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

Abstract

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.

Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation

“…Cell and animal studies have provided clues regarding how Li + ions may affect the AD disease pathology (Nery et al, 2014;Sofola-Adesakin et al, 2014;Zhao et al, 2014;Budni et al, 2017;Habib et al, 2017;Cardillo et al, 2018;Kerr et al, 2018;Habib et al, 2019;Rocha et al, 2020;Wilson et al, 2020). Due to its ability to down-regulate translation, Li + caused a reduction in protein synthesis and thus Aβ 42 levels in an adult-onset Drosophila model of AD (Sofola-Adesakin et al, 2014) Li + reduces Aβ production by affecting the processing/cleavage of the amyloid-β precursor protein (AβPP) in cells and mice, presumably by down-regulating the levels of phosphorylated AβPP.…”

“…One study on mice with traumatic brain injury reported that Li + -treatment improved spatial learning and reduced Aβ production, possibly by reducing the levels of both AβPP and the AβPP-cleaving enzyme BACE1 (Yu et al, 2012). More recent mice studies have reported that treatment with Li + ions improved Aβ clearance from the brain (Pan et al, 2018), reduced oxidative stress levels (Xiang et al, 2020), improved spatial memory (Habib et al, 2019), and reduced the amounts of Aβ plaques and phosphorylated tau while also improving spatial memory (Liu et al, 2020).…”

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

“…The AD symptoms are significantly reduced by the Li + ions treatment [ 57 , 128 , 129 ], which showed a substantial improvement regarding Aβ clearance [ 130 ], enhance spatial memory [ 131 ], reduced oxidative stress level [ 132 ] and decreased the amount of Aβ plaques [ 133 ] in AD brain. Berntsson et al [ 134 ] used biophysical techniques, NMR, Fluorescence quenching, CD, and IR, to monitor the elusive in vitro interaction between Li + and Aβ peptide.…”

Amino Acids as the Potential Co-Former for Co-Crystal Development: A Review

“…A study on the safety, pharmacokinetics, and therapeutic efficacy of the lithium salicylate- l -proline co-crystal showed that the co-crystal could reduce β-amyloid plaques and phosphorylation by reducing nerve inflammation and inactivating 3-β-glycogen synthase kinase [ 99 ]. A comparative study of the prophylactic effects of the lithium salicylate- l -proline co-crystal, lithium salicylate, and lithium carbonate showed that, at low doses, they could prevent spatial cognitive decline and depression-like behavior; however, the co-crystal showed an advantage in preventing associative memory decline and irritability in mice [ 100 ].…”