Chronic treatment with tocotrienol, an isoform of vitamin E, prevents intracerebroventricular streptozotocin-induced cognitive impairment and oxidative–nitrosative stress in rats Vinod Tiwari, Anurag Kuhad, Mahendra Bishnoi, Kanwaljit Chopra ⁎ Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC Center of Advanced Study, Panjab University, Chandigarh-160 014, India abstract article info Article history: Received 6 February 2009 Received in revised form 10 May 2009 Accepted 18 May 2009 Available online 21 May 2009 Keywords: Oxidative stress ICV STZ Cognitive impairment Vitamin E Tocotrienol Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, which is associated with increased oxidative stress in the brain of rats. In the present study, we investigated the effect of both the isoforms of vitamin E, α-tocopherol and tocotrienol against ICV STZ-induced cognitive impairment and oxidative–nitrosative stress in rats. Adult male Wistar rats were injected with ICV STZ (3 mg/kg) bilaterally. The learning and memory behavior was assessed using Morris water maze and elevated plus maze. The rats were sacrificed on day 21 and parameters of oxidative stress, nitrite levels and acetylcholinesterase activity were measured in brain homogenate. α-Tocopherol as well as tocotrienol treated groups showed significantly less cognitive impairment in both the behavioral paradigms but the effect was more potent with tocotrienol. Both isoforms of vitamin E effectively attenuated the reduction in glutathione and catalase and reduced the malonaldehyde, nitrite as well as cholinesterase activity in the brains of ICV STZ rats in a dose dependent manner. The study demonstrates the effectiveness of vitamin E isoforms, of which tocotrienol being more potent in preventing the cognitive deficits caused by ICV STZ in rats and suggests its potential in the treatment of neurodegenerative diseases such as Alzheimer's disease. © 2009 Elsevier Inc. All rights reserved. 1. Introduction Alzheimer's disease (AD) is a progressive and irreversible neuropsychiatric disorder characterized by neuronal degeneration and cognitive deteriorations. The most prominent neurochemical change in Alzheimer's brain is a reduced concentration of acetylcho- line in the hippocampus and neocortex, caused by degeneration of cholinergic neurons (Kristensen, 1990; Perry et al., 1999). It accounts for 50% of dementia cases (Areosa and Sherriff, 2003). Oxidative stress, an imbalance between free radicals and antiox- idant system, plays a critical role in the pathogenesis of AD (Gary et al., 2005; Butterfield, 2004). Oxidative stress can affect all classes of macromolecules (sugar, lipids, proteins, and DNA), leading inevitably to neuronal dysfunction (Polidori and Mecocci, 2002). Brain tissue contains a large amount of polyunsaturated fatty acids which are particularly vulnerable to free radical attacks (Gutteridge, 1995). Several other studies provide evidence to link neuronal damage with excessive generation of free radicals, which may be due to factors such as oxidative stress (Olanow, 1993), inflammation (Stuchbury and Munch, 2005) or abnormal proteins (Mandelkow et al., 2007). Anti- oxidant enzymes like glutathione peroxidase (GPx) and glutathione reductase (GR) have a prominent role in the management of oxidative stress within the cell; they convert superoxide radicals and peroxides to innocuous forms, often with the concomitant oxidation of reduced glutathione (GSH), to its oxidized form (GSSG) and recycles GSSG to GSH to maintain the antioxidant potential (Ishrat et al., 2006). Intracerebroventricular injection of streptozotocin in subdiabeto- genic dose in rats causes reduced energy metabolism/oxidative stress leading to cognitive dysfunction by inhibiting the synthesis of adenosine triphosphate (ATP) and acetyl-CoA. This ultimately results into cholinergic deficiency supported by reduced cholineacetyltrans- ferase (ChAT) activity in hippocampus and an increased cholinester- ase (ChE) activity in the brain of ICV-STZ rats (Blokland and Jolles, 1993; Sharma and Gupta, 2001a,b; Sonkusare et al., 2005). Since oxidative damage is implicated in the etiology of neurolo- gical complications, treatment with antioxidants has been used as a therapeutic approach in various types of neurodegenerative diseases (Ahmad et al., 2005; Ansari et al., 2004). It has been observed that the use of antioxidants as well as dietary improvements with regard to the consumption of fruits and vegetables high in antioxidant activity and neuroprotective agents may decrease the risk of memory deficits of the Alzheimer's disease type (Weinstock and Shoham, 2004). Recently Coenzyme Q10 (CoQ10), a vitamin-like lipophilic antioxidant com- pound, has been reported to improve cognitive dysfunction and biochemical alterations in hippocampus and cerebral cortex of ICV- STZ treated rats (Ishrat et al., 2006). Pharmacology, Biochemistry and Behavior 93 (2009) 183–189 ⁎ Corresponding author. Tel.: +91 172 2534105; fax: +91 172 2541142. E-mail address: dr_chopra_k@yahoo.com (K. Chopra). 0091-3057/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2009.05.009 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh