Is lithium neuroprotective? An updated mechanistic illustrated review

Ghanaatfar, Fateme; Ghanaatfar, Ali; Isapour, Parisa; Farokhi, Negin; Bozorgniahosseini, Seyedehnahal; Javadi, Mahshid; Gholami, Mina; Ulloa, Luis; Coleman-Fuller, Natalie; Motaghinejad, Majid

doi:10.1111/fcp.12826

Cited by 26 publications

(6 citation statements)

References 245 publications

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“…However, whether TREM2 also has neuroprotective effects after TBI has not yet been elucidated. The protein kinase B (Akt)/cAMP-responsive element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) axis has been proven to have neuroprotective effects against neurodegeneration by preventing neuroinflammation, oxidative stress, apoptosis, and mitochondrial dysfunction [ 30 ]. In addition, this signalling pathway can alleviate critical illness-related corticosteroid insufficiency after TBI by promoting neuronal survival [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

Jin

Zhang

Wang

et al. 2022

J Neuroinflammation

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Background Neuroinflammation is one of the most important processes in secondary injury after traumatic brain injury (TBI). Triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to exert neuroprotective effects in neurodegenerative diseases and stroke by modulating neuroinflammation, and promoting phagocytosis and cell survival. However, the role of TREM2 in TBI has not yet been elucidated. In this study, we are the first to use COG1410, an agonist of TREM2, to assess the effects of TREM2 activation in a murine TBI model. Methods Adult male wild-type (WT) C57BL/6 mice and adult male TREM2 KO mice were subjected to different treatments. TBI was established by the controlled cortical impact (CCI) method. COG1410 was delivered 1 h after CCI via tail vein injection. Western blot analysis, immunofluorescence, laser speckle contrast imaging (LSCI), neurological behaviour tests, brain electrophysiological monitoring, Evans blue assays, magnetic resonance imaging (MRI), and brain water content measurement were performed in this study. Results The expression of endogenous TREM2 peaked at 3 d after CCI, and it was mainly expressed on microglia and neurons. We found that COG1410 improved neurological functions within 3 d, as well as neurological functions and brain electrophysiological activity at 2 weeks after CCI. COG1410 exerted neuroprotective effects by inhibiting neutrophil infiltration and microglial activation, and suppressing neuroinflammation after CCI. In addition, COG1410 treatment alleviated blood brain barrier (BBB) disruption and brain oedema; furthermore, COG1410 promoted cerebral blood flow (CBF) recovery at traumatic injury sites after CCI. In addition, COG1410 suppressed neural apoptosis at 3 d after CCI. TREM2 activation upregulated p-Akt, p-CREB, BDNF, and Bcl-2 and suppressed TNF-α, IL-1β, Bax, and cleaved caspase-3 at 3 d after CCI. Moreover, TREM2 knockout abolished the effects of COG1410 on vascular phenotypes and microglial states. Finally, the neuroprotective effects of COG1410 were suppressed by TREM2 depletion. Conclusions Altogether, we are the first to demonstrate that TREM2 activation by COG1410 alleviated neural damage through activation of Akt/CREB/BDNF signalling axis in microglia after CCI. Finally, COG1410 treatment improved neurological behaviour and brain electrophysiological activity after CCI. Graphical Abstract

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Section: Introductionmentioning

confidence: 99%

TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

Jin

Zhang

Wang

et al. 2022

J Neuroinflammation

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“…In contrast, low-dose lithium has been found to protect against mild cognitive impairment (MCI) and dementia by increasing the GMV 91 , 92 . A review showed that lithium increases the GMV by preventing inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction via the phosphatidylinositol-3 (PI3)/Akt/GSK-3β and PI3/Akt/cAMP response element-binding protein/brain-derived neurotrophic factor signaling pathways 93 . Our results are inconsistent with these findings, as regional GMV increases did not overcome the reduction of the whole-brain GMV.…”

Section: Discussionmentioning

confidence: 99%

Low-dose lithium adjunct to atypical antipsychotic treatment nearly improved cognitive impairment, deteriorated the gray-matter volume, and decreased the interleukin-6 level in drug-naive patients with first schizophrenia symptoms: a follow-up pilot study

