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
Authors: Huayan Hou
Jun Tan
R Douglas Shytle
Sadia Afrin Munna
Darrell Sawmiller
Ahsan Habib
Cesario V Borlongan
Selina Koilraj
David Rongo
Glenn Currier
Journal: Journal of Neuroscience Research (2019)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Alzheimer's disease; cognitive impairment; depression; irritability; transgenic mice.
Affiliations: Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida., Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, Florida.

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. 

Retracted: No

PubPeer comments:
 This paper extensively cites a recently retracted paper ([Cell Death and Disease (2017)] ) with overlapping authors. The retraction notice for that 2017 paper states,  The Editors have retracted this article because an investigation by the University of South Florida concluded that Figs. 7b, e and 8cu2013e present **inappropriately duplicated images and that these images and the text associated with them are not scientifically defensible**. Adam Smith, Brian Giunta, Glenn Currier, and Douglas Ronald Shytle agree with this retraction. Ahsan Habib, Darrell Sawmiller, and Takashi Mori disagree with this retraction. Jun Tan, Yang Xiang, David Rongo, Huayan Hou, and Song Li have not responded to any correspondence from the publisher about this retraction. The publisher was unable to contact Jun Tian, Jin Zeng, and Shengnuo Fan. (emphasis added) Did the University of South Florida investigation include this 2019 paper? With the seriousness of this retraction statement, could the authors please comment on their comfort with *this* paper s conclusions, given that it seems to draw heavily on the conclusions of the 2017 paper, for example, in the following section:  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., 2017)**. We found that 8u2010 as well as 28u2010week oral treatment with LISPRO produced superior reduction of hippocampal pathology, including Au03b2 plaque deposition, tau hyperphosphorylation, neuroinflammation, and neurodegeneration, in two transgenic Alzheimer su2010like mice models (Tg2576, 3XTgu2010AD). In cell culture studies, LISPRO reduced tau hyperphosphorylation, microglial inflammation, and glycogen synthase kinase 3u2010beta activity and was superior to lithium carbonate in enhancing neuronal stem cell differentiation. Pharmacokinetic studies indicated that LISPRO treatment provided significantly higher brain lithium levels and more steady plasma lithium levels in both normal and transgenic Alzheimer su2010like mice when compared to lithium carbonate. Moreover, a 2u2010week oral treatment of lithium carbonate in normal mice increased proinflammatory cyclooxygenaseu20102 expression in the kidneys, while the molar equivalent of lithium administered as LISPRO did not **(Habib et al., 2017)**. --------------------- Funding information. This work was supported by the NIH NIA (R01AG050253, R01AT007411, R21AG055116 and R21AG049477) and the Silver Endowment to J.T. , 
 ![file] The Methods says elevated plus maze was run for 5 min which is 300 s. Open arm time + closed arm time exceeded 300 s for the non Tg control group. Please provide raw data. , 
 ![file] Why are error bars not shown in (a)? , 
 #3 If the commentor is not already aware, the was an expression of concern published on a different paper, which reads in part,  The remaining authors noted that the corresponding author has access to all of the data underlying the findings in this article and were unable to comment on the concerns raised. I have attempted to reach the corresponding author at his previous institutional address and the institution has not responded to my inquiries about whether he is still affiliated with them. It isn t clear how these concerns will be resolved without further assistance from the institution. See https: pubpeer.com publications BA0604B56429507F1DB4AD20975827#2 ,