PMID- 30210290
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 1662-5099 (Print)
IS  - 1662-5099 (Electronic)
IS  - 1662-5099 (Linking)
VI  - 11
DP  - 2018
TI  - Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets 
      for Dementia Using Animal Models.
PG  - 297
LID - 10.3389/fnmol.2018.00297 [doi]
LID - 297
AB  - Lithium has long been used for the treatment of psychiatric disorders, due to its 
      robust beneficial effect as a mood stabilizing drug. Lithium's effectiveness for 
      improving neurological function is therefore well-described, stimulating the 
      investigation of its potential use in several neurodegenerative conditions 
      including Alzheimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases. A 
      narrow therapeutic window for these effects, however, has led to concerted 
      efforts to understand the molecular mechanisms of lithium action in the brain, in 
      order to develop more selective treatments that harness its neuroprotective 
      potential whilst limiting contraindications. Animal models have proven pivotal in 
      these studies, with lithium displaying advantageous effects on behavior across 
      species, including worms (C. elegans), zebrafish (Danio rerio), fruit flies 
      (Drosophila melanogaster) and rodents. Due to their susceptibility to genetic 
      manipulation, functional genomic analyses in these model organisms have provided 
      evidence for the main molecular determinants of lithium action, including 
      inhibition of inositol monophosphatase (IMPA) and glycogen synthase kinase-3 
      (GSK-3). Accumulating pre-clinical evidence has indeed provided a basis for 
      research into the therapeutic use of lithium for the treatment of dementia, an 
      area of medical priority due to its increasing global impact and lack of 
      disease-modifying drugs. Although lithium has been extensively described to 
      prevent AD-associated amyloid and tau pathologies, this review article will focus 
      on generic mechanisms by which lithium preserves neuronal function and improves 
      memory in animal models of dementia. Of these, evidence from worms, flies and 
      mice points to GSK-3 as the most robust mediator of lithium's neuro-protective 
      effect, but it's interaction with downstream pathways, including Wnt/beta-catenin, 
      CREB/brain-derived neurotrophic factor (BDNF), nuclear factor (erythroid-derived 
      2)-like 2 (Nrf2) and toll-like receptor 4 (TLR4)/nuclear factor-kappaB (NFkappaB), have 
      identified multiple targets for development of drugs which harness lithium's 
      neurogenic, cytoprotective, synaptic maintenance, anti-oxidant, anti-inflammatory 
      and protein homeostasis properties, in addition to more potent and selective 
      GSK-3 inhibitors. Lithium, therefore, has advantages as a multi-functional 
      therapy to combat the complex molecular pathology of dementia. Animal studies 
      will be vital, however, for comparative analyses to determine which of these 
      defense mechanisms are most required to slow-down cognitive decline in dementia, 
      and whether combination therapies can synergize systems to exploit lithium's 
      neuro-protective power while avoiding deleterious toxicity.
FAU - Kerr, Fiona
AU  - Kerr F
AD  - Department of Life Sciences, School of Health & Life Sciences, Glasgow Caledonian 
      University, Glasgow, United Kingdom.
FAU - Bjedov, Ivana
AU  - Bjedov I
AD  - UCL Cancer Institute, University College London, London, United Kingdom.
FAU - Sofola-Adesakin, Oyinkan
AU  - Sofola-Adesakin O
AD  - Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, 
      United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20180828
PL  - Switzerland
TA  - Front Mol Neurosci
JT  - Frontiers in molecular neuroscience
JID - 101477914
PMC - PMC6121012
OTO - NOTNLM
OT  - GSK-3
OT  - dementia
OT  - lithium
OT  - neuro-inflammation
OT  - neurogenesis
OT  - oxidative damage
OT  - proteostasis
OT  - synaptic maintenance
EDAT- 2018/09/14 06:00
MHDA- 2018/09/14 06:01
PMCR- 2018/01/01
CRDT- 2018/09/14 06:00
PHST- 2018/06/07 00:00 [received]
PHST- 2018/08/03 00:00 [accepted]
PHST- 2018/09/14 06:00 [entrez]
PHST- 2018/09/14 06:00 [pubmed]
PHST- 2018/09/14 06:01 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fnmol.2018.00297 [doi]
PST - epublish
SO  - Front Mol Neurosci. 2018 Aug 28;11:297. doi: 10.3389/fnmol.2018.00297. 
      eCollection 2018.