Purpose: Diabetes is associated with memory and learning disorder. The purpose of this study is to determine the effect of acute oral administration of loganin on memory in diabetic male rats. Methods: 42 male Wistar rats (250-300 g) were divided into six groups: Control, Diabetic (1 week), Diabetic (12 weeks), Loganin, Diabetic (1 week) + Loganin, Diabetic (12 weeks) + Loganin. Diabetes was induced by IP injection of Streptozotocin (60 mg/kg). Loganin (40 mg/kg, po) was administrated 1 hour before test. Then, spatial memory was compared between groups with Morris Water Maze tests. Results: Administration of loganin during acquisition, significantly (p<0.05) decreased both escape latency and traveled distance to find hidden platform in 1 and 12 weeks diabetic rats. In evaluation of recall phase of memory, loganin significantly (p<0.05) increased time and distance spent in the target quadrant in 1 and 12 weeks diabetic rats. Conclusion: Acute administration of loganin could improve spatial memory in diabetic rats

Gisou Mohaddes

Saeideh Hasani Azami

Shirin Babri

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  Advanced Pharmaceutical Bulletin, 2013, 3(1), 91-95 doi: http://dx.doi.org/10.5681/apb.2013.015 http://apb.tbzmed.ac.ir/  *Corresponding author: Gisou Mohaddes, Associate Professor, Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Tel/Fax: +98(411)3364664, E-mail: gmohades@yahoo.com     Copyright © 2013 by Tabriz University of Medical Sciences Effect  of  Acute  Administration  of  loganin  on  Spatial  Memory  in Diabetic Male Rats Shirin Babri1, Saeideh Hasani Azami1, Gisou Mohaddes2* 1Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 2 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.          Introduction Diabetes mellitus is a very common metabolic disorder characterized  by  hyperglycemia  and  insufficiency  of secretion  or  action  of  endogenous  insulin.1  Diabetes causes  complications  affecting  the  retina,  kidney, muscle and blood vessels, and the nervous system.2  Many studies show that changes in cerebral structure and function in diabetes are related to hyperglycemia-induced  end  organ  damage,  macrovascular  disease, hypoglycemia, insulin resistance, and amyloid lesions.3 On the one hand, diabetes induces cytochrome c release from mitochondria into cytoplasm that may play a role in  apoptosis  of  the  CA1  pyramidal  neurons.4  On  the other  hand,  diabetes  causes  a  reduction  in neurogenesis.5  There  are  also  electrophysiological  and  structural abnormalities of the brain in diabetic patients providing good reasons to believe that cognitive functions may be impaired  in  diabetes  mellitus.6  Moreover,  oxidative stress could contribute to learning and memory deficits in diabetes.7 Loganin as an iridoid glycoside first was found in Flos lonicerae, Fruit cornus, and Strychonos nux vomica.8 It has been used as a traditional medicine in Japan and China.9 According to one study, loganin has a plasma glucose  lowering  action  in  normal  rats  and  regulates immune  function  and  has  anti-inflammatory, neuroprotective and anti-shock effects.8,9 In  an  Alzheimer's  model  of  study,  Kwon  and colleagues proved that loganin could have anti-amnesic and  anti  acetylcholinesterase  activity  in  the hippocampus  and  frontal  cortex.10  Furthermore,  our recent  studies  showed  that  acute  administration  of loganin  improves  memory  in  passive  avoidance  tests and chronic application of it exhibits protective effect on spatial learning and memory in diabetic rats.11,12 In  this  study,  we  evaluated  the  effect  of  acute  oral administration  of  loganin  on  learning  and  memory deficits in one and 12 weeks diabetic rats in the Morris water maze tasks.   Materials and Methods Streptozotocin  (STZ)  was  purchased  from  Tocris Bioscience (Bristol, UK) and dissolved in normal saline immediately before use. Loganin was purchased from Extrasynthese (France) and dissolved in normal saline.  Animals Male Wistar rats, weighing (250–300) g, were used in the present experiment. All animals were maintained at a constant temperature (20±1) and on a 12 h light: 12 h dark cycle. They had free access to water and food ad libitum.  The  Regional  Ethics  Committee  of  Tabriz University  of  Medical  Sciences  approved  all experimental procedures.  A R T I C L E  I N F O                             A B S T R A C T Article Type: Research Article Article History: Received: 4 September 2012 Revised: 17 October 2012 Accepted: 17 October 2012 ePublished: 7 February 2013  Keywords: Loganin Diabetes Spatial memory Rat Purpose: Diabetes is associated with memory and learning disorder. The purpose of this study is to determine the effect of acute oral administration of loganin on memory in diabetic male rats. Methods: 42 male Wistar rats (250-300 g) were divided into six groups: Control, Diabetic (1 week), Diabetic (12 weeks), Loganin, Diabetic (1 week) + Loganin,  Diabetic  (12  weeks)  +  Loganin.  