Elucidating the pivotal molecular mechanisms, therapeutic and neuroprotective effects of lithium in traumatic brain injury

Abstract

Introduction: Traumatic brain injury (TBI) refers to damage to brain tissue by mechanical or blunt force via trauma. TBI is often associated with impaired cognitive abilities, like difficulties in memory, learning, attention, and other higher brain functions, that typically remain for years after the injury. Lithium is an elementary light metal that is only utilized in salt form due to its high intrinsic reactivity. This current review discusses the molecular mechanisms and therapeutic and neuroprotective effects of lithium in TBI.

Method: The "Boolean logic" was used to search for articles on the subject matter in PubMed and PubMed Central, as well as Google Scholar.

Results: Lithium's therapeutic action is extremely complex, involving multiple effects on gene secretion, neurotransmitter or receptor-mediated signaling, signal transduction processes, circadian modulation, as well as ion transport. Lithium is able to normalize multiple short- as well as long-term modifications in neuronal circuits that ultimately result in disparity in cortical excitation and inhibition activated by TBI. Also, lithium levels are more distinct in the hippocampus, thalamus, neo-cortex, olfactory bulb, amygdala as well as the gray matter of the cerebellum following treatment of TBI.

Conclusion: Lithium attenuates neuroinflammation and neuronal toxicity as well as protects the brain from edema, hippocampal neurodegeneration, loss of hemispheric tissues, and enhanced memory as well as spatial learning after TBI.

Keywords: TBI; bipolar disorder; lithium; neuroinflammation; neuroprotection; neurotransmission.

FIGURE 1

Shows the pathogenesis of TBI and the effect of lithium treatment on TBI‐associated neuroinflammation. Refer to the text for detailed explanations. APP, amyloid precursor protein; BACE1, β‐site APP‐cleaving enzyme 1; COX, cyclooxygenase; CSPα, cysteine string protein α; FoxO1, forkhead box protein O1; GSK‐3, glycogen synthase kinase 3; IFN‐γ, interferon gamma; IL, interleukin; LPS, lipopolysaccharide; MMP‐9, matrix metallopeptidase‐9; NF‐κB, nuclear factor‐κB; NO, nitric oxide; PGE‐2, prostaglandin E2; PI3K, phosphoinositide 3‐kinase; ROS, reactive oxygen species; SNARE, soluble N‐ethylmaleimide‐sensitive factor activating protein receptor; TLR4, toll‐loke receptor 4; TNF‐α, tumor necrosis factor‐alpha; TyrH, tyrosine hydroxylase; VAMP2, vesicle‐associated membrane protein 2; α‐syn, α‐synuclein.

FIGURE 2

Show the key brain regions lithium influences. Note: Colors are used to show the regions in the diagram.

FIGURE 3

Show the key signaling pathways via which lithium triggers attenuation of TBI and/or neuroprotection. Refer to the text for detailed explanations. AP‐1, activator protein 1; APC, adenomatous polyposis coli; APP, amyloid precursor protein; Bcl‐2, B‐cell lymphoma 2; BDNF, brain‐derived neurotrophic factor; BPntase or RnPIP, nucleotide bisphosphate 39‐nucleotidase; CKIa, casein kinase Ia; CREB, cyclic adenosine monophosphate response element‐binding protein; DAG, diacylglycerol; GSK‐3, glycogen synthase kinase 3; HSP, heat‐shock protein; IMPase, inositol monophosphatase; InsP3, inositol triphosphate; LRP6, lipo‐protein related protein 6; MEK, Ras/Raf/MAPK; PKA, protein kinase A; PKC, protein kinase C; RSK, ribosomal S6 kinase; VEGF, vascular endothelial growth factor; Wnt, wingless‐related integration site.