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Traumatic Brain Injury and Mood Stabilizers: Recent Cumulative Evidence
Accepted Manuscript Traumatic Brain Injury and Mood stabilizers: Recent cumulative evidence Leonardo C. Welling, Mariana S. Welling, Eberval G. Figueiredo PII:
S1878-8750(17)31193-2
DOI:
10.1016/j.wneu.2017.07.093
Reference:
WNEU 6155
To appear in:
World Neurosurgery
Received Date: 1878-8750 1878-8750 Revised Date:
1878-8750 1878-8750
Accepted Date: 1878-8750 1878-8750
Please cite this article as: Welling LC, Welling MS, Figueiredo EG, Traumatic Brain Injury and Mood stabilizers: Recent cumulative evidence, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.07.093. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Traumatic Brain Injury and Mood stabilizers: Recent cumulative evidence
RI PT
Leonardo C. Welling1, Mariana S. Welling1, Eberval G. Figueiredo2
1) Department of Neurological Surgery. State University of Ponta Grossa
SC
2) Department of Neurology, University of Sao Paulo
Traumatic brain injury (TBI) is the primary cause of morbidity and death in
M AN U
young adults in industrialized countries. The catastrophic effects of TBI on patients are more amplified by the fact that there are few treatment options. Notably, TBI encloses an initial primary injury that mechanically injures neurons, glia, and vascular structures, that are often followed by a secondary injury cascade that begins hours or days after the initial trauma (Figure 1). This secondary brain injury is very complex. Its pathophysiology is puzzling and will
TE D
likely require pharmacological agents which act in a coordinated fashion to increase cell survival and decrease cell death pathways (1). In this context, recently, GSK-3 mediated signaling has received increased attention. There is evidence
of
the
role
of
GSK-3-mediated
signaling
as
an
important
EP
neuroprotective mechanism against TBI. These studies have shown that GSK-3 inhibitors including lithium, a mood stabilizer that acts across multiple pathways,
AC C
has neuroprotective properties in TBI (2). The first report of lithium`s use was in 1859. Taking into account the
theoretical hypothesis of capacity to dissolve nitrogen-containing products, this drug had been used for the treatment of rheumatological diseases and gout. At the end of the 19th century, lithium was introduced in the treatment of bipolar disorder, and since then has been widely used for neuropsychiatric disorders (3). Recent studies, based on this observed neuroprotective effect, have investigated the effects of lithium on TBI. In murine models of TBI researchers have found that lithium attenuates hippocampal neurodegeneration, interleukin-
ACCEPTED MANUSCRIPT
1β expression, brain edema, loss of hemispheric tissue and inhibits microglia activation as well as matrix metallopeptidase-9 expression (MMP-9) and cyclooxygenase-2 induction. It should be observed that blood brain barrier integrity is maintained through the inhibition of MMP-9 expression (4,5).
RI PT
According to Yu et al., low doses of combined lithium and valproate were more useful in attenuating TBI injury than either agent used alone (6). Previous studies have found that treatment with lithium and valproate could synergistically
excitotoxicity in central nervous system (7).
SC
enhance GSK-3 inhibition over that of lithium alone, and prevent glutamate
These findings raise the possibility that the mood stabilizers lithium and
M AN U
valproate, either alone or in combination, may be repurposed as drugs to treat neurological disorders with excitotoxic components, best exemplified by traumatic brain injury. In addition, recently discovered synergistic effects, may permit lower doses that might result in fewer side effects and better tolerability. Further investigation into the use of mood stabilizers as neuroprotective agents in
References
TE D
TBI is warranted.
1) Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain
EP
injury in adults. Lancet Neurol. 2008; 7: 728−741.
AC C
2) Leeds PR, Yu F, Wang Z, Chiu CT, Zhang Y, Leng Y, et al. A new avenue for lithium: intervention in traumatic brain injury. ACS Chem Neurosci 2014; 5(6): 422-33.
3) Shorter E. The history of lithium therapy. Bipolar disord 2009; 11: 4-9.
4) Dell'Osso L, Del Grande C, Gesi C, Carmassi C, Musetti L. A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. Neuropsychiatr Dis Treat. 2016; 12: 1687-1703.
ACCEPTED MANUSCRIPT
5) Reis C, Wang Y, Akyol O, Ho WM, Ii RA, Stier G, et al. What's New in Traumatic Brain Injury: Update on Tracking, Monitoring and Treatment. Int J Mol
RI PT
Sci. 2015; 16(6):11903-11965.
6) Yu F, Wang Z, Tanaka M, Chiu CT, Leeds P, et al. Posttrauma cotreatment with lithium and valproate: reduction of lesion volume, attenuation of blood-brain barrier disruption, and improvement in motor coordination in mice
SC
with traumatic brain injury. J Neurosurg. 2013; 119 (3): 766−773.
M AN U
7) Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM. Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci. 2008; 28 (10): 2576−2588.
