A new avenue for lithium: intervention in traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a leading cause of disability and death from trauma to central nervous system (CNS) tissues. For patients who survive the initial injury, TBI can lead to neurodegeneration as well as cognitive and motor deficits, and is even a risk factor for the future development of neurodegenerative disorders such as Alzheimer's disease. Preclinical studies of multiple neuropathological and neurodegenerative disorders have shown that lithium, which is primarily used to treat bipolar disorder, has considerable neuroprotective effects. Indeed, emerging evidence now suggests that lithium can also mitigate neurological deficits incurred from TBI. Lithium exerts neuroprotective effects and stimulates neurogenesis via multiple signaling pathways; it inhibits glycogen synthase kinase-3 (GSK-3), upregulates neurotrophins and growth factors (e.g., brain-derived neurotrophic factor (BDNF)), modulates inflammatory molecules, upregulates neuroprotective factors (e.g., B-cell lymphoma-2 (Bcl-2), heat shock protein 70 (HSP-70)), and concomitantly downregulates pro-apoptotic factors. In various experimental TBI paradigms, lithium has been shown to reduce neuronal death, microglial activation, cyclooxygenase-2 induction, amyloid-β (Aβ), and hyperphosphorylated tau levels, to preserve blood-brain barrier integrity, to mitigate neurological deficits and psychiatric disturbance, and to improve learning and memory outcome. Given that lithium exerts multiple therapeutic effects across an array of CNS disorders, including promising results in preclinical models of TBI, additional clinical research is clearly warranted to determine its therapeutic attributes for combating TBI. Here, we review lithium's exciting potential in ameliorating physiological as well as cognitive deficits induced by TBI.

Keywords: Anti-inflammation; GSK-3 (glycogen synthase kinase-3) inhibitor; TBI (traumatic brain injury); behavioral deficits and cognitive improvements; combined therapy treatment; controlled cortical impact; functional recovery; lithium; mood stabilizer; neuroprotection; neuroregeneration; preclinical model.

Figure 1

Lithium intervention in traumatic brain injury (TBI). Following TBI, a complex series of pathophysiological events are triggered that ultimately induce neurodegeneration and loss of neurological function. Preclinical studies on TBI have demonstrated that the mood stabilizing drug lithium exerts numerous beneficial effects on neuroinflammation, neuronal protection, and functional recovery. The neuroprotective effects of this novel pharmacological strategy on the modulation of TBI-induced oxidative stress, mitochondrial dysfunction, oligodendrogenesis, neurogenesis, as well as the ability to promote angiogenesis have not been fully determined. Arrows indicate increases or decreases in the respective effects due to lithium-induced actions on each pathophysiological category. Blocked ends indicate lithium-mediated prevention of these pathophysiological events. Question marks (?) indicate known effects of lithium, but not yet verified in TBI models.