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Transiently lowering tumor necrosis factor-α synthesis ameliorates neuronal cell loss and cognitive impairments induced by minimal traumatic brain injury in mice.

Baratz R, Tweedie D, Wang JY, Rubovitch V, Luo W, Hoffer BJ, Greig NH, Pick CG - J Neuroinflammation (2015)

Bottom Line: TNF-α levels are reported to become rapidly elevated post TBI and, potentially, can lead to secondary neuronal damage.This was accompanied by a neuronal loss and an increase in astrocyte number (evaluated by neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) immunostaining), as well as an elevation in the apoptotic death marker BH3-interacting domain death agonist (BID) at 72 h.These results implicate that TNF-α in mTBI induced secondary brain damage and indicate that pharmacologically limiting the generation of TNF-α post mTBI may mitigate such damage, defining a time-dependent window of up to 12 h to achieve this reversal.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. renanaba@post.tau.ac.il.

ABSTRACT

Background: The treatment of traumatic brain injury (TBI) represents an unmet medical need, as no effective pharmacological treatment currently exists. The development of such a treatment requires a fundamental understanding of the pathophysiological mechanisms that underpin the sequelae resulting from TBI, particularly the ensuing neuronal cell death and cognitive impairments. Tumor necrosis factor-alpha (TNF-α) is a cytokine that is a master regulator of systemic and neuroinflammatory processes. TNF-α levels are reported to become rapidly elevated post TBI and, potentially, can lead to secondary neuronal damage.

Methods: To elucidate the role of TNF-α in TBI, particularly as a drug target, the present study evaluated (i) time-dependent TNF-α levels and (ii) markers of apoptosis and gliosis within the brain and related these to behavioral measures of 'well being' and cognition in a mouse closed head 50 g weight drop mild TBI (mTBI) model in the presence and absence of post-treatment with an experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide.

Results: mTBI elevated brain TNF-α levels, which peaked at 12 h post injury and returned to baseline by 18 h. This was accompanied by a neuronal loss and an increase in astrocyte number (evaluated by neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) immunostaining), as well as an elevation in the apoptotic death marker BH3-interacting domain death agonist (BID) at 72 h. Selective impairments in measures of cognition, evaluated by novel object recognition and passive avoidance paradigms - without changes in well being, were evident at 7 days after injury. A single systemic treatment with the TNF-α synthesis inhibitor 3,6'-dithiothalidomide 1 h post injury prevented the mTBI-induced TNF-α elevation and fully ameliorated the neuronal loss (NeuN), elevations in astrocyte number (GFAP) and BID, and cognitive impairments. Cognitive impairments evident at 7 days after injury were prevented by treatment as late as 12 h post mTBI but were not reversed when treatment was delayed until 18 h.

Conclusions: These results implicate that TNF-α in mTBI induced secondary brain damage and indicate that pharmacologically limiting the generation of TNF-α post mTBI may mitigate such damage, defining a time-dependent window of up to 12 h to achieve this reversal.

No MeSH data available.


Related in: MedlinePlus

mTBI induces a time-dependent rise in brain TNF-αlevels. Right (ipsilateral to mTBI) cerebral cortex protein extracts were prepared from sham or mTBI mice at the indicated time points post injury. (A) Time-dependent brain levels of TNF-α at baseline (sham) and post injury. At 12 h post mTBI, TNF-α levels peaked (132.8 vs. 53.4 (sham) pg/ml, p < 0.0001). By 18 h post injury, TNF-α levels returned to baseline (50.5 pg/ml). (B) Treatment with 3,6′-dithiothalidomide (3,6-DT) at 1 h after mTBI prevented the TNF-α elevation evident at 12 h post mTBI (3,6′-DT + mTBI 67.1 pg/ml vs. mTBI 132.8 pg/ml, p < 0.0001). In both (A) and (B), **** was significantly different from all other groups (p < 0.0001).
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Fig1: mTBI induces a time-dependent rise in brain TNF-αlevels. Right (ipsilateral to mTBI) cerebral cortex protein extracts were prepared from sham or mTBI mice at the indicated time points post injury. (A) Time-dependent brain levels of TNF-α at baseline (sham) and post injury. At 12 h post mTBI, TNF-α levels peaked (132.8 vs. 53.4 (sham) pg/ml, p < 0.0001). By 18 h post injury, TNF-α levels returned to baseline (50.5 pg/ml). (B) Treatment with 3,6′-dithiothalidomide (3,6-DT) at 1 h after mTBI prevented the TNF-α elevation evident at 12 h post mTBI (3,6′-DT + mTBI 67.1 pg/ml vs. mTBI 132.8 pg/ml, p < 0.0001). In both (A) and (B), **** was significantly different from all other groups (p < 0.0001).

Mentions: As illustrated in Figure 1, mice challenged with mTBI demonstrated a time-dependent rise in brain protein levels of TNF-α that were increased by 2.5-fold, peaked at 12 h post injury, and returned to baseline by 18 h [F(3,13) = 30.529, p < 0.0001]. LSD post hoc analyses confirmed that the 12-h mTBI group was significantly different from all other groups (p < 0.0001). Levels were elevated to 132.9 pg/ml at 12 h versus a baseline value of 53.4 pg/ml. In animals subjected to mTBI and administered 3,6′-dithiothalidomide 1 h post injury, the elevated TNF-α 12 h post injury response was ameliorated. Specifically, mice treated with 3,6′-dithiothalidomide post injury had similar brain TNF-α levels as the sham group, 67.0 and 53.4 pg/ml, respectively, F(4,17) = 14.579, p < 0.0001, Figure 1B. LSD post hoc analyses confirmed that the mTBI 12-h group was significantly different from all other groups (p < 0.0001).Figure 1


Transiently lowering tumor necrosis factor-α synthesis ameliorates neuronal cell loss and cognitive impairments induced by minimal traumatic brain injury in mice.

