Interactions between Sirt1 and MAPKs regulate astrocyte activation induced by brain injury in vitro and in vivo View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-03-29

AUTHORS

Dan Li, Nan Liu, Hai-Hua Zhao, Xu Zhang, Hitoshi Kawano, Lu Liu, Liang Zhao, Hong-Peng Li

ABSTRACT

BACKGROUND: Astrocyte activation is a hallmark of traumatic brain injury resulting in neurological dysfunction or death for an overproduction of inflammatory cytokines and glial scar formation. Both the silent mating type information (Sirt1) expression and mitogen-activated protein kinase (MAPK) signal pathway activation represent a promising therapeutic target for several models of neurodegenerative diseases. We investigated the potential effects of Sirt1 upregulation and MAPK pathway pharmacological inhibition on astrocyte activation in vitro and in vivo. Moreover, we attempted to confirm the underlying interactions between Sirt1 and MAPK pathways in astrocyte activation after brain injury. METHODS: The present study employs an interleukin-1β (IL-1β) stimulated primary cortical astrocyte model in vitro and a nigrostriatal pathway injury model in vivo to mimic the astrocyte activation induced by traumatic brain injury. The activation of GFAP, Sirt1, and MAPK pathways were detected by Western blot; astrocyte morphological hypertrophy was assessed using immunofluorescence staining; in order to explore the neuroprotective effect of regulation Sirt1 expression and MAPK pathway activation, the motor and neurological function tests were assessed after injury. RESULTS: GFAP level and morphological hypertrophy of astrocytes are elevated after injury in vitro or in vivo. Furthermore, the expressions of phosphorylated extracellular regulated protein kinases (p-ERK), phosphorylated c-Jun N-terminal kinase (p-JNK), and phosphorylated p38 activation (p-p38) are upregulated, but the Sirt1 expression is downregulated. Overexpression of Sirt1 significantly increases the p-ERK expression and reduces the p-JNK and p-p38 expressions. Inhibition of ERK, JNK, or p38 activation respectively with their inhibitors significantly elevated the Sirt1 expression and attenuated the astrocyte activation. Both the overproduction of Sirt1 and inhibition of ERK, JNK, or p38 activation can alleviate the astrocyte activation, thereby improving the neurobehavioral function according to the modified neurological severity scores (mNSS) and balance latency test. CONCLUSIONS: Thus, Sirt1 plays a protective role against astrocyte activation, which may be associated with the regulation of the MAPK pathway activation induced by brain injury in vitro and in vivo. More... »

PAGES

67

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URI

http://scigraph.springernature.com/pub.10.1186/s12974-017-0841-6

DOI

http://dx.doi.org/10.1186/s12974-017-0841-6

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28356158


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41 Jun N
42 MAPK
43 MAPK pathway
44 MAPK pathway activation
45 MAPK pathway pharmacological inhibition
46 SIRT1
47 SIRT1 expression
48 SIRT1 upregulation
49 Western blot
50 activation
51 activation of GFAP
52 astrocyte activation
53 astrocyte model
54 astrocyte morphological hypertrophy
55 astrocytes
56 blot
57 brain injury
58 cortical astrocyte model
59 cytokines
60 death
61 disease
62 dysfunction
63 effect
64 expression
65 formation
66 function
67 function tests
68 glial scar formation
69 hallmark
70 hypertrophy
71 immunofluorescence
72 inflammatory cytokines
73 information expression
74 inhibition
75 inhibition of ERK
76 inhibitors
77 injury
78 injury model
79 interaction
80 interleukin-1β
81 kinase
82 kinase (MAPK) signal pathway activation
83 latency test
84 levels
85 mating type information (Sirt1) expression
86 mitogen-activated protein kinase (MAPK) signal pathway activation
87 model
88 modified neurological severity score
89 morphological hypertrophy
90 motor
91 neurobehavioral function
92 neurodegenerative diseases
93 neurological dysfunction
94 neurological function tests
95 neurological severity score
96 neuroprotective effects
97 nigrostriatal pathway injury model
98 order
99 overexpression
100 overexpression of SIRT1
101 overproduction
102 overproduction of Sirt1
103 p38 activation
104 p38 expression
105 pathway
106 pathway activation
107 pathway injury model
108 pathway pharmacological inhibition
109 pharmacological inhibition
110 phosphorylated p38 activation
111 potential effects
112 present study
113 primary cortical astrocyte model
114 promising therapeutic target
115 protective role
116 protein kinase
117 protein kinase (MAPK) signal pathway activation
118 regulation
119 regulation Sirt1 expression
120 role
121 scar formation
122 scores
123 severity score
124 signal pathway activation
125 silent mating type information (Sirt1) expression
126 study
127 target
128 terminal kinase
129 test
130 therapeutic target
131 traumatic brain injury
132 type information (Sirt1) expression
133 upregulation
134 vitro
135 vivo
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