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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.
Highlights
Alzheimer’s disease (AD) affects memory and cognition irreversibly, and is one of the most critical public health concerns for the elderly
Using male Sprague-Dawley rats, the plasma and brain profiles measured by atomic absorption spectroscopy (AAS) indicated that LP produces a very steady level of lithium at 48 h after treatment, whereas the level of lithium was almost undetectable after 48 h of lithium carbonate (LC) treatment.[21]
Despite a narrow therapeutic window (0.6–1.5 mM) and the potential for serious adverse events, lithium has been used as the first-line therapy to reduce manic episodes and suicidality in patients with bipolar disorder owing to lack of better alternatives.[32]
Summary
Alzheimer’s disease (AD) affects memory and cognition irreversibly, and is one of the most critical public health concerns for the elderly. Extracellular amyloid plaques (mostly amyloid-β, Aβ)[1] and intracellular neurofibrillary tangles (NFTs; paired helical filament of hyperphosphorylated tau)[2] are neuropathological hallmarks of AD, which severely affect the hippocampus and neocortex.[3] Currently, the United States. FDA approved as a mood stabilizer for the treatment of bipolar disorder, it is commonly prescribed off-label for other neuropsychiatric symptoms, including suicidality and impulsive aggression,[6] as well as neurodegenerative diseases such as AD.[8] Nunes and colleagues observed in a 18-. An important mechanism of lithium is that it inhibits certain enzymes in a noncompetitive manner by displacing the required divalent cation, magnesium.[10] Klein and Melton identified glycogen synthase kinase 3β (GSK3β) as one such molecular target of lithium.[11] In the context of AD, this enzyme phosphorylates tau at most serine and threonine residues in the paired helical
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