Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders

Forlenza, Orestes Vicente; Aprahamian, Ivan; Paula, Vanessa de; Hájek, Tomáš

doi:10.2174/1567205013666160219112854

Cited by 36 publications

(29 citation statements)

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“…It was reported that lithium and VPA had neuroprotective effects in vivo and in vitro via inhibition of the glycogen synthase kinase-3 (GSK-3) pathway [27]. Lithium modifies pathological cascades implicated in many neurodegenerative disorders, which includes Alzheimer’s disease (AD), Huntington’s disease (HD), multiple system atrophy (MSA), and ALS [28]. However, lithium treatment for ALS patients is not the best strategy in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

Jiang

Wang

Yin

et al. 2016

IJMS

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Background: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. Results: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. Conclusion: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

Jiang

Wang

Yin

et al. 2016

IJMS

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“…Based in part on evidence that lithium therapy may prevent cognitive decline in bipolar disorder, a growing body of studies using diverse preclinical and clinical models has provided evidence for potential disease‐modifying properties of lithium in treating neurodegenerative diseases, including AD (Forlenza, de Paula, Machado‐Vieira, Diniz, & Gattaz, ). Overall, the available evidence suggest that the neuroprotective effects of lithium found in diverse preclinical models of neurodegeneration translate into therapeutic benefits in cognitive function and reduced biomarkers in clinical trials of mild cognitively impaired amnestic and AD patients at lower lithium doses than those typically used for mood stabilization (Forlenza, Aprahamian, de Paula, & Hajek, ). Other studies also suggest that long‐term lithium treatment inhibits or slows down the core pathophysiologic features of AD in preclinical as well as in human study (Fajardo, Fajardo, LeBlanc, & MacPherson, ; Zhang et al, ).…”

Section: Introductionmentioning

confidence: 99%

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice

Habib

Shytle

Sawmiller

et al. 2019

J of Neuroscience Research

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Alzheimer's disease (AD) is characterized by progressive decline of cognition and associated neuropsychiatric signs including weight loss, anxiety, depression, agitation, and aggression, which is particularly pronounced in the female gender. Previously, we have shown that a novel ionic co-crystal of lithium salicylate proline (LISPRO)is an improved lithium formulation compared to the carbonate or salicylate form of lithium in terms of safety and efficacy in reducing AD pathology in Alzheimer's mice.The current study is designed to compare the prophylactic effects of LISPRO, lithium carbonate (LC), and lithium salicylate (LS) on cognitive and noncognitive impairments in female transgenic APPswe/PS1dE9 AD mice. Female APPswe/PS1dE9 mice at 4 months of age were orally treated with low-dose LISPRO, LS, or LC for 9 months at 2.25 mmol lithium/kg/day followed by determination of body weight, growth of internal organs, and cognitive and noncognitive behavior. No significant differences in body or internal organ weight, anxiety or locomotor activity were found between lithium treated and untreated APPswe/PS1dE9 cohorts. LISPRO, LC, and LS prevented spatial cognitive decline, as determined by Morris water maze and depression as determined by tail suspension test. In addition, LISPRO treatment was superior in preventing associative memory decline determined by contextual fear conditioning and reducing irritability determined by touch escape test in comparison with LC and LS. In conclusion, low-dose LISPRO, LC, and LS treatment prevent spatial cognitive decline and depression-like behavior, while LISPRO prevented hippocampal-dependent associative memory decline and irritability in APPswe/PS1dE9 mice. K E Y W O R D SAlzheimer's disease, cognitive impairment, depression, irritability, transgenic mice | 1067 HABIB et Al.

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“…[10] In addition, lithium has been associated with an improvement in neurocognitive impairment in patients with Alzheimer's disease. [11] Lithium has complex pharmacological effects but unequivocal is the inhibition of glycogen synthase kinase-3-beta (GSK-3-β), a serine-threonine protein kinase, that mediates neuronal function, cellular substrates for learning and memory, as well as neuronal apoptosis and inflammation signaling pathways. [12–14] In addition to the potential promise of lithium as an adjuvant from preliminary work, its low cost would facilitate access in low- and middle-income countries which carries the greatest burden of HIV.…”

Section: Introductionmentioning

confidence: 99%

Moderate to severe HIV-associated neurocognitive impairment

et al. 2016

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Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders

Abstract: In absence of disease modifying treatments for any neurodegenerative disorders, the fact that at least 3 studies supported the effect of lithium in aMCI/AD is noteworthy. Future studies should focus on defining the dose range necessary for neuroprotective effects to occur.

Cited by 36 publications

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Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice

Moderate to severe HIV-associated neurocognitive impairment

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