Potential application of lithium in Parkinson's and other neurodegenerative diseases

Abstract

Lithium, the long-standing hallmark treatment for bipolar disorder, has recently been identified as a potential neuroprotective agent in neurodegeneration. Here we focus on introducing numerous in vitro and in vivo studies that have shown lithium treatment to be efficacious in reducing oxidative stress and inflammation, increasing autophagy, inhibiting apoptosis, and decreasing the accumulation of α-synulcein, with an emphasis on Parkinson's disease. A number of biological pathways have been shown to be involved in causing these neuroprotective effects. The inhibition of GSK-3β has been the mechanism most studied; however, other modes of action include the regulation of apoptotic proteins and glutamate excitotoxicity as well as down-regulation of calpain. This review provides a framework of the neuroprotective effects of lithium in neurodegenerative diseases and the putative mechanisms by which lithium provides the protection. Lithium-only treatment may not be a suitable therapeutic option for neurodegenerative diseases due to inconsistent efficacy and potential side-effects, however, the use of low dose lithium in combination with other potential or existing therapeutic compounds may be a promising approach to reduce symptoms and disease progression in neurodegenerative diseases.

Moderate to severe HIV-associated neurocognitive impairment

“…[10,13] However, controlled clinical data demonstrating neuroprotection with clinical endpoints were lacking. The improvement in GDS we observed in the lithium arm is similar to the improvement noted by Letendre et al [8] (median improvement 0.29 while we found a median improvement of 0.47) in an open-label 12-week lithium study in patients with HAND.…”

Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-κB Inhibitor Wogonin

“…Lithium has further been shown to favorably influence other neurodegenerative diseases including Huntington´s chorea, Alzheimer´s disease, Parkinson´s disease, amyotrophic lateral sclerosis as well as spinocerebellar ataxias type 1 and type 3 [28-30, 64, 65]. Mechanisms invoked in the neuroprotective effect of lithium include direct or Akt-mediated inhibition of glycogen synthase kinase GSK-3β, Akt-mediated inhibition of the proapoptotic forkhead box class O transcription factor Foxo3a and murine double minute (MDM), stimulation of production and activity of neuroprotective brain derived neurotrophic factor BDNF, up-regulation of antiapoptotic protein Bcl-2, as well as down-regulation of proapoptotic transcription factor p53, of the proapoptotic proteins Bad and Bax, of glutamate excitotoxicity, of calpain and of oxidative stress [30,66]. The stimulating effect of NFκB on Orai1/STIM1 expression, I CRAC and SOCE observed here could, at least in theory, impact on neuronal cell survival and contribute to the beneficial effect of lithium.…”

“…Orai1 and SOCE are up-regulated by PI3K dependent signaling and thus sensitive to chorein [24]. Stimulators of Orai1 expression and SOCE include lithium [25][26][27], which may slow neurodegeneration [28][29][30].…”

Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

“…Additional benefits of lithium therapy include neuroprotective [14,15], anti-inflammatory [16] and anti-apoptotic effects [17], which have been exploited to treat central nervous system trauma [18,19] and chronic neurodegenerative diseases, such as Huntington’s disease, amyotrophic lateral sclerosis and Parkinson’s disease [20,21]. In the peripheral nervous system, it has been shown that lithium administration can foster functional recovery and re-myelination after injury [22,23].…”