Zhuo,

Hu,

Chen

et al. 2023

Schizophr

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This study was conducted to investigate the effects of long-term low-dose lithium adjunct to antipsychotic agent use on the cognitive performance, whole-brain gray-matter volume (GMV), and interleukin-6 (IL-6) level in drug-naive patients with first-episode schizophrenia, and to examine relationships among these factors. In this double-blind randomized controlled study, 50 drug-naive patients with first-episode schizophrenia each took low-dose (250 mg/day) lithium and placebo (of the same shape and taste) adjunct to antipsychotic agents (mean, 644.70 ± 105.58 and 677.00 ± 143.33 mg/day chlorpromazine equivalent, respectively) for 24 weeks. At baseline and after treatment completion, the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognitive performance, 3-T magnetic resonance imaging was performed to assess structural brain alterations, and serum IL-6 levels were quantified by immunoassay. Treatment effects were assessed within and between patient groups. Relationships among cognitive performance, whole-brain GMVs, and the IL-6 level were investigated by partial correlation analysis. Relative to baseline, patients in the lithium group showed improved working memory, verbal learning, processing speed, and reasoning/problem solving after 24 weeks of treatment; those in the placebo group showed only improved working memory and verbal learning. The composite MCCB score did not differ significantly between groups. The whole-brain GMV reduction was significantly lesser in the lithium group than in the placebo group (0.46% vs. 1.03%; P < 0.001). The GMV and IL-6 reduction ratios correlated with each other in both groups (r = −0.17, P = 0.025). In the lithium group, the whole-brain GMV reduction ratio correlated with the working memory improvement ratio (r = −0.15, P = 0.030) and processing speed (r = −0.14, P = 0.036); the IL-6 reduction ratio correlated with the working memory (r = −0.21, P = 0.043) and verbal learning (r = −0.30, P = 0.031) improvement ratios. In the placebo group, the whole-brain GMV reduction ratio correlated only with the working memory improvement ratio (r = −0.24, P = 0.019); the IL-6 reduction ratio correlated with the working memory (r = −0.17, P = 0.022) and verbal learning (r = −0.15, P = 0.011) improvement ratios. Both treatments implemented in this study nearly improved the cognitive performance of patients with schizophrenia; relative to placebo, low-dose lithium had slightly greater effects on several aspects of cognition. The patterns of correlation among GMV reduction, IL-6 reduction, and cognitive performance improvement differed between groups.

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“…Lithium activates both the PI3K/AKT/CREB pathway and the cAMP/PKA/CREB pathway, leading to increased production of BDNF. This activation inhibits oxidative stress, inflammation, and apoptosis, achieving neuroprotective effects 97 . Additionally, the inhibition of GSK-3β/CREB/BDNF 98 and MAPK/ERK/CREB/BDNF 73 signaling pathways can upregulate BDNF expression, thereby alleviating cerebral ischemia-reperfusion injury.…”

Section: Molecular Mechanismmentioning

confidence: 99%

Exploring the Neuroprotective Effects of Lithium in Ischemic Stroke: A literature review

Wang,

Lu,

Shi

et al. 2024

Int. J. Med. Sci.

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Ischemic stroke ranks among the foremost clinical causes of mortality and disability, instigating neuronal degeneration, fatalities, and various sequelae. While standard treatments, such as intravenous thrombolysis and endovascular thrombectomy, prove effective, they come with limitations. Hence, there is a compelling need to develop neuroprotective agents capable of improving the functional outcomes of the nervous system. Numerous preclinical studies have demonstrated that lithium can act in multiple molecular pathways, including glycogen synthase kinase 3(GSK-3), the Wnt signaling pathway, the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) signaling pathway, brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR), and glutamate receptors. Through these pathways, lithium has been shown to affect inflammation, autophagy, apoptosis, ferroptosis, excitotoxicity, and other pathological processes, thereby improving central nervous system (CNS) damage caused by ischemic stroke. Despite these promising preclinical findings, the number of clinical trials exploring lithium's efficacy remains limited. Additional trials are imperative to thoroughly ascertain the effectiveness and safety of lithium in clinical settings. This review delineates the mechanisms underpinning lithium's neuroprotective capabilities in the context of ischemic stroke. It elucidates the intricate interplay between these mechanisms and sheds light on the involvement of mitochondrial dysfunction and inflammatory markers in the pathophysiology of ischemic stroke. Furthermore, the review offers directions for future research, thereby advancing the understanding of the potential therapeutic utility of lithium and establishing a theoretical foundation for its clinical application.

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Is lithium neuroprotective? An updated mechanistic illustrated review

Cited by 26 publications

References 245 publications

TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice

Low-dose lithium adjunct to atypical antipsychotic treatment nearly improved cognitive impairment, deteriorated the gray-matter volume, and decreased the interleukin-6 level in drug-naive patients with first schizophrenia symptoms: a follow-up pilot study

Exploring the Neuroprotective Effects of Lithium in Ischemic Stroke: A literature review

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