Diabetes  was  induced  by  IP  injection  of Streptozotocin (60 mg/kg). Loganin (40 mg/kg, po) was administrated 1 hour before test. Then,  spatial  memory  was compared between  groups  with Morris Water Maze tests.  Results:  Administration  of  loganin  during  acquisition,  significantly  (p<0.05) decreased both escape latency and traveled distance to find hidden platform in 1 and 12 weeks  diabetic  rats.  In  evaluation  of  recall  phase  of  memory,  loganin  significantly (p<0.05) increased time and distance spent in the target quadrant in 1 and 12 weeks diabetic  rats.  Conclusion:  Acute  administration  of  loganin  could  improve  spatial memory in diabetic rats.    92  | Babri et al. Advanced Pharmaceutical Bulletin, 2013, 3(1), 91-95  Copyright © 2013 by Tabriz University of Medical Sciences Experimental Design Male Wistar rats (n = 42) were divided into six groups (n = 7 each): control, diabetic (1 week), diabetic (12 week), loganin, diabetic (1 week) + loganin, diabetics (12  week)  +  loganin.  Experimental  diabetes  was induced  by  a  single  dose  of  STZ  (60  mg/kg, intraperitoneal  (ip)).  Three  days  after  STZ  injection, fasting blood glucose levels were determined. Animals were  considered  diabetic  if  plasma  glucose  levels exceeded  300  mg/dl.13  Loganin  (40  mg/kg,  po)  was administrated once after confirming diabetes. Animals were  tested  for  spatial  memory  1  h  after  loganin treatment.10  Morris Water Maze Test The Morris water maze was black circular pool (136 cm in diameter and 100 cm in height). The pool was filled to a depth of 60 cm with water (20±1 °C) and divided into four quadrants of equal area (NE, SE, SW and NW). A platform (10 cm in diameter) was centered in one of the four quadrants of the pool and submerged 1 cm below the water surface so that it was invisible at water level. The swimming was monitored by a video camera, which was positioned directly above the center of the pool. The pool was located in a test room, which contained various prominent visual cues.14  One  week  after  surgery,  the  rats  were  trained  in  the water  maze.  The  single  training  session  consisted  of eight trials (in two blocks) with four different starting positions  that  were  equally  distributed  around  the perimeter of the maze. The task requires rats to swim to the hidden platform guided by distal spatial cues. After mounting the platform, the rats were allowed to remain there for 20 s, and then were placed in a holding cage for 30 s until the start of the next trial. Rats were given a maximum of 60 s to find the platform and if it failed to  find  the  platform  in  60  s,  it  was  placed  on  the platform  and  allowed  to  rest  for  20  s.  Latency  to platform  and  distance  traveled  were  collected  and analyzed  later.  After  completion  of  the  training,  the animals  were  returned  to  their  home  cages  until retention testing 24 h later. The probe trial consisted of 60 s free swim period without a platform and the time swum in the target quadrant was recorded. In order to assess the possibility of drug interference with  animal  sensory  and  motor  coordination  or  the animal motivation, the capability of rats to escape to a visible platform was tested in this study. The trained rats were given four trials for visuo-motor coordination on the visible platform.15   Statistics  SPSS  13.0  software  was  used  for  statistical comparisons of data, and data expressed as the means ± SEM. For comparisons between Block 1 and Block 2 in each  group,  a  paired-sample  T  test  was  used.  The statistical  analysis  of  the  data  between  groups  was carried  out  by  one-way  ANOVA  followed  by  Tukey test. In all comparisons, P<0.05 was the criterion for statistical significance.  Results In  comparison  of  block  1  and  block  2,  diabetes increased escape latency and traveled distance (Figures 1, 2) in 1 and 12 weeks diabetic rats during acquisition phase.  Loganin  (40  mg/kg)  significantly  decreased latency time (P<0.05) and traveled distance (P<0.05) in 1 and 12 weeks diabetic rats.   Figure  1.  Effect  of  loganin  on  the  traveled  distance  to  find hidden platform in two consecutive blocks (b1 and b2). In the diabetic rats, loganin (40 mg/kg, po) were administered 60 min before  the  tests.  Data  represent  means  ±  S.E.M.  (n=7). *P<0.05,  significantly  different  when  compared  with  the  b1 same group.   Figure 2. Effect of loganin on the escape latency to find hidden platform in two consecutive blocks (b1 and b2). In the diabetic rats, loganin (40 mg/kg, po) were administered 60 min before the  tests.  Data  represent  means  ±  S.E.M.  (n=7).  *P<0.05, significantly different when compared with the b1 same group.  Probe test data were compared between groups. One-way  ANOVA  of  the  distance  traveled  in  the  target quadrant  revealed  significant  differences  (P<0.05) between groups. Loganin (40 mg/kg) increased the time and distance in the target quadrant after the platform was removed (Figures 3, 4). No treatments significantly changed swimming speed in the target quadrant (Figure 5). Loganin  gavage  60  min  before  visual  trial  (visible platform) also showed no difference in escape latency and  traveled  distance  to  find  the  visible  platform, compared to the control group (data are not shown).  |    93 Loganin Improves Diabetic Amnesia Advanced Pharmaceutical Bulletin, 2013, 3(1), 91-95  Copyright © 2013 by Tabriz University of Medical Sciences   Figure  3.  Effect  of  loganin  on  the  traveled  distance  in  trial sessions  of  the  Morris  water  maze  test.    Data  represent means± S.E.M. (n=7). *P<0.05 significantly different when compared with the control group. #P<0.05 significantly different when compared with the 1 week diabetic group. ФP<0.05 significantly  different  when  compared  with  the  12 weeks diabetic group.   Figure  4.  Effect  of  loganin  on  the  escape  latency  in  trial sessions  of  the  Morris  water  maze  test.    Data  represent means± S.E.M. (n=7). *P<0.05 significantly different when compared with the control group. #P<0.05 significantly different when compared with the 1 week diabetic group. ФP<0.05 significantly  different  when  compared  with  the  12 weeks diabetic group.    Figure  5.  Effect  of  loganin  on  the  swimming  speed  in  trial sessions  of  the  Morris  water  maze  test.    Data  represent means± S.E.M. (n=7). Loganin did not change the swimming speed.   Discussion In the present study, loganin was used for the first time in  evaluating  memory  impairment  of  Streptozotocin-induced diabetes. Our results showed that diabetic (1, 12  weeks)  rats  had  an  increased  escape  latency  time and traveled distance to find the hidden platform in a MWM task. Loganin administration with a dose of 40 mg/kg/po  improved  the  acquisition  and  retrieval  in diabetic  rats.  In  addition,  the  results  of  the  visible platform  test  suggest  that  loganin  does  not  have  an effect on mood or sensorimotor activity in rats; rather, it  appears  to  shorten  escape  latency  by  enhancing memory due  to  the effect  on  brain areas  involved  in memory consolidation, such as the hippocampus. Diabetes mellitus is a chronic disease characterized by widespread complications in CNS and PNS.16 Learning and  memory  in  animal  model  of  diabetes  are impaired.17  Chronic  hyperglycemia  is  associated  with oxidative  stress-induced  neuronal  and  Schwann  cell death  and  the  reduction  of  neural  size  in  the  rat brain.18,19 Also, learning deficits in diabetic rats have been associated with changes in hippocampal synaptic plasticity.20  As  previously  mentioned,  loganin  is  an  iridoid glycoside  that  is  found  in  many  traditional  Chinese, Japan,  and  Korea  herbs.10  Loganin,  is  an  active compound and was found to exhibit immune-regulating and  anti-inflammatory  activity.21,22  It  has  hepato-protective,  renal  protective  and  neuroprotective effects.8,23,24  In addition Kwon and colleagues showed that loganin may  have  anti-amnesic  activity  in  alleviating  certain memory  impairments  observed  in  Alzheimer's disease.10  Our  recent  study  also  showed  that  loganin improves passive avoidance learning in diabetic male rats.11  Although the exact mechanism of action of loganin on diabetic deficit of learning and memory is not clear, it may  act  by  preventing  oxidative  stress,  inhibiting  acetyl cholinesterase activity  in the hippocampus  and inhibiting  advanced  glycation  end  product  formation and  NF-κB  induced  inflammation  in  the  hepatic tissue.10,25,26  Some  other  possible  mechanisms  of loganin  action  include  inhibition  of  release  of  Cyt-c from  mitochondria  into  cytoplasm  of  hippocampal pyramidal  neurons  and  reduction  of  apoptosis  levels and induction of neurogenesis and angiogenesis in the brain.4,8,27  Nevertheless, further studies are needed to increase the understanding of the physiological mechanisms leading to this memory enhancing effect of loganin.  Conclusion In  summary,  our  results  suggested  that  loganin alleviates  diabetes-induced  memory  impairments. Therefore,  loganin  could  be  used  as  an  agent  of treatment for the learning and memory-deficit cause by diabetes.    94  | Babri et al. Advanced Pharmaceutical Bulletin, 2013, 3(1), 91-95  Copyright © 2013 by Tabriz University of Medical Sciences Acknowledgements This  study  was  financially  supported  by  the Neuroscience Research Centre of Tabriz University of Medical Sciences. The article is derived from the MSc dissertation  of  Ms  Saeedeh  Hasani  Azami  entitled ‘‘Effect  of  loganin  on  spatial  memory  and  passive avoidance learning in diabetic male rats’’.  Conflict of Interest There is no conflict of interest in this study.  References 1.  Maritim  AC,  Sanders  RA,  Watkins  JB.  Diabetes, Oxidative  Stress,  and  Antioxidants:  A  Review.  J Biochem Mol Toxicol 2003; 17(1): 24-38. 2.  Sima  AA,  Kamiya  H,  Li  ZG.  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Effect of Acute Administration of loganin on Spatial Memory in Diabetic Male Rats

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