Lithium Ameliorates Neurodegeneration, Suppresses Neuroinflammation, and Improves Behavioral Performance in a Mouse Model of Traumatic Brain Injury

Abstract

Although traumatic brain injury (TBI) is recognized as one of the leading causes of death from trauma to the central nervous system (CNS), no known treatment effectively mitigates its effects. Lithium, a primary drug for the treatment of bipolar disorder, has been known to have neuroprotective effects in various neurodegenerative conditions such as stroke. Until this study, however, it has not been investigated as a post-insult treatment for TBI. To evaluate whether lithium could have beneficial effects following TBI, lithium at a dose of 1.5 mEq/kg was administered after injury. Assessed at 3 days and 3 weeks post-injury using hematoxylin and eosin staining, lithium treatment was found to reduce lesion volume. Lithium at doses of 2.0 and 3.0 mEq/kg also significantly reduced lesion volume at 3 days after injury, and the therapeutic window was at least 3 h post-injury. TBI-induced neuronal death, microglial activation, and cyclooxygenase-2 induction were all attenuated by lithium at 3 days after injury. In addition, lithium treatment reduced TBI-induced matrix metalloproteinase-9 expression and preserved the integrity of the blood-brain barrier. As for behavioral outcomes, lithium treatment reduced anxiety-like behavior in an open-field test, and improved short- and long-term motor coordination in rotarod and beam-walk tests. Lithium robustly increased serine phosphorylation of glycogen synthase kinase-3β (GSK-3β), suggesting that the underlying mechanisms responsible for lithium's protective effects are triggered by increasing phosphorylation of this kinase and thereby inhibiting its activity. Our results support the notion that lithium has heretofore unrecognized capacity to mitigate the neurodegenerative effects and improve functional outcomes in TBI.

Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3β inhibition-independent pathways

“…28 Cells were seeded on glass cover slips at a density of 125,000/cm 2 and incubated under standard cell culture conditions in a humidified atmosphere at 5% CO 2 . Oxygen-glucose deprivation (OGD) was induced by transferring cells to Sterofundin medium (Braun, Germany) containing 1 mM mannitol and incubated at 37 C in a hypoxic chamber (1% O 2 , 5% CO 2 , remainder N 2 ) for 45 min with subsequent re-incubation under standard cell culture conditions for 24 h. Treatment with lithium (1 mM) was done 24 h before OGD and repeated at the beginning of reoxygenation.…”

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

“…58 Mild or severe traumatic brain injury induces hyperactivity in male and female mice Significant hyperactive exploration in the OF is a frequently reported effect of CCI delivered over parietal cortex in mice. 33,[59][60][61][62][63] In the current experiment, hyperactivity in injured mice ( Fig. 2A,B) was the result of more-continuous exploration in mice with TBI (fewer starts and stops; Fig.…”

“…3C,D), corroborating previous findings in C57BL/6 mice when tested in an OF after parietal CCI. 33,59,62 However, testing of anxiety in the classic elevated plus maze (EPM) post-TBI yields disparate results. Washington and colleagues 72 reported that cortically injured mice spent a greater amount of time in anxiogenic regions of the EPM on the 20th day postinjury and concluded that brain injury results in increased ''risk-taking'' behaviors in mice.…”

A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice

“…10,11,[13][14][15][16][17]111,[115][116][117][119][120][121] These deficits, as reviewed in Osier and colleagues 122 and Thompson and coworkers, 123 can exceed those seen in our model, match them, or be more transient, depending on the severity of the impact. 10,11,124 For example, one of the least severe of these approaches, mild midline fluid percussion 1.4 atmosphere impact to the dura, produces TBI with little or no contusive injury to the brain, but causes optic nerve damage, similar to that in our TBI model. [125][126][127] Nonetheless, mild midline fluid percussion involves an open skull injury and thus does not mimic mild TBI in humans.…”