Limits...
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 impairments in performance in both a Y-maze and novel object recognition (NOR) preference index paradigms that are ameliorated by 3,6′-dithiothalidomide when administered up to 12 but not 18 h post injury. (A) Performance of mice was quantitatively assessed in a Y-maze and (B) in a NOR paradigm at 7 days following mTBI as a preference index that was calculated as (time associated with the novel − time with the old arm or object)/(time with the novel + time with the old arm or object). Values are mean ± SEM values; a one-way ANOVA indicates that mTBI animals had a deficit in spatial (Y-maze) and visual (NOR) memory performance compared with all the other groups (*p < 0.05) with the exception of animals dosed with 3,6′-dithiothalidomide at 18 h post injury. No differences were found between any of the other groups (control (sham) 1 and 12 h 3,6′-dithiothalidomide dosing), suggesting complete amelioration by 3,6′-dithiothalidomide when administered within 12 h of injury.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: mTBI induces impairments in performance in both a Y-maze and novel object recognition (NOR) preference index paradigms that are ameliorated by 3,6′-dithiothalidomide when administered up to 12 but not 18 h post injury. (A) Performance of mice was quantitatively assessed in a Y-maze and (B) in a NOR paradigm at 7 days following mTBI as a preference index that was calculated as (time associated with the novel − time with the old arm or object)/(time with the novel + time with the old arm or object). Values are mean ± SEM values; a one-way ANOVA indicates that mTBI animals had a deficit in spatial (Y-maze) and visual (NOR) memory performance compared with all the other groups (*p < 0.05) with the exception of animals dosed with 3,6′-dithiothalidomide at 18 h post injury. No differences were found between any of the other groups (control (sham) 1 and 12 h 3,6′-dithiothalidomide dosing), suggesting complete amelioration by 3,6′-dithiothalidomide when administered within 12 h of injury.

Mentions: When evaluated by Y-maze at 7 days post procedure, vehicle-treated mTBI-challenged mice demonstrated a significant impairment in spatial memory, as compared to sham control animals. This mTBI-induced deficit was ameliorated by a single dose of 3,6′-dithiothalidomide administered either 1 or 12 h post injury. However, when 3,6′-dithiothalidomide administration was withheld until 18 h, mice displayed impairment and, together with the mTBI vehicle group, their preference index was significantly reduced compared to sham controls [F(4,57) = 6.462, p < 0.01] (Figure 2A). LSD post hoc analyses confirmed that the mTBI + vehicle and the mTBI + 18 h 3,6′-dithiothalidomide groups were significantly different from all other groups (p < 0.05).Figure 2


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 impairments in performance in both a Y-maze and novel object recognition (NOR) preference index paradigms that are ameliorated by 3,6′-dithiothalidomide when administered up to 12 but not 18 h post injury. (A) Performance of mice was quantitatively assessed in a Y-maze and (B) in a NOR paradigm at 7 days following mTBI as a preference index that was calculated as (time associated with the novel − time with the old arm or object)/(time with the novel + time with the old arm or object). Values are mean ± SEM values; a one-way ANOVA indicates that mTBI animals had a deficit in spatial (Y-maze) and visual (NOR) memory performance compared with all the other groups (*p < 0.05) with the exception of animals dosed with 3,6′-dithiothalidomide at 18 h post injury. No differences were found between any of the other groups (control (sham) 1 and 12 h 3,6′-dithiothalidomide dosing), suggesting complete amelioration by 3,6′-dithiothalidomide when administered within 12 h of injury.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: mTBI induces impairments in performance in both a Y-maze and novel object recognition (NOR) preference index paradigms that are ameliorated by 3,6′-dithiothalidomide when administered up to 12 but not 18 h post injury. (A) Performance of mice was quantitatively assessed in a Y-maze and (B) in a NOR paradigm at 7 days following mTBI as a preference index that was calculated as (time associated with the novel − time with the old arm or object)/(time with the novel + time with the old arm or object). Values are mean ± SEM values; a one-way ANOVA indicates that mTBI animals had a deficit in spatial (Y-maze) and visual (NOR) memory performance compared with all the other groups (*p < 0.05) with the exception of animals dosed with 3,6′-dithiothalidomide at 18 h post injury. No differences were found between any of the other groups (control (sham) 1 and 12 h 3,6′-dithiothalidomide dosing), suggesting complete amelioration by 3,6′-dithiothalidomide when administered within 12 h of injury.
Mentions: When evaluated by Y-maze at 7 days post procedure, vehicle-treated mTBI-challenged mice demonstrated a significant impairment in spatial memory, as compared to sham control animals. This mTBI-induced deficit was ameliorated by a single dose of 3,6′-dithiothalidomide administered either 1 or 12 h post injury. However, when 3,6′-dithiothalidomide administration was withheld until 18 h, mice displayed impairment and, together with the mTBI vehicle group, their preference index was significantly reduced compared to sham controls [F(4,57) = 6.462, p < 0.01] (Figure 2A). LSD post hoc analyses confirmed that the mTBI + vehicle and the mTBI + 18 h 3,6′-dithiothalidomide groups were significantly different from all other groups (p < 0.05).Figure 2

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