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.

Peripheral blood brain-derived neurotrophic factor in bipolar disorder: a comprehensive systematic review and meta-analysis

“…Thirtyfive studies, comprising a total of 2238 bipolar disorder patients and 1560 healthy control subjects, were eligible for review and included in the meta-analysis with a minimum of one pair-wise comparison each. [11][12][13][19][20][21]26, Exclusion of full 63 text articles and reports were based on (a) data on BDNF levels were unavailable, [66][67][68] (b) patients not suffering from bipolar disorder, [69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84] (c) the study not evaluating peripheral BDNF levels, (d) the study being a review or a comment, [107][108][109][110][111][112][113][114][115][116][117][118][119] (e) the study not comparing states or comparing bipolar patients with healthy control subjects [120][121][122] and/or (f) the study investigated treatment of experimental nature 123,124 and (g) the study presenting duplicate data presented in an included article. …”

Lithium: A Novel Therapeutic Drug for Traumatic Brain Injury

“…Furthermore, lithium has stabilizing properties of the inositol triphosphate-dependent receptor (IP 3 R) calcium channel localized to the membrane of the endoplasmic reticulum (ER), which is the primary storage of calcium as well as the major regulator of calcium concentration within the cell, by depleting IR 3 supply to the IP 3 R [20,21]. Excessive activation of this channel triggers a wide array of neuropathological processes including apoptosis, impairments in synaptic plasticity and memory encoding, inflammatory responses and the formation of tauopathy and Aβ accumulation [22][23][24] (Figure 2). Our recent study shows that lithium reduces excessive calcium release from ER in 3xTg AD rodent models [25].…”

Neurotrophic effects of lithium stimulate the reduction of ischemic and neurodegenerative brain damage

“…Данный эффект терапии осуществлялся за счет увеличения секреции BDNF [70], который усиливает клеточное деление и дифференцировку клеток-предше-ственников нейронов, наряду с уменьшением активации микроглии и макрофагов [71]. Длительное применение препаратов лития подавляет активность GSK-3 вокруг по-раженных участков спинного мозга крыс и способствует росту аксонов при травме спинного мозга [72,73].…”