Baratz R, Tweedie D, Wang JY, Rubovitch V, Luo W, Hoffer BJ, Greig NH, Pick CG - J Neuroinflammation (2015)

mTBI induces a time-dependent rise in brain TNF-αlevels. Right (ipsilateral to mTBI) cerebral cortex protein extracts were prepared from sham or mTBI mice at the indicated time points post injury. (A) Time-dependent brain levels of TNF-α at baseline (sham) and post injury. At 12 h post mTBI, TNF-α levels peaked (132.8 vs. 53.4 (sham) pg/ml, p < 0.0001). By 18 h post injury, TNF-α levels returned to baseline (50.5 pg/ml). (B) Treatment with 3,6′-dithiothalidomide (3,6-DT) at 1 h after mTBI prevented the TNF-α elevation evident at 12 h post mTBI (3,6′-DT + mTBI 67.1 pg/ml vs. mTBI 132.8 pg/ml, p < 0.0001). In both (A) and (B), **** was significantly different from all other groups (p < 0.0001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4352276&req=5

Fig1: mTBI induces a time-dependent rise in brain TNF-αlevels. Right (ipsilateral to mTBI) cerebral cortex protein extracts were prepared from sham or mTBI mice at the indicated time points post injury. (A) Time-dependent brain levels of TNF-α at baseline (sham) and post injury. At 12 h post mTBI, TNF-α levels peaked (132.8 vs. 53.4 (sham) pg/ml, p < 0.0001). By 18 h post injury, TNF-α levels returned to baseline (50.5 pg/ml). (B) Treatment with 3,6′-dithiothalidomide (3,6-DT) at 1 h after mTBI prevented the TNF-α elevation evident at 12 h post mTBI (3,6′-DT + mTBI 67.1 pg/ml vs. mTBI 132.8 pg/ml, p < 0.0001). In both (A) and (B), **** was significantly different from all other groups (p < 0.0001).
Mentions: As illustrated in Figure 1, mice challenged with mTBI demonstrated a time-dependent rise in brain protein levels of TNF-α that were increased by 2.5-fold, peaked at 12 h post injury, and returned to baseline by 18 h [F(3,13) = 30.529, p < 0.0001]. LSD post hoc analyses confirmed that the 12-h mTBI group was significantly different from all other groups (p < 0.0001). Levels were elevated to 132.9 pg/ml at 12 h versus a baseline value of 53.4 pg/ml. In animals subjected to mTBI and administered 3,6′-dithiothalidomide 1 h post injury, the elevated TNF-α 12 h post injury response was ameliorated. Specifically, mice treated with 3,6′-dithiothalidomide post injury had similar brain TNF-α levels as the sham group, 67.0 and 53.4 pg/ml, respectively, F(4,17) = 14.579, p < 0.0001, Figure 1B. LSD post hoc analyses confirmed that the mTBI 12-h group was significantly different from all other groups (p < 0.0001).Figure 1

Bottom Line: TNF-α levels are reported to become rapidly elevated post TBI and, potentially, can lead to secondary neuronal damage.This was accompanied by a neuronal loss and an increase in astrocyte number (evaluated by neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) immunostaining), as well as an elevation in the apoptotic death marker BH3-interacting domain death agonist (BID) at 72 h.These results implicate that TNF-α in mTBI induced secondary brain damage and indicate that pharmacologically limiting the generation of TNF-α post mTBI may mitigate such damage, defining a time-dependent window of up to 12 h to achieve this reversal.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. renanaba@post.tau.ac.il.

ABSTRACT

Background: The treatment of traumatic brain injury (TBI) represents an unmet medical need, as no effective pharmacological treatment currently exists. The development of such a treatment requires a fundamental understanding of the pathophysiological mechanisms that underpin the sequelae resulting from TBI, particularly the ensuing neuronal cell death and cognitive impairments. Tumor necrosis factor-alpha (TNF-α) is a cytokine that is a master regulator of systemic and neuroinflammatory processes. TNF-α levels are reported to become rapidly elevated post TBI and, potentially, can lead to secondary neuronal damage.

Methods: To elucidate the role of TNF-α in TBI, particularly as a drug target, the present study evaluated (i) time-dependent TNF-α levels and (ii) markers of apoptosis and gliosis within the brain and related these to behavioral measures of 'well being' and cognition in a mouse closed head 50 g weight drop mild TBI (mTBI) model in the presence and absence of post-treatment with an experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide.

Results: mTBI elevated brain TNF-α levels, which peaked at 12 h post injury and returned to baseline by 18 h. This was accompanied by a neuronal loss and an increase in astrocyte number (evaluated by neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) immunostaining), as well as an elevation in the apoptotic death marker BH3-interacting domain death agonist (BID) at 72 h. Selective impairments in measures of cognition, evaluated by novel object recognition and passive avoidance paradigms - without changes in well being, were evident at 7 days after injury. A single systemic treatment with the TNF-α synthesis inhibitor 3,6'-dithiothalidomide 1 h post injury prevented the mTBI-induced TNF-α elevation and fully ameliorated the neuronal loss (NeuN), elevations in astrocyte number (GFAP) and BID, and cognitive impairments. Cognitive impairments evident at 7 days after injury were prevented by treatment as late as 12 h post mTBI but were not reversed when treatment was delayed until 18 h.

Conclusions: These results implicate that TNF-α in mTBI induced secondary brain damage and indicate that pharmacologically limiting the generation of TNF-α post mTBI may mitigate such damage, defining a time-dependent window of up to 12 h to achieve this reversal.

No MeSH data available.


Related in: MedlinePlus