(Streptozotocin) ( ) (Regeneration) (Micro vascular) (Retinopathy) (Neuropathy) (Nephropathy) (Dementia) (Macrovascular)

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1 1 Micro vascular Retinopathy Neuropathy Nephropathy Macrovascular 2 Regeneration 3 Dementia 4 kiasalari@yahoocom * * najafabady@yahoocom khalili@shahedacir Streptozotocin Crocus sativus 30 Shuttle box Tokey p<0/0 p< 0/ p < /0 p< 0/008 90/7/3 91/1/30

2 mg/dl mg/dl Dentate -2, cc Nitric Oxide Synthase 7 6,4 30 0/5 cc 2 Heterogenesis Neurodegenerative 10 8 Plexiglas 40 cm 15 cm 30 cm g

3 46 ACBABACACBCACAC ۴۵ ۴۰ ۳۵ ۳۰ ۲۵ ۲۰ ۱۵ ۱۰ * Control Cs ۳۰ Cs ۶۰ Diabetic Diabetic+ Cs ۳۰ Diabetic+ Cs ۶۰ ۵ ۰ BCA = ACB triad / Initial IL ۶۰ ۵۰ Initial latency 30 Mean± SEM 8 1 p< 0/05 * latency Control Cs ۳۰ Cs ۶۰ Diabetic Diabetic+ Cs ۳۰ Diabetic+ Cs ۶۰ # %46/15 ۴۰ ۳۰ ** % 46/15= 6 / = ۲۰ ۱۰ ۰ Shuttle box BPT Co ۹ Tehran ± SEM 0/05 0/01 Step through latency 30 Step-through latency STL 8 p # 2 ** Mean ۱۲۰ ۱۰۰ * Initial IL= Latency ILs 24 8 ۸۰ ۶۰ ۴۰ ۲۰ ۰ A, B, C Control Cs ۳۰ 3 p< 0/05 * Cs ۶۰ * Diabetic Diabetic+ Cs ۳۰ Mean ± SEM * * Diabetic+ Cs ۶۰ 3 STL= Step Through Latency 8

4 47-1 2/3148/23 ± 30 2/3025/45 ± 2/383/55 ± 2/3 2/47 27/48 ± 30 23/1 ± 2/275/75 2/2765/9 ± ILS ± 3/48 3/4348/5 ± 6/25 6/4525/62 3/3525/98 ± ± 5/21 5/4821/89 3/332/1 ± 3/2 ± 4/81 4/5381/67 3/5048/89 ± 5/39 79/63 ± 3/4375/7 ± 4/9989/98 ± 4/89 3/4965/8 ± 6/7328/9 ± STLS 3 p < 0/ One-way p<0/05 ANOVA 30 2/30 ± 38/55 IL 2/65 ±27/9 IL 1 30 Recall 3/2 ± 33/1 3/65±49/8 STL STL 1 STL p<0/045 3/48±43/5

5 48 Nonsteroidal Anti- NSAID Inflammatory Drug Oxidative Stress Lipid Peroxidation IGF= Iinsulin- Like Growth Factor Brain Derivative Neurotrophic BDNF=Factor Cholinergic Antagonize 22 18

6 49 plasticity Neuroreport, ۲۰۰۲; ۱۳۱۸۰۱-۱۸۰۴ ۸ Scartezzini P, Speroni E Review on some plants of Indian traditional medicine with antioxidant activity J Ethnopharmacol ۲۰۰۰; ۷۱۲۳-۴۳ ۹ Zhang, Shoyama, Sugiura M, Saito H Effects of Crocus sativus L on the ethanol-induced impairment of passive avoidance performances in mice Biol Pharm Bull ۱۹۹۴; ۱۷ ۲۱۷-۲۱ ۱۰ Abe K, Saito H Effects of saffron extract and its constituent crocin on learning behaviour and long-term potentiation Phytother Res ۲۰۰۰; ۱۴ ۱۴۹-۱۵۲ ۱۱ Roghani M, JoghataieMT, Jalali MR, Baluchnejadmojarad T Time Course of Changes in Passive Avoidance and -maze Performance in Male Diabetic Rats IranBiomed J ۲۰۰۶; ۲ ۹۹-۱۰۴ ۱۲ Mansouri E, Panahi M, Ghaffari MA, Ghorbani A Effects of grape seed proanthocyanidin extract on oxidative stress induced by diabetes in rat kidney Iran Biomed J ۲۰۱۱; ۱۵ ۳ ۱۰۰-۶ ۱۳ Nitta A, Murai R, Suzuki N, Ito H, Nomoto H, Katoh G, Furukawa Diabetic neuropathies in brain are induced by deficiency of BDNF Neurotoxicol Teratol, ۲۰۰۲; ۲۴ ۶۹۵-۷۰۱ ۱۴ Bhutada P, Mundhada, Bansod K, Tawari S, Patil S, Dixit P Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes Behav Brain Res ۲۰۱۱; ۲۲۰ ۱ ۳۰-۴۱ ۱۵ Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S Saffron in the treatment of patients with mild to moderate Alzheimer's disease a ۱۶-week, randomized and placebo-controlled trial J Clin Pharm Ther ۲۰۱۰; ۳۵ ۵ ۵۸۱-۸ ۱۶ Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats Eur J Pharmacol ۲۰۱۱; ۶۶۷ ۱-۳ ۲۲۲-۹ ۱۷ Papandreou MA, Tsachaki M, Efthimiopoulos S, Cordopatis P, Lamari FN, Margarity M Memory enhancing effects of saffron in aged mice are correlated with antioxidant protection Behav Brain Res ۲۰۱۱; ۱۹ ۲ ۱۹۷-۲۰۴ ۱۸ Carr DB, Goate A, Morris JC Current concepts in the pathogenesis of Alzheimers disease Am J Med ۱۹۹۷; ۱۰۳ ۳-۱۰ ۱۹ Tariot PN, Federoff HJ Current treatment for Alzheimer disease and future prospects Alzheimer Dis Assoc Disord ۲۰۰۳; ۱۷ ۱۰۵-۱۱۳ ۲۰ Chu WZ, Qian C Expressions of Abeta ۱-۴۰, Abeta ۱-۴۲, tau ۲۰۲, tau ۳۹۶ and tau ۴۰۴ after intracerebroventricular injection of streptozotocin in rats Di i Jun ۲۰۰۵; ۲۵ ۱۶۸-۱۷۰ ۲۱ Heo HJ, Kim DO, Shin SC, Kim MJ, Kim BG, Shin DH Effect of antioxidant flavanone, naringenin, from Citrus junoson neuroprotection J Agric Food / ۱ King H, Aubert RE, Herman WH Global burden of diabetes ۱۹۹۵-۲۰۲۵ Diabetes Care ۱۹۹۸; ۲۱ ۹ ۱۴۱۴-۳۱ ۲ Gleckman R, Morr J Diabetes-related foot infection Contemp Intern Med ۱۹۹۴; ۶ ۵۷-۶۴ ۳ Galer BS, Gianas A, Jensen MP Painful diabetic polyneuropathy epidemiology, pain description, and quality of life Diabetes Res Clin Pract ۲۰۰۰; ۴۷۱۲۳-۱۲۸ ۴ Jackson-Guilford J, Leander JD, Nisenbaum LK The effect of streptozotocin-induced diabetes on cell proliferation in the rat dentate gyrus Neurosci Lett ۲۰۰۰; ۲۹۳۹۱-۹۴ ۵ Biessels GJ, Smale S, Duis SE, Kamal A, Gispen WH The effect of gamma-linolenic acid-alpha-lipoic acid on functional deficits in the peripheral and central nervous system of streptozotocin-diabetic rats J Neurol Sci ۲۰۰۱; ۱۸۲ ۹۹-۱۰۶ ۶ Parihar MS, Chaudhary M, Shetty R, Hemnani T Susceptibility of hippocampus and cerebral cortex to oxidative damage in streptozotocin treated mice prevention by extracts of Withania somnifera and Aloe vera J Clin Neurosci ۲۰۰۴; ۱۱۳۹۷-۴۰۲ ۷ Reagan LP, McEwen BS Diabetes, but not stress, reduces neuronal nitric oxide synthase expression in rat hippocampus implications for hippocampal synaptic

7 Chem ۲۰۰۴; ۵۲۱۵۲۰-۵ ۲۲ Pitsikas N, Zisopoulou S, Tarantilis PA, Kanakis CD, Polissiou MG, Sakellaridis N Effects of the active constituents of Crocus sativus L, crocins on recognition and spatial rats' memory Behav Brain Res ۲۰۰۷; ۱۸۳ ۲ ۱۴۱-۶ ۲۳ Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats Eur J Pharmacol ۲۰۱۱; ۶۶۷ ۱-۳ ۲۲۲-۹ ۲۴ Choi JG, ang WM, Kang TH, Oh MS Effects of optimized-sopungsunkiwon on memory impairment and enhancement Neurosci Lett ۲۰۱۱; ۴۹۱ ۲ ۹۳-۸ 50

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9 Original Article The effect of aqueous Crocus sativus L saffron extract on learning and memory in male streptozotocin-induced diabetic rats Zahra Kiasalari, PhD Assistant Professor of Physiology, Department of Physiology, Neurophysiology and Herbal Medicine Research Center, School of Medicine, Shahed University, Tehran, Iran kiasalari@yahoocom * Mohsen Khalili, PhD Professor of Physiology, Department of Physiology, Neurophysiology and Herbal Medicine Research Center, School of Medicine, Shahed University Tehran,Tehran, Iran*Corresponding author najafabady@yahoocom Leyla Ghanbarian, MD student, Department of Physiology, School of Medicine, Shahed University, Tehran, Iran khalili@shahedacir Abstract Background Diabetes mellitus is accompanied with disturbances in learning, memory, and cognitive skills in the human society and experimental animals Considering the potential anti-diabetic effect of the medicinal plant Crocus sativus Saffron and the augmenting effect of its consumption on the memory and mental health, this study was conducted to evaluate the effect of chronic interaperitoneal administration of CrocusS extract on learning and memory in diabetic rats Methods In this experimental study a total of ۶۰ male rats were divided into normal and diabetic groups Then, each of these groups was divided into three subgroups Two of these subgroups received ۳۰ and ۶۰ crocuss extract in the treatment periods, but the third group didnt receive any treatment At the end of treatment period, each of these subgroups was evaluated by two ways - maze alternative behavior percentage and shuttle box initial latencies IL and step-through latencies STL in passive avoidance test Finally, obtained data were subjected to one way ANOVA test and post hoc Tokey analysis Results Treatment of the diabetic animals with the extract could antagonized the augmenting effect of diabetics on initial latency P< ۰۰۵ Also, treatment of the diabetic rats with the extract ۶۰ increased the reduced step through latency time recall of the data induced by diabetic in the animals P< ۰۰۵ However, obtained data from maze test show that the extract could not improved the spatial memory disruption due to diabetics Conclusion Chronic CrocusS injection is effective on the capability of maintaining information in the stores memory and reminding in the diabetic rats However, the extract could not improve the spatial memory in the diabetic rats Keywords crocus sativus, Learning, Memory, Diabetes mellitus Razi Journal of Medical Sciences Vol ۱۹, No ۹۵, Apr-May ۲۰۱۲ ۵۱