The Effect of Acetyl-L-Carnitine on Learning and Spatial Memory Deficit in Diabetic Rats


1 Associate Professor, Department of Pharmacology, School of Medicine, Shahed University, Tehran, Iran

2 Professor, Neurophysiology Research Center, Shahed University, Tehran, Iran

3 Student of Medicine, School of Medicine, Shahed University, Tehran, Iran


Background & Aims: Diabetes mellitus is a chronic metabolic disorder that in the long-term is accompanied with deficits in learning, memory, and cognitive skills. Due to the existing evidence regarding the anti-diabetic potential of acetyl-L-carnitine (ALC), the effect of its long-term administration on learning and spatial memory deficits was investigated in diabetic rats. Methods: In this experimental study, 32 male Wistar rats were randomly divided into 4 groups: control, ALC-treated control, diabetic, and ALC-treated diabetic. ALC was injected IP at a dose of 50 mg/kg for 5 weeks after 7th day and for induction of diabetes streptozotocin was injected intraperitoneally (IP) at a single dose of 60 mg/kg. For evaluation of learning and memory, initial latency (IL) and step-through latency (STL) were determined at the end of the study using the passive avoidance test. Moreover, alternation behavior percentage, as an index of spatial memory, was obtained using Y-maze. In addition, brain malondialdehyde (MDA) level, as a marker of oxidative stress, was evaluated. Results: At the end of the study, a significant decrease was observed in STL in diabetic groups. Moreover, STL was significantly higher in the ALC-treated diabetic group than the diabetic group. Furthermore, alternation behavior percentage in both diabetic groups was lower than the control group. This parameter showed a significant increase in the ALC-treated diabetic group in comparison with the diabetic group. Administration of ALC to animals did not produce any significant changes in memory and learning in the treated control group. In addition, brain malondialdehyde level was significantly lower in the ALC-treated diabetic group than the diabetic group. Conclusion: Long-term administration of ALC at a dose of 50 mg/kg increases the ability to save information in the memory reservoir and remember in passive avoidance test, and enhances short-term spatial recognition memory in diabetic animals. This is in part due to the attenuation of brain oxidative stress.


  1. Tripathi BK, Srivastava AK. Diabetes mellitus: complications and therapeutics. Med Sci Monit 2006; 12(7): RA130-RA147.
  2. Jackson-Guilford J, Leander JD, Nisenbaum LK. The effect of streptozotocin-induced diabetes on cell proliferation in the rat dentate gyrus. Neurosci Lett 2000; 293(2): 91-4.
  3. 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 2001; 182(2): 99-106.
  4. Baydas G, Nedzvetskii VS, Nerush PA, Kirichenko SV, Yoldas T. Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus. Life Sci 2003; 73(15): 1907-16.
  5. Reagan LP, McEwen BS. Diabetes, but not stress, reduces neuronal nitric oxide synthase expression in rat hippocampus: implications for hippocampal synaptic plasticity. Neuroreport 2002; 13(14): 1801-4.
  6. Williams R, Tuomilehto J, Bjork S. The economics of diabetes care: An international perspective. In: Songer TJ, editor. Assessing direct and indirect cost of diabetes.London, UK: Blackwell Science; 2000.
  7. Thal LJ, Calvani M, Amato A, Carta A. A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology 2000; 55(6): 805-10.
  8. Famularo G, Moretti S, Alesse E, Trinchieri V, Angelucci A, Santini G, et al. Reduction of glutamate levels in HIV-infected subjects treated with acetylcarnitine. J NeuroAIDS 1999; 2(2): 65-73.
  9. Sano M, Bell K, Cote L, Dooneief G, Lawton A, Legler L, et al. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer's disease. Arch Neurol 1992; 49(11): 1137-41.
  10. Rai G, Wright G, Scott L, Beston B, Rest J, Exton-Smith AN. Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer's dementia. Curr Med Res Opin 1990; 11(10): 638-47.
  11. Ayazi N, Khalili M. The effect of acetyl L carnitine on learning and memory deficit in kainite epileptic rats [Thesis]. Tehran, Iran: Shahed University; 2011. [In Persian].
  12. Goo MJ, Choi SM, Kim SH, Ahn BO. Protective effects of acetyl-L-carnitine on neurodegenarative changes in chronic cerebral ischemia models and learning-memory impairment in aged rats. Arch Pharm Res 2012; 35(1): 145-54.
  13. Baluchnejadmojarad T, Roghani M, Roghani-Dehkordi F. Antinociceptive effect of Teucrium polium leaf extract in the diabetic rat formalin test. J Ethnopharmacol 2005; 97(2): 207-10.
  14. Liu Y, Tian X, Gou L, Sun L, Ling X, Yin X. Luteolin attenuates diabetes-associated cognitive decline in rats. Brain Res Bull 2013; 94: 23-9.
  15. Alipour M, Salehi I, Ghadiri SF. Effect of exercise on diabetes-induced oxidative stress in the rat hippocampus. Iran Red Crescent Med J 2012; 14(4): 222-8. [In Persian].
  16. Zhen YF, Zhang J, Liu XY, Fang H, Tian LB, Zhou DH, et al. Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology (Berl) 2013; 227(1): 93-100.
  17. Zhao Q, Matsumoto K, Tsuneyama K, Tanaka K, Li F, Shibahara N, et al. Diabetes-induced central cholinergic neuronal loss and cognitive deficit are attenuated by tacrine and a Chinese herbal prescription, kangen-karyu: elucidation in type 2 diabetes db/db mice. J Pharmacol Sci 2011; 117(4): 230-42.
  18. Tuzcu M, Baydas G. Effect of melatonin and vitamin E on diabetes-induced learning and memory impairment in rats. Eur J Pharmacol 2006; 537(1-3): 106-10.
  19. Sasaki-Hamada S, Sacai H, Oka JI. Diabetes onset influences hippocampal synaptic plasticity in streptozotocin-treated rats. Neuroscience 2012; 227: 293-304.
  20. Zhang T, Liu X, Li Q, Wang J, Jia W, Sun X. Exacerbation of ischemia-induced amyloid-beta generation by diabetes is associated with autophagy activation in mice brain. Neurosci Lett 2010; 479(3): 215-20.
  21. Annadurai T, Vigneshwari S, Thirukumaran R, Thomas PA, Geraldine P. Acetyl-L-carnitine prevents carbon tetrachloride-induced oxidative stress in various tissues of Wistar rats. J Physiol Biochem 2011; 67(4): 519-30.
  22. Hota KB, Hota SK, Chaurasia OP, Singh SB. Acetyl-L-carnitine-mediated neuroprotection during hypoxia is attributed to ERK1/2-Nrf2-regulated mitochondrial biosynthesis. Hippocampus 2012; 22(4): 723-36.
  23. Kobayashi S, Iwamoto M, Kon K, Waki H, Ando S, Tanaka Y. Acetyl-L-carnitine improves aged brain function. Geriatr Gerontol Int 2010; 10(Suppl 1): S99-106.