Lithium Benzoate Exerts Neuroprotective Effect by Improving Mitochondrial Function, Attenuating Reactive Oxygen Species, and Protecting Cognition and Memory in an Animal Model of Alzheimer’s Disease

Abstract

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease affecting many cellular pathways, including protein aggregation, mitochondrial dysfunction, oxidative stress (OS), and neuroinflammation. Currently, no effective treatment for AD exists. Objective: We aim to determine the effect of lithium benzoate (LiBen) in protecting neurons from amyloid-β (Aβ) or other neurotoxin insults. Methods: Primary rat cortical neurons were co-treated with neurotoxins and LiBen were used to examine its effect in cell viability, reactive oxygen species (ROS) clearance, and mitochondria functions by MTT, CellRox fluorescence staining, and seahorse assay. Then, Barnes maze and prepulse inhibition test were performed in APP/PS1 mice that received chronic LiBen treatment to assess its effect on cognitive protection. Oral bioavailability of LiBen was also assessed by pharmacokinetic study in rat plasma. Results: In this study, we discovered that LiBen can attenuate cellular ROS level, improve mitochondrial function, increase cell viability against multiple different insults of mitochondrial dysfunction, Aβ accumulation, and neuroinflammation, and promote neurogenesis. We demonstrated that LiBen has advantages over lithium or sodium benzoate alone as LiBen displays superior neuroprotective efficacy and oral bioavailability than the other two agents when being applied either alone or in combination. Furthermore, chronic administration of LiBen showed protection for cognition as well as spatial memory and reduced the senile plaque deposition in brains of AD animal models. Conclusion: LiBen stands as a promising therapeutic agent for delaying the progression of and improving cognition in AD.

Molecular mechanisms and therapeutic potential of lithium in Alzheimer’s disease: repurposing an old class of drugs

“…Lithium ascorbate, which has low acute and chronic toxicity, has been found to mitigate ischemia-induced brain damage and play a significant neuroprotective role ( Torshin et al, 2022 ). In studies on AD, lithium benzoate and lithium cholesterol sulfate have been shown to improve cognitive and memory functions in animal models through multiple pathways ( Hu et al, 2022 ; Lu et al, 2022 ). Nanolithium, which utilizes Medesis Pharma’s innovative drug delivery technology (Aonys ® ) to enhance the bioavailability of lithium and reduce its toxicity, has demonstrated potential in preclinical studies with the microdose lithium formulation (NP03) for the treatment of AD ( Wilson et al, 2020 ).…”

“…Lithium exposure in neuronal cultures can reduce total tau and P-tau levels and protect against Aβ toxicity ( Hong et al, 1997 ; Muñoz-Montaño et al, 1997 ; Alvarez et al, 1999 ; Lovestone et al, 1999 ; Rametti et al, 2008 ). In Aβ-overexpressing AD transgenic mice, lithium therapy has been found to inhibit GSK-3 activity, reduce Aβ deposition and tau phosphorylation, regulate autophagy, inflammation, oxidative stress, cholinergic and glucose metabolism, enhance neurogenesis and synaptic plasticity, maintain mitochondrial homeostasis, and improve cognitive function ( Fiorentini et al, 2010 ; Toledo and Inestrosa, 2010 ; Zhang et al, 2011 ; Sudduth et al, 2012 ; Trujillo-Estrada et al, 2013 ; Wilson et al, 2017 ; Pan et al, 2018 ; Wilson et al, 2018 ; Habib et al, 2019 ; Liu M. et al, 2020 ; Wilson et al, 2020 ; Xiang et al, 2020 ; Xiang et al, 2021 ; Gherardelli et al, 2022 ; Lu et al, 2022 ; Wiseman et al, 2023 ). Similarly, in transgenic mice overexpressing pathogenic mutant tau, lithium therapy inhibited GSK-3 activity and tau phosphorylation ( Noble et al, 2005 ; Engel et al, 2006 ; Caccamo et al, 2007 ; Leroy et al, 2010 ; Shimada et al, 2012 ).…”

“…Additionally, dysfunction of mitochondria can lead to an increase in ROS production. Lithium benzoate can reduce ROS levels in cells, enhance spare respiratory capacity for the mitochondrial function, and protect against apoptosis ( Lu et al, 2022 ). The cellular antioxidant network, which comprises catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), plays an important role in scavenging ROS ( Ashleigh et al, 2023 ).…”

“…It is noteworthy that lithium has the potential to target multiple pathological events in AD, as evidenced by promising results in preclinical and clinical trials. Preclinical studies have shown that lithium can reduce amyloid deposition and tau phosphorylation, regulate autophagy, inflammation, oxidative stress, cholinergic and glucose metabolism, enhance neurogenesis and synaptic plasticity, maintain mitochondrial homeostasis, and improve cognitive function ( Fiorentini et al, 2010 ; Toledo and Inestrosa, 2010 ; Zhang et al, 2011 ; Sudduth et al, 2012 ; Trujillo-Estrada et al, 2013 ; Wilson et al, 2017 ; Pan et al, 2018 ; Wilson et al, 2018 ; Habib et al, 2019 ; Liu M. et al, 2020 ; Wilson et al, 2020 ; Xiang et al, 2020 ; Xiang et al, 2021 ; Gherardelli et al, 2022 ; Lu et al, 2022 ; Wiseman et al, 2023 ). Clinical studies have indicated that lithium therapy can reduce the risk of AD, halt the progression of early-stage AD, and maintain cognitive stability over extended periods ( Forlenza et al, 2019 ; Haussmann et al, 2021 ).…”

Therapeutic effects of oral benzoic acid application during acute murine campylobacteriosis

“…In fact, anti-inflammatory effects were attributed to the inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, resulting in reduced proinflammatory cytokine release [61,[64][65][66][67]. In addition, neuroprotective effects and anti-inflammatory properties in nervous tissues were shown for neurological diseases such as Alzheimer's disease [68,69].…”