Legend:
TE D
Figure 1. After traumatic brain injury several and complex mechanisms of secondary are initiated. They may generate edema, necrosis and hemorrhage
AC C
EP
impairing the final outcome.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1878-8750(17)31193-2
DOI:
10.1016/j.wneu.2017.07.093
Reference:
WNEU 6155
To appear in:
World Neurosurgery
Received Date: 1878-8750 1878-8750 Revised Date:
1878-8750 1878-8750
Accepted Date: 1878-8750 1878-8750
Please cite this article as: Welling LC, Welling MS, Figueiredo EG, Traumatic Brain Injury and Mood stabilizers: Recent cumulative evidence, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.07.093. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Traumatic Brain Injury and Mood stabilizers: Recent cumulative evidence
RI PT
Leonardo C. Welling1, Mariana S. Welling1, Eberval G. Figueiredo2
1) Department of Neurological Surgery. State University of Ponta Grossa
SC
2) Department of Neurology, University of Sao Paulo
Traumatic brain injury (TBI) is the primary cause of morbidity and death in
M AN U
young adults in industrialized countries. The catastrophic effects of TBI on patients are more amplified by the fact that there are few treatment options. Notably, TBI encloses an initial primary injury that mechanically injures neurons, glia, and vascular structures, that are often followed by a secondary injury cascade that begins hours or days after the initial trauma (Figure 1). This secondary brain injury is very complex. Its pathophysiology is puzzling and will
TE D
likely require pharmacological agents which act in a coordinated fashion to increase cell survival and decrease cell death pathways (1). In this context, recently, GSK-3 mediated signaling has received increased attention. There is evidence
of
the
role
of
GSK-3-mediated
signaling
as
an
important
EP
neuroprotective mechanism against TBI. These studies have shown that GSK-3 inhibitors including lithium, a mood stabilizer that acts across multiple pathways,
AC C
has neuroprotective properties in TBI (2). The first report of lithium`s use was in 1859. Taking into account the
theoretical hypothesis of capacity to dissolve nitrogen-containing products, this drug had been used for the treatment of rheumatological diseases and gout. At the end of the 19th century, lithium was introduced in the treatment of bipolar disorder, and since then has been widely used for neuropsychiatric disorders (3). Recent studies, based on this observed neuroprotective effect, have investigated the effects of lithium on TBI. In murine models of TBI researchers have found that lithium attenuates hippocampal neurodegeneration, interleukin-
ACCEPTED MANUSCRIPT
1β expression, brain edema, loss of hemispheric tissue and inhibits microglia activation as well as matrix metallopeptidase-9 expression (MMP-9) and cyclooxygenase-2 induction. It should be observed that blood brain barrier integrity is maintained through the inhibition of MMP-9 expression (4,5).
RI PT
According to Yu et al., low doses of combined lithium and valproate were more useful in attenuating TBI injury than either agent used alone (6). Previous studies have found that treatment with lithium and valproate could synergistically
excitotoxicity in central nervous system (7).
SC
enhance GSK-3 inhibition over that of lithium alone, and prevent glutamate
These findings raise the possibility that the mood stabilizers lithium and
M AN U
valproate, either alone or in combination, may be repurposed as drugs to treat neurological disorders with excitotoxic components, best exemplified by traumatic brain injury. In addition, recently discovered synergistic effects, may permit lower doses that might result in fewer side effects and better tolerability. Further investigation into the use of mood stabilizers as neuroprotective agents in
References
TE D
TBI is warranted.
1) Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain
EP
injury in adults. Lancet Neurol. 2008; 7: 728−741.
AC C
2) Leeds PR, Yu F, Wang Z, Chiu CT, Zhang Y, Leng Y, et al. A new avenue for lithium: intervention in traumatic brain injury. ACS Chem Neurosci 2014; 5(6): 422-33.
3) Shorter E. The history of lithium therapy. Bipolar disord 2009; 11: 4-9.
4) Dell'Osso L, Del Grande C, Gesi C, Carmassi C, Musetti L. A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. Neuropsychiatr Dis Treat. 2016; 12: 1687-1703.
ACCEPTED MANUSCRIPT
5) Reis C, Wang Y, Akyol O, Ho WM, Ii RA, Stier G, et al. What's New in Traumatic Brain Injury: Update on Tracking, Monitoring and Treatment. Int J Mol
RI PT
Sci. 2015; 16(6):11903-11965.
6) Yu F, Wang Z, Tanaka M, Chiu CT, Leeds P, et al. Posttrauma cotreatment with lithium and valproate: reduction of lesion volume, attenuation of blood-brain barrier disruption, and improvement in motor coordination in mice
SC
with traumatic brain injury. J Neurosurg. 2013; 119 (3): 766−773.
M AN U
7) Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM. Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci. 2008; 28 (10): 2576−2588.
Legend:
TE D
Figure 1. After traumatic brain injury several and complex mechanisms of secondary are initiated. They may generate edema, necrosis and hemorrhage
AC C
EP
impairing the final outcome.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT