Behavioural Brain Research 241 (2013) 105–111 Contents lists available at SciVerse ScienceDirect Behavioural Brain Research j ourna l ho mepage: www.elsevier.com/locate/bbr Research report Intracerebroventricular administration of an insulin analogue recovers STZ-induced cognitive decline in rats Akiko Sheala Shingo a,∗ , Tomomichi Kanabayashi b , Shozo Kito c , Toshio Murase a a Okinaka Memorial Institute for Medical Research, Tokyo, Japan b Biopathology Institute, Ohita, Japan c Chigasaki Tokushu-kai Clinic, Kanagawa, Japan h i g h l i g h t s  STZ into the dorsal third ventricle resulted in a definite cognition decline.  Insulin into STZ-injected rats rescued from the cognitive decline with an elevated learning.  Insulin treatment also resulted in changes in IDE, IR, Akt, SST and Ab in the hippocampus.  The STZ-induced decrease of granule cell layer neurons was recovered by insulin administration.  Insulin may be a promising therapeutic agent to attenuate cognitive decline. a r t i c l e i n f o Article history: Received 25 September 2012 Received in revised form 30 November 2012 Accepted 4 December 2012 Available online 10 December 2012 Keywords: Cognition Hippocampus Insulin Morris water maze Streptozotocin a b s t r a c t We previously demonstrated that intracerebroventricular streptozotocin (STZ-icv) injection induced cognitive dysfunction and led to decreased expression levels of phospho-cyclic AMP responsive ele- ment binding protein (pCREB), Akt, and insulin degrading enzyme (IDE) and increased amyloid beta (Ab) deposition in the hippocampus. In the present study, we aimed to investigate whether treatment with an insulin analogue could pre- vent STZ-induced cognitive decline by reducing or eliminating these changes in the hippocampus. To test this hypothesis, we administrated a long-acting insulin analogue, detemir, into the third ventricle (3V) of STZ-treated rats and assessed cognitive outcomes using the Morris water maze (MWM), immunohisto- chemistry, and Golgi-Cox staining. Insulin injection successfully rescued STZ-induced cognitive decline, as evidenced by a marked elevation in learning ability. Detemir treatment also resulted in changes in hip- pocampal levels of IDE, insulin receptor (IR), Akt, somatostatin (SST), and Ab. The STZ-induced decrease of granule cell layer neurons was also recovered by detemir administration. These results provide evidence that ‘brain diabetes’ and Alzheimer-type dementia involve similar mechanisms and show that insulin may be a promising therapeutic agent to attenuate cognitive decline. © 2012 Elsevier B.V. All rights reserved. Abbreviations: 3V, dorsal third ventricle; Ab, amyloid beta; AD, Alzheimer’s dis- ease; BBB, blood–brain barrier; CA, cornu ammonis; ChAT, choline acetyltransferase; DAB, 3, 3  diaminobenzidine tetrahydrochloride; DG, dentate gyrus; DM, diabetes mellitus; ERK, extracellular-related kinase; GLUT, glucose transporter protein; IDE, insulin degrading enzyme; IR, insulin receptor; MWM, Morris water maze; PBS, phosphate-buffered saline; pCREB, phospho-cyclic AMP responsive element binding protein; PFA, paraformaldehyde; PI3K, phosphatidylinositol-3-kinase; PKA, protein kinase A; PKC, protein kinase C; STZ, streptozotocin; SST, somatostatin. ∗ Corresponding author at: 2-2-2 Toranomon Minato-ku Tokyo, 105-8470 Japan. Tel.: +81 33588 1111x7893; fax: +81 33583 3496. E-mail address: akisheashin@toranomon.gr.jp (A.S. Shingo). 1. Introduction Understanding the pathophysiological mechanisms underlying cognitive decline is a major goal of neuroscience research. A variety of disease models have been developed to closely examine these mechanisms and identify therapeutic targets. One such model is the intracerebroventricularly streptozotocin (STZ-icv) injected rats that show an Alzheimer’s disease (AD)-like phenotype. We previ- ously demonstrated that STZ injection into the dorsal third ventricle (3V) increased amyloid beta (Ab) deposition up to 1.7-fold. This was accompanied by reductions in cognitive, memory, and learn- ing abilities and impairments in intracerebral insulin signalling. STZ injection was associated with decreased hippocampal expres- sions of phospho-cyclic AMP responsive element binding protein (pCREB), Akt, and insulin degrading enzyme (IDE) [1]. 0166-4328/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2012.12.005