RETRACTED ARTICLE:LISPRO mitigates β-amyloid and associated pathologies in Alzheimer’s mice

Abstract

Lithium has been marketed in the United States of America since the 1970s as a treatment for bipolar disorder. More recently, studies have shown that lithium can improve cognitive decline associated with Alzheimer’s disease (AD). However, the current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate chemical forms) have a narrow therapeutic window and unstable pharmacokinetics that, without careful monitoring, can cause serious adverse effects. Here, we investigated the safety profile, pharmacokinetics, and therapeutic efficacy of LISPRO (ionic co-crystal of lithium salicylate and l-proline), lithium salicylate, and lithium carbonate (Li2CO3). We found that LISPRO (8-week oral treatment) reduces β-amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3β in transgenic Tg2576 mice. Specifically, cytokine profiles from the brain, plasma, and splenocytes suggested that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines, and suppresses renal cyclooxygenase 2 expression in transgenic Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain lithium levels and more steady plasma lithium levels in both B6129SF2/J (2-week oral treatment) and transgenic Tg2576 (8-week oral treatment) mice compared with Li2CO3. Oral administration of LISPRO for 28 weeks significantly reduced β-amyloid plaques and tau-phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Taken together, our data suggest that LISPRO may be a superior form of lithium with improved safety and efficacy as a potential new disease modifying drug for AD.

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

“…Within the medial temporal lobes, the hippocampus has been considered to be critical for spatial memory function and is therefore the focus of this study. In our previous study, we found that LISPRO treatment prevents the progression of amyloid deposition in the hippocampus and cortex in Tg2576 and 3XTg‐AD mice models (Habib et al, ). Due to abundant amyloid deposition in the cortex and hippocampus by 12 months of age, the transgenic APPswe/PS1dE9 mouse model of AD also shows spatial and stress‐induced memory deficits.…”

“…Since mice of this age normally consume approximately 5 g chow per day, this gave a dose of 83 mg kg −1 day −1 LC, 325 mg kg −1 day −1 LS, 583 mg kg −1 day −1 LISPRO, and 2.25 mmol lithium/kg/day. This dosage was chosen based on our previous study (Habib et al, ) to give plasma lithium concentrations of 0.05–0.2 mmol/L, which fall in the lower range of clinical therapy for AD (Forlenza et al, ). Nontransgenic wild‐type (WT) littermates cohort (Non‐Tg Ctrl, n = 10) were fed normal chow, 2018 Teklad protein rodent diet as a control.…”

“…Surprisingly, an ionic co‐crystal of lithium salicylate and l‐proline (LISPRO) exhibited modulated pharmacokinetics compared with lithium carbonate, with a smaller peak and more steady level of lithium in the blood and brain (Smith et al, ). In a subsequent study, we determined the safety, pharmacokinetics, and therapeutic efficacy of LISPRO, in comparison with lithium carbonate and lithium salicylate in preclinical mouse models of AD (Habib et al, ). We found that 8‐ as well as 28‐week oral treatment with LISPRO produced superior reduction of hippocampal pathology, including Aβ plaque deposition, tau hyperphosphorylation, neuroinflammation, and neurodegeneration, in two transgenic Alzheimer's‐like mice models (Tg2576, 3XTg‐AD).…”

“…Pharmacokinetic studies indicated that LISPRO treatment provided significantly higher brain lithium levels and more steady plasma lithium levels in both normal and transgenic Alzheimer's‐like mice when compared to lithium carbonate. Moreover, a 2‐week oral treatment of lithium carbonate in normal mice increased proinflammatory cyclooxygenase‐2 expression in the kidneys, while the molar equivalent of lithium administered as LISPRO did not (Habib et al, ).…”

“…Since AD shows sexual dimorphism, with female patients displaying greater prevalence, incidence, and severity than males (Dye, Miller, Singer, & Levine, ; Koran, Wagener, & Hohman, ; Phung et al, ), we focused our study on female AD mice at a single age (12 months of age). In addition, for consistency, we employed the same chronic dosing regimen of LISPRO that was used in our prior study (Habib et al, ).…”