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P1‐269: A 12‐week, double‐blind, placebo‐controlled, dose‐range finding study of CHF5074 in patients with mild cognitive impairment
Author(s) -
Ross Joel,
Sharma Sanjiv K.,
Winston Jaron,
Frigerio Enrico,
Fiorentini Francesco,
Fernandez Mercedes,
Giardino Luciana,
Norris Dottie,
Cicirello Helen,
Casula Daniela,
Imbimbo Bruno
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.549
Subject(s) - tolerability , medicine , cohort , placebo , pharmacodynamics , adverse effect , pharmacokinetics , vital signs , pharmacology , anesthesia , pathology , alternative medicine
sant drug to treat acute mania and depression, has been found to improve neurogenesis and protect brain against ischemic injury. However the effect of lithium on the cholinergic system remained an enigma. The aim of this study was to investigate whether lithium has neuroprotective activity and the mechanisms on scopolamine-induced amnesia. Methods: The learning and memory was impaired by administration of scopolamine (1mg/kg, i.p.) in rats. Animals were treated with lithium (40mg/kg) twice daily. Morris water maze was used to assess cognitive activity, and the expressions of relative molecular and synaptic plasticity-associated proteins were determined by Western blotting, immunohistochemistry with specific antibodies. Results: Administration of lithium can significantly ameliorate scopolamine-induced spatial memory deficits in MWM. There was a obvious increase in levels of p-Akt/Akt, p-GSK3 b(S9)/GSK-3, p-CREB/CREB, GluR1 and GluR2 after lithium treatment tested by western blotting analysis, and golgi staining indicated that synapse density was reversed after lithium injection. Furthermore, lithium not only inhibited acetylcholinesterase activity but also the expression of quinone reductase 2(QR2). We constructed the plasmid of GSK-3 beta and QR2, then transfacted with them in HEK293 cells. The result showed QR2 was associated with GSK-3 beta directly. Conclusions: Lithium improved memory and protected the neurons from scopolamine-induced deficits through decreasing QR2 expression, suggested that lithium may be a potential therapy for Alzheimer’s disease.