Behavioural Pharmacology Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine — a PDE1 inhibitor Rahul Deshmukh ⁎, Vivek Sharma, Sidharth Mehan, Nidhi Sharma, K.L. Bedi Division of Neuropharmacology, Department of Pharmacology, I. S. F. College of Pharmacy, Moga-142001, Punjab, India abstract article info Article history: Received 14 June 2009 Received in revised form 24 July 2009 Accepted 12 August 2009 Available online 21 August 2009 Keywords: Vinpocetine Phosphodiesterase1 Cognitive dysfunction Oxidative stress Streptozotocin Sporadic dementia of Alzheimer's type Enhancing cyclic nucleotides signaling by inhibition of phosphodiesterases (PDEs) is known to be beneficial in disorders associated with cognitive decline. The present study was designed to investigate the effect of vinpocetine (PDE1 inhibitor) on intracerebroventricular (i.c.v.) streptozotocin induced experimental sporadic dementia of Alzheimer's type. Infusion of streptozotocin impaired learning and memory, increased oxidative– nitritive stress and induced cholinergic hypofunction in rats. Chronic treatment with vinpocetine (5, 10 and 20 mg/kg i.p.) for 21 days following first i.c.v. streptozotocin infusion significantly improved learning and memory in Morris water maze and passive avoidance paradigms. Further, vinpocetine significantly reduced the oxidative–nitritive stress, as evidenced by decrease in malondialdehyde (MDA) and nitrite levels, and restored the reduced glutathione (GSH) levels. Significant increase in acetylcholinesterase activity and lactate dehydrogenase levels was observed in the present model indicating cholinergic hypofunction and increase in neuronal cell damage. Chronic treatment with vinpocetine also reduced significantly the increase in acetylcholinesterase activity and lactate dehydrogenase levels indicating restorative capacity of vinpocetine with respect to cholinergic functions and preventing the neuronal damage. The observed beneficial effects of vinpocetine on spatial memory may be due to its ability to favorably modulate cholinergic functions, prevent neuronal cell damage and possibly through its antioxidant mechanism also. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by a progressive decline in cognitive functions including learning and memory (Monczor, 2005; Han, 2005). Aging is associated with modification of many brain neurotransmitter and second messenger systems directly involved in signal transduction. The signal transduction events that are deficient in the aged include calcium mobilization, phosphatidylinositol breakdown, cyclic nucleo- tides formation and neurotransmitters (Fulop and Seres, 1994). Cyclic nucleotides viz cAMP and cGMP have been shown to play important role in synaptic plasticity and learning and memory (Bernabeu et al. 1996; Bernabeu et al. 1997; Prickaerts et al. 2002). Furthermore, cyclic nucleotides – by activating cAMP response element binding protein (CREB) through PKA and PKG – have been reported to play important role in cognitive functions (Silva et al., 1998; Lu et al., 1999). Inhibition of phosphodiesterase (PDE) enzymes is a way to enhance second messenger mediated signaling and consequently influence the pathways involved in learning and memory. Phosphodiesterases are enzymes that break down cyclic nucleotides i.e. cAMP or cGMP or both. The family of PDEs is large and thus far eleven classes viz PDE1–PDE11 have been identified based on their substrates (Frey et al. 1993; Son et al. 1998). Type I phosphodiesterases (PDE1) are a family of Ca 2+ - calmodulin-modulated phosphodiesterases involved in the regulation of both cGMP and cAMP through their degradation (Bender and Beavo, 2006). PDE1 has been reported to show significant expression in neurons of the hippocampus and cortex (Lugnier, 2006) suggesting that this enzyme may control intraneuronal cGMP and cAMP levels in areas that are important for memory formation and storage. Vinpocetine (14-ethoxycarbonyl-(3a,16a-ethyl)-14,15-eburnamine; Cavinton) – a PDE1 inhibitor – is a synthetic derivative of the lesser periwinkle plant (Vinca minor) alkaloid vincamine and is widely used as a neuroprotective agent for the prevention and treatment of central nervous system disorders of cerebrovascular origin (Bonoczk et al., 2000; Vas and Gulyas, 2005). Vinpocetine has further been reported to improve cerebral blood flow (Immamoto et al., 1984). PDE-1 inhibition has been reported to cause cerebral artery dilatation by elevations of cGMP levels (Kruuse et al., 2001). Vinpocetine has also been demonstrated to inhibit veratridine induced opening Na + channel activity and glutamate release (Tretter and Adam, 1998, Stiges et al., 2006). Further cAMP (Dohovics et al., 2003) and cGMP (Kovalev et al., 2003) dependent effects of vinpocetine have been related to its action on Na + conductivity. Furthermore, vinpocetine has been shown to facilitate long-term potentiation (Molnar and Gaal, 1992), enhance the structural dynamics European Journal of Pharmacology 620 (2009) 49–56 ⁎ Corresponding author. Tel.: +91 9988904375 (mobile). E-mail address: login2rd@gmail.com (R. Deshmukh). 0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.08.027 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar