RETRACTED ARTICLE:LISPRO mitigates β-amyloid and associated pathologies in Alzheimer’s mice

• Published in: Cell death & disease 2017-06, Vol.8 (6), p.e2880-e2880
• Main Authors: Habib, Ahsan, Sawmiller, Darrell, Li, Song, Xiang, Yang, Rongo, David, Tian, Jun, Hou, Huayan, Zeng, Jin, Smith, Adam, Fan, Shengnuo, Giunta, Brian, Mori, Takashi, Currier, Glenn, Shytle, Douglas Ronald, Tan, Jun
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/100; 13/106; 13/21; 13/31; 13/51; 13/95; 14; 14/1; 14/19; 14/63; 631/378/1689/1283; 631/80/458/1733; 631/92/436/1729; 64/110; 64/60; 692/700/139/422; 82/1; 82/29; 82/51; 96; 96/106; 96/21; 96/31; Alzheimer's disease; Antibodies; Biochemistry; Bipolar disorder; Cell Biology; Cell Culture; Citric acid; Cognitive ability; Cyclooxygenase-2; Cytokines; Glycogen; Glycogen synthase kinase 3; Immunology; Inflammation; Kinases; Life Sciences; Lithium; Neurodegenerative diseases; Oral administration; original-article; Pharmacokinetics; Phosphorylation; Proline; Salicylic acid; Senile plaques; Splenocytes; Synaptic density; Synaptophysin; Tau protein; Transgenic mice; β-Amyloid
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.279

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 (Li 2 CO 3 ). We found that LISPRO (8-week oral treatment) reduces β -amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3 β 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 Li 2 CO 3 . 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.