Behavioural pharmacology Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats Hamid Kalalian-Moghaddam a , Tourandokht Baluchnejadmojarad a,n , Mehrdad Roghani b , Fatemeh Goshadrou c , Abdolaziz Ronaghi c a Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran b Neurophysiology Research Center and Department of Physiology, Shahed University, Tehran, Iran c Department of Physiology, Paramedical Science Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran article info Article history: Received 20 April 2012 Received in revised form 4 October 2012 Accepted 13 October 2012 Keywords: Berberine Diabetes mellitus Streptozotocin Learning and memory Synaptic plasticity Apoptosis abstract Chronic diabetes mellitus initiates apoptosis and negatively affects synaptic plasticity in the hippocampus with ensuing impairments of learning and memory. Berberine, an isoquinoline alkaloid, exhibits anti-diabetic, antioxidant and nootropic effects. This study was conducted to evaluate the effect of berberine on hippocampal CA1 neuronal apoptosis, synaptic plasticity and learning and memory of streptozotocin (STZ)-diabetic rats. Long-term potentiation (LTP) in perforant path-dentate gyrus synapses was recorded for assessment of synaptic plasticity and field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. PS amplitude and fEPSP significantly decreased in diabetic group versus control, and chronic berberine treatment (100 mg/kg/day, p.o.) restored PS amplitude and fEPSP and ameliorated learning and memory impairment and attenuated apoptosis of pyramidal neurons in the CA1 area, as determined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling method. In summary, chronic berberine treatment of STZ-diabetic rats significantly ameliorates learning and memory impairment and part of its beneficial effect could be attributed to improvement of synaptic dysfunction and anti-apoptotic property. & 2012 Elsevier B.V. All rights reserved. 1. Introduction Diabetes mellitus is a complicated prevalent metabolic dis- order (Khan et al., 2012) with functional changes of the nervous system (Northam et al., 2009). Diabetes gradually impairs hippocampus-dependent cognitive functions and synaptic plasti- city (Artola, 2008; Reisi et al., 2008; Reisi et al., 2010). Passive avoidance learning and memory deficits develop in streptozotocin (STZ)-diabetic rats (Kucukatay et al., 2007). Impairment of spatial learning in a hippocampus-dependent complex maze has also been reported in such animals (Stranahan et al., 2008). Changes in hippocampal synaptic plasticity have already been described in diabetes (Iwai et al., 2009). Part of deficits in performing the spatial learning and memory tasks in diabetes is attributed to induction of apoptosis of CA1 pyramidal neurons (Ye et al., 2011). Although conventional agents in conjunction with lifestyle management are being used to control diabetes and its complica- tions (Khan et al., 2012) but there has been no effective long-term treatment for diabetes-induced neuropathy (Choi and Son, 2011). Until now, no specific treatments have been available for the management and/or prevention of cognitive dysfunction in diabetes (Biessels et al., 2007). Berberine is an isoquinoline alkaloid, which is mainly found in such plants as berberis, with anxiolytic, analgesic, anti-inflammatory, antipsychotic, antidepressant, and antiamnesic effects (Imanshahidi and Hosseinzadeh, 2008; Kulkarni and Dhir, 2008a; Kulkarni and Dhir, 2010). A number of clinical and preclinical investigations have shown beneficial effects of berberine in diabetes (Bhutada et al., 2011; Cok et al., 2011; Gu et al., 2010; Zhang et al., 2008). Berberine could also enhance insulin resistance and B cell regeneration (Kong et al., 2009; Zhou et al., 2009), act as a potential antioxidant (Zhou and Zhou, 2011), and being a potent acetylcholinesterase inhibitor (Huang et al., 2010). The protective effect of berberine against hydrogen peroxide- induced apoptosis could be related to its antioxidant activity and imply its therapeutic relevance in oxidative stress-related disorders (Zhu et al., in press). Moreover, antiamnesic effect of berberine through augmenting cholinergic neuronal system activity has already been reported (Peng et al., 1997). Berberine has also beneficial effects on neural health and function and can protect neurons from various brain insults (Zhu and Qian, 2006) and may Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology 0014-2999/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2012.10.020 n Corresponding author. Tel./fax: þ98 88058709. E-mail address: tmojarad@yahoo.com (T. Baluchnejadmojarad). Please cite this article as: Kalalian-Moghaddam, H., et al., Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in.... Eur J Pharmacol (2012), http://dx.doi.org/10.1016/j.ejphar.2012.10.020 European Journal of Pharmacology ] (]]]]) ]]]–]]]