 1 h after TBI at both protein and mRNA levels. The increased expression was detected in microglia and neurons. Inhibition of CatS significantly reduced the level of TBI-induced inflammatory factors in brain tissue and alleviated brain edema. Additionally, administration of LHVS led to a decrease in neuronal degeneration and improved neurobehavioral function. These results imply that CatS is involved in the secondary injury after TBI and provide a new perspective for preventing secondary injury after TBI.

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Related in: MedlinePlus

LHVS pretreatment reduces neuronal degeneration after traumatic brain injury (TBI). Upper panel: Fluoro-Jade C (FJC) staining of the pericontusional cortex in the sham group (a), TBI group (b), TBI + vehicle group (c), and TBI + LHVS (30 nM) group (d). Bottom panel: quantification of neurodegenerating (FJC-positive) cells in each group (n = 6 mice per group). Pretreatment with 30 nM LHVS significantly reduced the number of degenerating neurons at 24 h after TBI. Vehicle treatment had no effect. Data are presented as mean ± SEM (n = 6). ***P < 0.001 versus sham group; #P < 0.05 versus TBI + vehicle group. Scale bar: 20 µm.
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fig7: LHVS pretreatment reduces neuronal degeneration after traumatic brain injury (TBI). Upper panel: Fluoro-Jade C (FJC) staining of the pericontusional cortex in the sham group (a), TBI group (b), TBI + vehicle group (c), and TBI + LHVS (30 nM) group (d). Bottom panel: quantification of neurodegenerating (FJC-positive) cells in each group (n = 6 mice per group). Pretreatment with 30 nM LHVS significantly reduced the number of degenerating neurons at 24 h after TBI. Vehicle treatment had no effect. Data are presented as mean ± SEM (n = 6). ***P < 0.001 versus sham group; #P < 0.05 versus TBI + vehicle group. Scale bar: 20 µm.

Mentions: Next we investigated the role of CatS in neuronal degeneration after TBI by using FJC staining to determine how LHVS pretreatment affects neuronal degeneration in the cortex at 24 h after TBI. We chose 30 nM LHVS because the results described above showed it to be the most effective concentration. Few FJC-positive neurons were observed in the cortex of sham-TBI mice (Figure 7(a)). TBI caused a significant increase in the number of degenerating neurons in the cortex (P < 0.001 versus sham group; Figure 7(b)). Vehicle treatment had no effect on the number of degenerating neurons (P > 0.05 versus TBI group; Figure 7(c)). However, LHVS treatment significantly reduced the number of degenerating cortical neurons compared with that in the vehicle-treated group (P < 0.05; Figure 7(d)). These results indicate that administration of LHVS can reduce neuronal degeneration in the cortex surrounding the contusive lesion and provide neuroprotective effects after TBI.


Inhibition of cathepsin S produces neuroprotective effects after traumatic brain injury in mice.

Xu J, Wang H, Ding K, Lu X, Li T, Wang J, Wang C, Wang J - Mediators Inflamm. (2013)

LHVS pretreatment reduces neuronal degeneration after traumatic brain injury (TBI). Upper panel: Fluoro-Jade C (FJC) staining of the pericontusional cortex in the sham group (a), TBI group (b), TBI + vehicle group (c), and TBI + LHVS (30 nM) group (d). Bottom panel: quantification of neurodegenerating (FJC-positive) cells in each group (n = 6 mice per group). Pretreatment with 30 nM LHVS significantly reduced the number of degenerating neurons at 24 h after TBI. Vehicle treatment had no effect. Data are presented as mean ± SEM (n = 6). ***P < 0.001 versus sham group; #P < 0.05 versus TBI + vehicle group. Scale bar: 20 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824312&req=5

fig7: LHVS pretreatment reduces neuronal degeneration after traumatic brain injury (TBI). Upper panel: Fluoro-Jade C (FJC) staining of the pericontusional cortex in the sham group (a), TBI group (b), TBI + vehicle group (c), and TBI + LHVS (30 nM) group (d). Bottom panel: quantification of neurodegenerating (FJC-positive) cells in each group (n = 6 mice per group). Pretreatment with 30 nM LHVS significantly reduced the number of degenerating neurons at 24 h after TBI. Vehicle treatment had no effect. Data are presented as mean ± SEM (n = 6). ***P < 0.001 versus sham group; #P < 0.05 versus TBI + vehicle group. Scale bar: 20 µm.
Mentions: Next we investigated the role of CatS in neuronal degeneration after TBI by using FJC staining to determine how LHVS pretreatment affects neuronal degeneration in the cortex at 24 h after TBI. We chose 30 nM LHVS because the results described above showed it to be the most effective concentration. Few FJC-positive neurons were observed in the cortex of sham-TBI mice (Figure 7(a)). TBI caused a significant increase in the number of degenerating neurons in the cortex (P < 0.001 versus sham group; Figure 7(b)). Vehicle treatment had no effect on the number of degenerating neurons (P > 0.05 versus TBI group; Figure 7(c)). However, LHVS treatment significantly reduced the number of degenerating cortical neurons compared with that in the vehicle-treated group (P < 0.05; Figure 7(d)). These results indicate that administration of LHVS can reduce neuronal degeneration in the cortex surrounding the contusive lesion and provide neuroprotective effects after TBI.

Bottom Line: The increased expression was detected in microglia and neurons.Inhibition of CatS significantly reduced the level of TBI-induced inflammatory factors in brain tissue and alleviated brain edema.Additionally, administration of LHVS led to a decrease in neuronal degeneration and improved neurobehavioral function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu 210002, China.

ABSTRACT
Cathepsin S (CatS) is a cysteine protease normally present in lysosomes. It has long been regarded as an enzyme that is primarily involved in general protein degradation. More recently, mounting evidence has shown that it is involved in Alzheimer disease, seizures, age-related inflammatory processes, and neuropathic pain. In this study, we investigated the time course of CatS protein and mRNA expression and the cellular distribution of CatS in a mouse model of traumatic brain injury (TBI). To clarify the roles of CatS in TBI, we injected the mice intraventricularly with LHVS, a nonbrain penetrant, irreversible CatS inhibitor, and examined the effect on inflammation and neurobehavioral function. We found that expression of CatS was increased as early as 1 h after TBI at both protein and mRNA levels. The increased expression was detected in microglia and neurons. Inhibition of CatS significantly reduced the level of TBI-induced inflammatory factors in brain tissue and alleviated brain edema. Additionally, administration of LHVS led to a decrease in neuronal degeneration and improved neurobehavioral function. These results imply that CatS is involved in the secondary injury after TBI and provide a new perspective for preventing secondary injury after TBI.

Show MeSH
Related in: MedlinePlus